Kirk's Current Veterinary Therapy XV [1 ed.] 1437726895, 9781437726893

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CVT XV Sections SECTION I

CRITICAL CARE

SECTION II

TOXICOLOGIC DISEASES

SECTION III

ENDOCRINE AND METABOLIC DISEASES

SECTION IV

ONCOLOGY AND HEMATOLOGY

SECTION V

DERMATOLOGIC AND OTIC DISEASES

SECTION VI

GASTROINTESTINAL DISEASES

SECTION VII

RESPIRATORY DISEASES

SECTION VIII CARDIOVASCULAR DISEASES SECTION IX

URINARY DISEASES

SECTION X

REPRODUCTIVE DISEASES

SECTION XI

NEUROLOGIC DISEASES

SECTION XII

OPHTHALMOLOGIC DISEASES

SECTION XIII INFECTIOUS DISEASES APPENDIX I

TABLE OF COMMON DRUGS: APPROXIMATE DOSAGES

APPENDIX II

TREATMENT OF PARASITES

Appendices From CVT XIII on Website Appendix III

AAFCO Dog and Cat Food Nutrient Profiles

The following tables are provided for reference purposes only. Although these data may be useful when interpreting clinical laboratory samples, some of the methods referenced in the footnotes have been supplanted by newer techniques. Thus the reader must use care when extrapolating between methodologies. In some cases, the studies cited have not been repeated with new analyzers, so although the general trends are still relevant, the exact values may vary considerably due to differences in instrumentation. The clinician should always consult the reference standards provided by the laboratory or the analyzer manufacturer when interpreting results of laboratory tests. Additionally all laboratory results should be viewed in the context of the specific patient and recent or current treatments. Appendix IV

Hematology—Coulter S Plus IV with Manual Differential Counts

Appendix V

Hematology—Technicon H-1 Hematology Analyzer

Appendix VI

Système International (SI) Units in Hematology

Appendix VII

Hematology—Manual or Semiautomated Methods

Appendix VIII

Appendix IX

Canine Hematology (Means) at Different Ages—Manual or Semiautomated Methods Canine Hematology (Means and Ranges) with Different Ages and Genders—Manual or Semiautomated Methods

Appendix X

Canine Hematology at Different Ages

Appendix XI

Effects of Pregnancy and Lactation on Canine Hematology (Means)

Appendix XII

Relative Distribution of Cell Types in Canine Bone Marrow

Appendix XIII

Feline Hematology (Means and Ranges) with Different Ages and Genders—Manual or Semiautomated Methods

Appendix XIV

Feline Hematology (Means) at Different Ages

Appendix XV

Effects of Pregnancy and Lactation on Feline Hematology (Means)

Appendix XVI

Relative Distribution of Cell Types in Feline Bone Marrow

Appendix XVII

Clinical Chemistry—Hitachi 911

Appendix XVIII

Clinical Chemistry—Selected Manual Procedures

Appendix XIX

Système International (SI) Units in Clinical Chemistry

Appendix XX

Serum Protein Fractions

Appendix XXI

Serum Iron and Iron-Binding Capacities in Iron-Deficient and Normal Dogs

Appendix XXII

Serum Immunoglobulin Concentrations of Normal Beagle Dogs at Various Ages

Appendix XXIII

Acid-Base and Blood Gases

Appendix XXIV

Coagulation Screening Tests

Appendix XXV

Specific Coagulation Tests

Appendix XXVI

Quantitative Tests of Gastrointestinal Function

Appendix XXVII

Tests of the Endocrine System

Appendix XXVIII

Système International (SI) Units for Hormone Assays

Appendix XXIX

Urinary and Renal Function Tests

Appendix XXX

Bronchoalveolar Lavage Fluid Cell Populations

Appendix XXXI

Cerebrospinal Fluid (CSF)

Appendix XXXII

Cerebrospinal Fluid Biochemical Analytes in Histologically Normal Cats

Appendix XXXIII

Characteristics of Body Cavity Fluids in Healthy Dogs and Cats

Appendix XXXIV

Cytologic Findings in Normal and Abnormal Canine Synovial Fluids

Appendix XXXV

Canine Semen

Appendix XXXVI

Canine Prostatic Fluid (Third Fraction)

Appendix XXXVII

Electrocardiography

Access the latest accepted methods for treating medical conditions of dogs and cats

Visit www.currentveterinarytherapy.com Gain an in-depth understanding of the latest therapies for dog and cat diseases by accessing this book’s companion website that features a wealth of supplemental resources:

• 86 web chapters and additional appendices that provide expert clinical guidance on topics that apply to current practice

• Fully searchable drug formulary that provides the most up-to-date drug information

• All references that link to original abstracts on PubMed • Fully searchable index that emphasizes diseases based on anatomic and physiologic disorders • Many images from the book presented in full color

Scratch off Below Bonagura

C

KIRK’S

URRENT VETERINARY THERAPY

XV

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C

KIRK’S

URRENT VETERINARY THERAPY

XV Editors

John D. Bonagura, DVM, MS, DACVIM (Cardiology, Internal Medicine) Professor Department of Veterinary Clinical Sciences College of Veterinary Medicine The Ohio State University Head, Cardiology and Interventional Medicine Service The Ohio State University Veterinary Medical Center Columbus, Ohio

David C. Twedt, DVM, DACVIM (Internal Medicine) Professor Department of Clinical Sciences College of Veterinary Medicine and Biomedical Sciences Colorado State University Fort Collins, Colorado

3251 Riverport Lane St. Louis, Missouri 63043

KIRK’S CURRENT VETERINARY THERAPY XV ISBN: 978-1-4377-2689-3 Copyright © 2014, 2009, 2000, 1995, 1992, 1989, 1986, 1983, 1980, 1977, 1974, 1971, 1968, 1966, 1964 by Saunders, an imprint of Elsevier, Inc. All rights reserved. No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopying, recording, or any information storage and retrieval system, without permission in writing from the publisher. Permissions may be sought directly from Elsevier’s Health Sciences Rights Department in Philadelphia, PA, USA: phone: (+1) 215 239 3804, fax: (+1) 215 239 3805, e-mail: [email protected]. You may also complete your request on-line via the Elsevier homepage (http://www.elsevier.com), by selecting “Customer Support” and then “Obtaining Permissions.”

Notice Knowledge and best practice in this field are constantly changing. As new research and experience broaden our knowledge, changes in practice, treatment and drug therapy may become necessary or appropriate. Readers are advised to check the most current information provided (i) on procedures featured or (ii) by the manufacturer of each product to be administered, to verify the recommended dose or formula, the method and duration of administration, and contraindications. It is the responsibility of the practitioner, relying on their own experience and knowledge of the patient, to make diagnoses, to determine dosages and the best treatment for each individual patient, and to take all appropriate safety precautions. To the fullest extent of the law, neither the Publisher nor the Editor assumes any liability for any injury and/or damage to persons or property arising out of or related to any use of the material contained in this book. The Publisher A Note about Drug Dosages Some chapters include dosage recommendations that may differ from information contained in the drug formulary found in Appendix I: Table of Common Drugs: Approximate Dosages, beginning on page 1307. We acknowledge the expertise of our individual chapter authors and want to share their individual preferences with you. We have taken great care to ensure the accuracy of all dosages provided throughout Kirk’s Current Veterinary Therapy XV. International Standard Book Number: 978-1-4377-2689-3

Vice President and Publisher: Linda Duncan Content Strategy Director: Penny Rudolph Content Manager: Shelly Stringer Publishing Services Manager: Catherine Jackson Senior Project Manager: David Stein Design Direction: Paula Catalano

Printed in the United States Last digit is the print number:  9  8  7  6  5  4  3  2  1

Consulting Editors Section I: Critical Care

Elisa M. Mazzaferro, MS, DVM, PhD, DACVECC Staff Criticalist Cornell University Veterinary Specialists Stamford, Connecticut Hyperthermia and Heat-Induced Illness

Section II: Toxicologic Diseases

Michael J. Murphy, DVM, JD, PhD Professor Emeritus University of Minnesota Stillwater, Minnesota Rodenticide Toxicoses Nephrotoxicants Small Animal Poisoning: Additional Considerations Related to Legal Claims Sources of Help for Toxicosis Treatment of Animal Toxicoses: Regulatory Points to Consider

Section III: Endocrine and Metabolic Diseases

Ellen N. Behrend, VMD, PhD, DACVIM Jozey Griffin Professor Clinical Sciences Auburn University Auburn, Alabama Occult Hyperadrenocorticism: Is It Real? Interpretation of Endocrine Diagnostic Test Results for Adrenal and Thyroid Disease Robert J. Kemppainen, DVM, PhD Professor Anatomy, Physiology and Pharmacology Auburn University College of Veterinary Medicine Auburn, Alabama Interpretation of Endocrine Diagnostic Test Results for Adrenal and Thyroid Disease

Section IV: Oncology and Hematology

Douglas H. Thamm, VMD, DACVIM (Oncology) Associate Professor and Barbara Cox Anthony Chair in Oncology Department of Clinical Sciences College of Veterinary Medicine Colorado State University Fort Collins, Colorado Talking to Clients about Cancer Anticancer Drugs: New Drugs

Christine S. Olver, DVM, PhD, DACVP Associate Professor Clinical Pathology Section Colorado State University Fort Collins, Colorado Lymphocytosis in Dogs and Cats Bone Marrow Dyscrasias

Section V: Dermatologic and Otic Diseases

Andrew Hillier, BVSc, MACVSc, DACVD Former Professor and Head of Dermatology and Otology Veterinary Clinical Sciences The Ohio State University Columbus, Ohio Senior Veterinary Specialist (Dermatology), Zoetis Cyclosporine Use in Dermatology Flea Control in Flea Allergy Dermatitis Treatment of Superficial Bacterial Folliculitis Lynette K. Cole, DVM, MS, DACVD Associate Professor Department of Veterinary Clinical Sciences College of Veterinary Medicine The Ohio State University Columbus, Ohio Principles of Therapy for Otitis Systemic Antimicrobials for Otitis

Section VI: Gastrointestinal Diseases

David C. Twedt, DVM, DACVIM (Internal Medicine) Professor Department of Clinical Sciences College of Veterinary Medicine and Biomedical Sciences Colorado State University Fort Collins, Colorado Copper Chelator Therapy Idiopathic Vacuolar Hepatopathy Feline Cholangitis Evaluation of Elevated Serum Alkaline Phosphatase in Dogs Hepatic Support Therapy Kenneth W. Simpson, BVM&S, MRCVS, PhD, DACVIM, DECVIM Professor of Small Animal Medicine Clinical Sciences Cornell University Ithaca, New York Cobalamin Deficiency in Cats Canine Colitis Feline Cholangitis

Section VII: Respiratory Diseases

Lynelle R. Johnson, DVM, MS, PhD, DACVIM (SAIM) Associate Professor Medicine & Epidemiology University of California—Davis Davis, California Rhinitis in Cats Chronic Bronchial Disorders in Dogs

Section VIII: Cardiovascular Diseases

John D. Bonagura, DVM, MS, DACVIM (Cardiology, Internal Medicine) Professor Department of Veterinary Clinical Sciences College of Veterinary Medicine The Ohio State University Head, Cardiology and Interventional Medicine Service The Ohio State University Veterinary Medical Center Columbus, Ohio Congenital Heart Disease Drugs for Treatment of Heart Failure in Dogs Management of Heart Failure in Dogs Ventricular Septal Defect Brian A. Scansen, DVM, MS, DACVIM Assistant Professor of Cardiology and Interventional Medicine Veterinary Clinical Sciences The Ohio State University Columbus, Ohio Tracheal Collapse Congenital Heart Disease

Section IX: Urinary Diseases

India F. Lane, DVM, MS, EdD Assistant Vice President Office of Academic Affairs and Student Success The University of Tennessee Knoxville, Tennessee Professor and Internist Department of Small Animal Clinical Sciences College of Veterinary Medicine The University of Tennessee Knoxville, Tennessee

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Consulting Editors

Section X: Reproductive Diseases

Michelle Anne Kutzler, DVM, PhD, DACT Banfield Professor of Companion Animal Industries Animal and Rangeland Sciences Oregon State University Corvallis, Oregon Postpartum Disorders in Companion Animals Early Age Neutering in Dogs and Cats Acquired Nonneoplastic Disorders of the Male External Genitalia

Section XI: Neurologic Diseases

Curtis W. Dewey, BS, DVM, MS Associate Professor Clinical Sciences College of Veterinary Medicine Cornell University Ithaca, New York Intracranial Arachnoid Cysts in Dogs New Maintenance Anticonvulsant Therapies for Dogs and Cats Peripheral and Central Vestibular Disorders in Dogs and Cats Craniocervical Junction Abnormalities in Dogs

Section XII: Ophthalmologic Diseases

Anne J. Gemensky Metzler, DVM, MS, DACVO Professor-Clinical Comparative Ophthalmology Veterinary Clinical Sciences College of Veterinary Medicine The Ohio State University Columbus, Ohio Evaluation of Blindness Amber Labelle, DVM, MS, DACVO Assistant Professor Veterinary Clinical Medicine University of Illinois Urbana—Champaign Urbana, Illinois Corneal Ulcers Canine Ocular Neoplasia Feline Ocular Neoplasia

Section XIII: Infectious Diseases Michael R. Lappin, DVM, PhD, DACVIM (SA Internal Medicine) The Kenneth W. Smith Professor Department of Clinical Sciences Colorado State University Fort Collins, Colorado Protozoal Gastrointestinal Disease Infectious Agent Differentials for Medical Problems Infectious Causes of Polyarthritis in Dogs Update on Vaccine-Associated Adverse Effects in Cats Toxoplasmosis Feline Infectious Peritonitis Virus Infections

Appendix I: Table of Common Drugs: Approximate Dosages

Mark G. Papich, DVM, MS Professor of Clinical Pharmacology College of Veterinary Medicine North Carolina State University Raleigh, North Carolina Veterinary Teaching Hospital College of Veterinary Medicine North Carolina State University Raleigh, North Carolina Respiratory Drug Therapy Appendix I: Table of Common Drugs: Approximate Dosages

Contributors Jonathan A. Abbott, DVM, DACVIM (Cardiology) Associate Professor of Cardiology Small Animal Clinical Sciences Virginia-Maryland Regional College of Veterinary Medicine Virginia Tech Blacksburg, Virginia Associate Professor Basic Sciences Virginia Tech Carilion School of Medicine and Research Institute Roanoke, Virginia Subaortic Stenosis Mark J. Acierno, MBA, DVM Associate Professor Veterinary Clinical Science The Louisiana State University Baton Rouge, Louisiana Continuous Renal Replacement Therapy

Karin Allenspach, Dr.Med.Vet., ECVIM-CA, FVH, PhD, FHEA Doctor Veterinary Clinical Sciences Royal Veterinary College London, Hertfordshire, Great Britain Inflammatory Bowel Disease Colleen M. Almgren, DVM, PhD Staff Veterinarian Clinical Toxicology Pet Poison Helpline/SafetyCall International Bloomington, Minnesota Toxin Exposures in Small Animals John D. Anastasio, DVM, DACVECC Associate Veterinarian Veterinary Emergency and Referral Center Norwalk, Connecticut Crystalloid Fluid Therapy

Larry G. Adams, DVM, PhD, DACVIM (SAIM) Professor Small Animal Internal Medicine Department of Veterinary Clinical Sciences Purdue University West Lafayette, Indiana Laser Lithotripsy for Uroliths

P. Jane Armstrong, DVM, MS, MBA Professor Small Animal Internal Medicine Veterinary Clinical Sciences Department University of Minnesota St. Paul, Minnesota Feline Hepatic Lipidosis Feline Cholangitis

Christopher A. Adin, DVM, DACVS Associate Professor Veterinary Clinical Sciences The Ohio State University Columbus, Ohio Mechanical Occluder Devices for Urinary Incontinence

Clarke E. Atkins, DVM Jane Lewis Seaks Distinguished Professor of Companion Animal Medicine Department of Clinical Sciences North Carolina State University Raleigh, North Carolina Feline Heartworm Disease

Darcy B. Adin, DVM Associate Cardiologist Cardiology MedVet Medical and Cancer Center for Pets Worthington, Ohio Tricuspid Valve Dysplasia

Anne Avery, VMD, PhD Associate Professor, Director Clinical Immunology Microbiology, Immunology and Pathology Colorado State University Fort Collins, Colorado Lymphocytosis in Dogs and Cats

Hasan Albasan, DVM, MS, PhD Minnesota Urolith Center Veterinary Medicine University of Minnesota St. Paul, Minnesota Canine Urate Urolithiasis Laser Lithotripsy for Uroliths Kelly E. Allen, MS, PhD Department of Veterinary Pathobiology Center for Veterinary Health Sciences Oklahoma State University Stillwater, Oklahoma Hepatozoon americanum Infections

Sandra M. Axiak-Bechtel, DVM, DACVIM Assistant Professor College of Veterinary Medicine University of Missouri Columbia, Missouri Pulmonary Neoplasia Todd W. Axlund, DVM, MS, ACVIM (Neurology) Metropolitan Veterinary Referral Group Akron, Ohio Treatment of Intracranial Tumors

Nicholas J. Bacon, MA, VetMB, DECVS, DACVS, MRCVS Clinical Assistant Professor of Surgical Oncology Small Animal Clinical Sciences University of Florida College of Veterinary Medicine Gainesville, Florida Tumor Biopsy and Specimen Submission Cindy Bahr Hospital Administrator Warner Center Pet Clinic Woodland Hills, California Neutriceutical Formulator Complete Vites LLC Calabasas, California Pregnancy Diagnosis in Companion Animals Dennis B. Bailey, DVM, DACVIM (Oncology) Staff Oncologist Oradell Animal Hospital Paramus, New Jersey Treatment of Adverse Effects from Cancer Therapy Claudia J. Baldwin, DVM, MS Associate Professor Veterinary Clinical Sciences Faculty Center for Food Security and Public Health Iowa State University Ames, Iowa Pregnancy Loss in the Bitch and Queen Lora R. Ballweber, MS, DVM, DACVM (Parasitology) Professor Microbiology, Immunology and Pathology Section Head, Parasitology Veterinary Diagnostic Laboratory College of Veterinary Medicine and Biomedical Sciences Colorado State University Fort Collins, Colorado Appendix II: Treatment of Parasites Tania Ann Banks, BVSc, FACVSc (Small Animal Surgery), GC (HEd) Lecturer and Consultant Surgeon Small Animal Surgery The University of Queensland St. Lucia and Gatton Campuses Queensland, Australia Soft Tissue Sarcomas

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Contributors

A. Catherine Barr, PhD President Elect, AAVLD Diplomate American Board of Toxicology Quality Assurance & Safety Manager Texas A&M Veterinary Medical Diagnostic Laboratory Amarillo, Texas Top Ten Toxic and Nontoxic Household Plants Vanessa R. Barrs, BVSc(hons), MVetClinStud, FANZCVSc (Feline Medicine) Associate Professor Small Animal Medicine Faculty of Veterinary Science The University of Sydney Sydney, New South Wales, Australia Rhinitis in Cats Joseph W. Bartges, DVM, PhD, DACVIM, DACVN Professor of Medicine and Nutrition Department of Small Animal Clinical Sciences The Acree Endowed Chair of Small Animal Research Department of Small Animal Clinical Sciences Internist and Nutritionist Small Animal Hospital Veterinary Medical Center The University of Tennessee Knoxville, Tennessee Minilaparotomy-Assisted Cystoscopy for Urocystoliths Top Ten Urinary Consult Questions Karin M. Beale, DVM, DACVD Dermatologist Gulf Coast Veterinary Specialists Houston, Texas Feline Demodicosis Adrienne Bentley, DVM, DACVS Staff Surgeon Veterinary Medical and Surgical Group Ventura, California Drainage Techniques for the Septic Abdomen Allyson Berent, DVM, DACVIM Director of Interventional Endoscopy Interventional Radiology/Interventional Endoscopy The Animal Medical Center New York, New York Interventional Strategies for Urinary Disease Alexa M.E. Bersenas, DVM, MS, DACVECC Associate Professor Clinical Studies Ontario Veterinary College University of Guelph Guelph, Ontario, Canada Antacid Therapy

Nick Bexfield, BVETMED, DSAM, DECVIM-CA, MRCVS Department of Veterinary Medicine University of Cambridge Cambridge, United Kingdom Ascites and Hepatic Encephalopathy Therapy for Liver Disease Adam J. Birkenheuer Associate Professor Department of Clinical Sciences College of Veterinary Medicine North Carolina State University Raleigh, North Carolina Thrombocytopenia Treatment of Canine Babesiosis Karyn Bischoff, DVM, MS, DABVT Assistant Professor Population Medicine and Diagnostic Sciences Diagnostic Toxicologist New York State Animal Health Diagnostic Center Cornell University Ithaca, New York Automotive Toxins Aflatoxicosis in Dogs Dana R. Bleifer, DVM Owner Warner Center Pet Clinic Woodland Hills, California Pregnancy Diagnosis in Companion Animals Manuel Boller, Dr.med.vet., MTR, DACVECC Senior Lecturer Emergency and Critical Care Faculty of Veterinary Science University of Melbourne Melbourne, Victoria, Australia Cardiopulmonary Resuscitation Michele Borgarelli, DVM, PhD, DECVIM-CA Associate Professor Small Animal Clinical Sciences Virginia-Maryland College of Veterinary Medicine Virginia Tech Blacksburg, Virginia Pulmonary Hypertension Shay Bracha, DVM Assistant Professor Oncology Department of Clinical Sciences Assistant Professor Department of Clinical Sciences-Oncology College of Veterinary Medicine Oregon State University Corvallis, Oregon Reproductive Oncology

Allison Bradley, DVM, DACVIM (SAIM) Department of Clinical Sciences College of Veterinary Medicine and Biomedical Sciences Colorado State University Fort Collins, Colorado Copper Chelator Therapy Benjamin M. Brainard, VMD, DACVA, DACVECC Associate Professor of Emergency and Critical Care Critical Care Small Animal Medicine and Surgery College of Veterinary Medicine University of Georgia Athens, Georgia Thromboelastography Janice M. Bright, BSN, MS, DVM, DACVIM (Cardiology) Professor of Cardiology Department of Clinical Science Cardiologist Veterinary Teaching Hospital Colorado State University Fort Collins, Colorado Cardioversion Susan J. Bright-Ponte, DVM Office of Surveillance and Compliance FDA Center for Veterinary Medicine Rockville, Maryland Reporting Adverse Events to the Food and Drug Administration—Center for Veterinary Medicine Treatment of Animal Toxicoses: Regulatory Points to Consider Marjorie B. Brooks, DVM, DACVIM Director Comparative Coagulation Laboratory Population Medicine and Diagnostic Sciences Cornell University Ithaca, New York von Willebrand Disease and Hereditary Coagulation Factor Deficiencies Michael R. Broome, DVM, MS, DABVP Advanced Veterinary Medical Imaging Tustin, California Radioiodine for Feline Hyperthyroidism Scott A. Brown, VMD, PhD, DACVIM Josiah Meigs Distinguished Teaching Professor Department of Physiology and Pharmacology Edward Gunst Professor of Small Animal Studies Department of Small Animal Medicine and Surgery College of Veterinary Medicine University of Georgia Athens, Georgia Use of Nonsteroidal Antiinflammatory Drugs in Kidney Disease

Contributors Ahna G. Brutlag, DVM, MS, DAPT Assistant Director of Veterinary Services Pet Poison Helpline and SafetyCall International Minneapolis, Minnesota Antidepressants and Anxiolytics C.A. Tony Buffington, DVM, PhD, DACVN Professor Veterinary Clinical Sciences The Ohio State University Columbus, Ohio Multimodal Environmental Enrichment for Domestic Cats Barret J. Bulmer, DVM, MS, DACVIM-Cardiology Staff Veterinarian Cummings School of Veterinary Medicine Tufts University Grafton, Massachusetts Tufts Veterinary Emergency Treatment and Specialties Cardiology Walpole, Massachusetts Mitral Valve Dysplasia Amanda K. Burrows, BVMS, MANZVSC, FANZVSC (Veterinary Dermatology) Adjunct Lecturer Department of Veterinary and Biomedical Science Director Animal Dermatology Clinic—Perth Director Dermatology Perth Veterinary Specialists Perth, Western Australia, Australia Actinic Dermatoses and Sun Protection Avermectins in Dermatology Kevin Byrne, DVM, MS Chief of Staff Allergy Ear and Skin Care for Animals LLC Bensalem, Pennsylvania Superficial Necrolytic Dermatitis Julie K. Byron, DVM, MS, DACVIM Associate Professor—Clinical Veterinary Clinical Science The Ohio State University Columbus, Ohio Urinary Incontinence: Treatment with Injectable Bulking Agents Amanda Callens, BS, LVMT Department of Small Animal Clinical Sciences College of Veterinary Medicine The University of Tennessee Knoxville, Tennessee Minilaparotomy-Assisted Cystoscopy for Urocystoliths Top Ten Urinary Consult Questions

Clay A. Calvert, DVM Professor Emeritus Small Animal Medicine and Surgery College of Veterinary Medicine University of Georgia Athens, Georgia Syncope Starr Cameron, BVetMed Resident, Neurology/Neurosurgery Department of Clinical Sciences Cornell University Hospital for Animals Ithaca, New York Peripheral and Central Vestibular Disorders in Dogs and Cats Nigel Campbell, BVetMed, PhD Clinical Assistant Professor College of Veterinary Medicine North Carolina State University Raleigh, North Carolina Analgesia of the Critical Patient Elizabeth A. Carsten, DVM, DACVIM (SAIM) Manager US Internal Medicine Consulting IDEXX Laboratories, Inc. Tucson, Arizona Esophagitis Sharon A. Center, BS, DVM, DACVIM Professor, Internal Medicine Clinical Sciences College of Veterinary Medicine Cornell University Ithaca, New York Acute Liver Failure Rosario Cerundolo, DVM, Cert. VD, DECVD, MRCVS Consultant in Dermatology Dick White Referrals Six Mile Bottom Suffolk, United Kingdom Alopecia X Daniel L. Chan, DVM, DACVECC, DACVN, FHEA, MRCV Senior Lecturer in Emergency and Critical Care Veterinary Clinical Sciences The Royal Veterinary College University of London North Mymms, Hertfordshire, United Kingdom Nutrition in Critical Care Dennis J. Chew, DVM, DACVIM (Internal Medicine) Professor Emeritus Veterinary Clinical Sciences College of Veterinary Medicine The Ohio State University Columbus, Ohio Feline Idiopathic Hypercalcemia Treatment of Hypoparathyroidism Urinary Incontinence: Treatment with Injectable Bulking Agents

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David B. Church, BVSc, PhD, MACVSc, MRCVS, ILTM Professor of Small Animal Studies Department of Clinical Sciences and Services The Royal Veterinary College University of London London, United Kingdom Feline Hypersomatotropism and Acromegaly Cécile Clercx, DVM, PhD, DECVIM-CA (Internal Medicine) Professor of Clinical Sciences of Companion Animals and Equine University of Liège Faculty of Veterinary Medicine Liège, Belgium Eosinophilic Pulmonary Diseases Craig A. Clifford, DVM, MS, DACVIM (Oncology) Medical Oncologist Director of Clinical Research Oncology Hope Veterinary Specialists Malvern, Pennsylvania Canine Hemangiosarcoma Joan R. Coates, DVM, MS, DACVIM (Neurology) Professor Service Leader—Neurology and Neurosurgery Service Department Veterinary Medicine and Surgery College of Veterinary Medicine University of Missouri Columbia, Missouri Canine Degenerative Myelopathy Richard E. Cober, DV, MS Clinical Instructor Cardiology and Interventional Medicine Veterinary Clinical Sciences Veterinary Medical Center The Ohio State University Columbus, Ohio Chesapeake Veterinary Cardiology Associates Maryland and Virginia Congenital Heart Disease Patrick W. Concannon, PhD Director Emeritus Laboratory for Comparative Reproduction Biomedical Sciences Cornell University College of Veterinary Medicine Ithaca, New York President International Veterinary Information Service Ithaca, New York Estrus Suppression in the Bitch

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Contributors

Edward S. Cooper, VMD, MS, DACVECC Associate Professor—Clinical, Small Animal Emergency and Critical Care Veterinary Clinical Sciences Head of Service—Small Animal Emergency and Critical Care Veterinary Medical Center The Ohio State University Columbus, Ohio Catecholamines in the Critical Care Patient Johanna C. Cooper, DVM, DACVIM (SAIM) Tufts Veterinary Emergency Treatment & Specialties Walpole, Massachusetts Diagnostic Approach to Hepatobiliary Disease Rhian Cope, BVSc, BSc (Hon 1), PhD, DABT, ERT, MRCVS Senior Advisor Hazardous Substances Environmental Risk Management Authority Wellington, New Zealand Pesticides: New Vertebrate Toxic Agents for Pest Species Brendan M. Corcoran, MVB, PhD, DPharm, MRCVS Professor Veterinary Clinical Studies Royal (Dick) School of Veterinary Studies and Roslin Institute The University of Edinburgh Edinburgh, Scotland, United Kingdom Interstitial Lung Diseases Étienne Côté, DVM, DACVIM (Cardiology, Small Animal Internal Medicine) Associate Professor Department of Companion Animals Atlantic Veterinary College University of Prince Edward Island Charlottetown, Prince Edward Island, Canada Feline Cardiac Arrhythmias Nancy B. Cottrill, DVM, MS, DACVO Staff Ophthalmologist Massachusetts Veterinary Referral Hospital Woburn, Massachusetts Anisocoria and Abnormalities of the Pupillary Light Reflex: The Neuroophthalmic Examination Jamie M. Burkitt Creedon, DVM, DACVECC Head of the Emergency and Critical Care Service Red Bank Veterinary Hospital of Cherry Hill Cherry Hill, New Jersey Critical Consultations Allentown, New Jersey Critical Illness–Related Corticosteroid Insufficiency

Cheryl L. Cullen, DVM, MVetSc, DACVO CullenWebb Animal Neurology & Ophthalmology Centre Riverview, New Brunswick, Canada Feline Corneal Disease William T.N. Culp Assistant Professor Department of Surgical and Radiological Sciences University of California—Davis Davis, California Interventional Oncology Suzanne M. Cunningham, DVM, DACVIM (Cardiology) Assistant Professor of Cardiology Clinical Sciences Tufts Cummings School of Veterinary Medicine North Grafton, Massachusetts Chronic Valvular Heart Disease in Dogs James T. Custis III, DVM, MS, DACVR (RO) Assistant Professor Veterinary Radiation Oncology Environmental and Radiological Health Sciences James L. Voss Veterinary Teaching Hospital and the Animal Cancer Center Colorado State University Fort Collins, Colorado Advances in Radiation Therapy for Nasal Tumors Ronaldo Casimiro da Costa, DVM, MSc, PhD, DACVIM-Neurology Assistant Professor and Service Head Neurology and Neurosurgery Veterinary Clinical Sciences The Ohio State University Columbus, Ohio Diagnosis and Treatment of Cervical Spondylomyelopathy Autumn P. Davidson, DVM, MS Clinical Professor Medicine and Epidemiology University of California—Davis Davis, California Staff Internist Internal Medicine Pet Care Veterinary Hospital Santa Rosa, California Dystocia Management Canine Brucellosis Douglas J. DeBoer, DVM Professor of Dermatology Department of Medical Sciences University of Wisconsin Madison, Wisconsin Allergen-Specific Immunotherapy Treatment of Dermatophytosis

Linda J. DeBowes, DVM, MS, DAVDC, DACVIM (Small Animal) Shoreline Veterinary Dental Clinic Seattle, Washington Feline Caudal Stomatitis Joao Felipe de Brito Galvao, MV, MS, DACVIM (SAIM) Internal Medicine Specialist and Medical Director Internal Medicine and Nuclear Medicine VCA Arboretum View Animal Hospital Downers Grove, Illinois Feline Idiopathic Hypercalcemia Treatment of Hypoparathyroidism Louis-Philippe de Lorimier, DVM, DACVIM (Oncology) Staff Medical Oncologist Medical Oncology Hôpital Vétérinaire Rive-Sud Brossard, Québec, Canada Canine Hemangiosarcoma Helio Autran de Morais, DVM, PhD, ACVIM (SAIM & Cardiology) Director Lois Bates Acheson Veterinary Teaching Hospital Oregon State University Corvallis, Oregon Acid-Base Disorders Robert C. DeNovo, DVM, DACVIM (SAIM) Professor Internal Medicine Associate Dean for Administration and Clinical Programs Department of Small Animal Clinical Sciences College of Veterinary Medicine The University of Tennessee Knoxville, Tennessee Canine Megaesophagus Stephen P. DiBartola, DVM, DACVIM (Internal Medicine) Professor of Medicine Veterinary Clinical Sciences College of Veterinary Medicine The Ohio State University Columbus, Ohio Acid-Base Disorders Pedro Paulo Vissotto de Paiva Diniz, DVM, PhD Assistant Professor of Small Animal Internal Medicine College of Veterinary Medicine Western University of Health Sciences Pomona, California Canine Bartonellosis

Contributors David C. Dorman, DVM, PhD Professor of Toxicology Department of Molecular Biomedical Sciences College of Veterinary Medicine North Carolina State University Raleigh, North Carolina Over-the-Counter Drug Toxicosis Steven Dow, DVM, PhD, DACVIM (SAIM) Professor Department of Clinical Sciences Internist Veterinary Teaching Hospital Colorado State University Fort Collins, Colorado Management of Immune-Mediated Hemolytic Anemia in Dogs Cancer Immunotherapy Immunotherapy for Infectious Diseases Patricia M. Dowling, DVM, MSc, DACVIM (LAIM), DACVCP Professor Veterinary Clinical Pharmacology Veterinary Biomedical Sciences Western College of Veterinary Medicine Saskatoon, Saskatchewan, Canada Rational Empiric Antimicrobial Therapy Kenneth J. Drobatz, DVM, MSCE, DACVIM, DACVECC Professor and Chief, Section of Critical Care Department of Clinical Studies Director, Emergency Service Critical Care Mathew J. Ryan Veterinary Hospital of the University of Pennsylvania University of Pennsylvania Philadelphia, Pennsylvania Oxygen Therapy Eric K. Dunayer, MS, VMD, DABT, DABVT Associate Professor Veterinary Clinical Sciences School of Veterinary Medicine St. Matthew’s University Grand Cayman, Cayman Islands Human Foods with Pet Toxicoses: Alcohol to Xylitol Janice A. Dye, DVM, MS, PhD, DACVIM (SA-IM) Principal Investigator Environmental Public Health Division National Health and Environmental Effects Research Laboratory, ORD US Environmental Protection Agency Research Triangle Park, North Carolina Respiratory Toxicants of Interest to Pet Owners

David A. Dzanis, DVM, PhD, DACVN Regulatory Discretion, Inc. Santa Clarita, California Nutrition in the Bitch and Queen During Pregnancy and Lactation Susan M. Eddlestone, DVM, DACVIM Associate Professor Veterinary Clinical Sciences School of Veterinary Medicine The Louisiana State University Baton Rouge, Louisiana Canine and Feline Monocytotropic Ehrlichiosis Nicole P. Ehrhart, VMS, MS, DACVS, ACVS Founding Fellow Surgical Oncology Professor, Surgical Oncology Department of Clinical Sciences Colorado State University Fort Collins, Colorado James Voss Veterinary Teaching Hospital Osteosarcoma Bruce E. Eilts, DVM, MS DACT Associate Professor School of Veterinary and Biomedical Sciences James Cook University Townsville, Queensland, Australia Professor Emeritus Department of Veterinary Clinical Sciences School of Veterinary Medicine The Louisiana State University Baton Rouge, Louisiana Medical Termination of Pregnancy Jonathan Elliott, MA, VetMB, PhD, Cert SAC, DECVPT, MRCVS Professor of Veterinary Clinical Pharmacology and Vice Principal for Research Veterinary Basic Sciences Royal Veterinary College University of London London, England Chronic Kidney Disease: International Renal Interest Society Staging and Management Gary C.W. England, BVetMed, PhD, DVetMed, DVR, DVRep, DECAR, DACT, FHEA, FRCVS Department of Veterinary Surgery School of Veterinary Medicine and Science University of Nottingham Sutton Bonington, Loughborough, United Kingdom Breeding Management of the Bitch

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Amara H. Estrada, DVM, DACVIM (Cardiology) Associate Professor and Associate Chair Small Animal Clinical Sciences University of Florida Gainesville, Florida Dilated Cardiomyopathy in Dogs Pulmonic Stenosis Cristian Falzone, DVM, DECVN Department of Neurology Small Animal Diagnostics Zugliano (VI), Italy Department of Neurology Malpensa Veterinary Clinic Samarate (VA), Italy Metabolic Brain Disorders Timothy M. Fan, DVM, PhD Associate Professor Veterinary Clinical Medicine University of Illinois at Urbana—Champaign Urbana, Illinois Osteosarcoma James P. Farese, DVM, DACVS (ACVS Founding Fellow of Surgical Oncology) Staff Surgeon VCA Animal Care Center of Sonoma County Rohnert Park, California Surgical Oncology Principles Claude Favrot, DVM Prof. Dr. Head of the Dermatology Service Clinic for Small Animal Internal Medicine Vetsuisse Faculty University of Zurich Zurich, Switzerland Diagnostic Criteria for Canine Atopic Dermatitis Anne Fawcett, BA (Hons), BVSc(Vet) (Hons), BVSc(Hons), MVetStud CMAVA Lecturer Faculty of Veterinary Science University of Sydney Sydney, New South Wales, Australia Associate Sydney Animal Hospitals Inner West Sydney, New South Wales, Australia Nontuberculous Cutaneous Granulomas in Dogs and Cats (Canine Leproid Granuloma and Feline Leprosy Syndrome)

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Contributors

Edward C. Feldman, DVM Professor of Small Animal Internal Medicine Department of Medicine & Epidemiology University of California—Davis Davis, California Hypercalcemia and Primary Hyperparathyroidism in Dogs Large Pituitary Tumors in Dogs with Pituitary-Dependent Hyperadrenocorticism Alberto L. Fernandez Mojica, DVM, DACVECC Associate Professor Small Animal Medicine and Surgery Assistant Medical Director Veterinary Teaching Hospital Small Animal Medicine and Surgery School of Veterinary Medicine St. Georges University St. Georges, Grenada, West Indies Intravenous Lipid Emulsion Therapy Jeanne E. Ficociello, VMD, MS, DACVIM Small Animal Internal Medicine VCA South Shore Animal Hospital South Weymouth, Massachusetts Neospora caninum Hille Fieten, DVM, MSc Clinical Sciences of Companion Animals Faculty of Veterinary Medicine Universiteit Utrecht Utrecht, The Netherlands Copper-Associated Hepatitis Julie R. Fischer, DVM, DACVIM Staff Internist Veterinary Specialty Hospital of San Diego Internal Medicine San Diego, California Persistent Escherichia coli Urinary Tract Infection Randall B. Fitch, DVM, MS, DACVS Ladera Ranch, California Evaluation of Canine Orthopedic Trauma Derek Flaherty, BVMS, DVA, DECVAA, MRCA, MRCVS Professor of Veterinary Anaesthesia and Analgesia School of Veterinary Medicine University of Glasgow Glasgow, Scotland, United Kingdom Anesthesia for the Critical Care Patient

Daniel J. Fletcher, PhD, DVM, DACVECC Assistant Professor Emergency and Critical Care Clinical Sciences College of Veterinary Medicine Cornell University Ithaca, New York Crystalloid Fluid Therapy Cardiopulmonary Resuscitation Treatment of Cluster Seizures and Status Epilepticus Andrea Flory, DVM, DACVIM (Oncology) Medical Oncologist Veterinary Specialty Hospital San Diego, California Chemotherapeutic Drug Handling and Safety Marnin A. Forman, DVM, DACVIM Head of Department Staff Internist Internal Medicine Cornell University Veterinary Specialists Stamford, Connecticut Feline Exocrine Pancreatic Disorders Lisa J. Forrest, VMD, DACVR (Radiology, Radiation Oncology) Professor Surgical Sciences Professor Carbone Cancer Center University of Wisconsin—Madison Madison, Wisconsin Nasal Tumors Susan F. Foster, BVSc, MVetClinStud, FANZCVS Adjunct Senior Lecturer in Small Animal Medicine Department of Veterinary Clinical Sciences Murdoch University Murdoch, Western Australia, Australia Small Animal Medical Consultant Vetnostics Sydney, Australia Nasopharyngeal Disorders Philip R. Fox, DVM, MSc, BSc, DACVIM/ECVIM-CA (Cardiology), DACVECC Head of Cardiology The Animal Medical Center New York, New York Director Caspary Institute of the Animal Medical Center New York, New York Arrhythmogenic Right Ventricular Cardiomyopathy in Cats

Linda A. Frank, MS, DVM, DACVD Professor of Dermatology Department of Small Animal Clinical Sciences College of Veterinary Medicine The University of Tennessee Knoxville, Tennessee Staphylococci Causing Pyoderma Lisa M. Freeman, DVM, PhD, DACVN Professor Department of Clinical Sciences Tufts Cummings School of Veterinary Medicine North Grafton, Massachusetts Nutritional Management of Heart Disease Valérie Freiche, DVM Vet Clinic Internal Medicine Alliance Bordeaux, France Brachycephalic Airway Obstruction Syndrome Cecilia Friberg, DVM, DACVD Owner, Veterinary Dermatologist Animal Dermatology Center of Chicago, P.C. Chicago, Illinois Ototoxicity Janet A.M. Fyfe, PhD Senior Scientist Mycobacterium Reference Laboratory Victorian Infectious Diseases Reference Laboratory North Melbourne, Victoria, Australia Deputy Head WHO Collaborating Centre for Mycobacterium Ulcerans (Western Pacific Region) North Melbourne, Victoria, Australia Nontuberculous Cutaneous Granulomas in Dogs and Cats (Canine Leproid Granuloma and Feline Leprosy Syndrome) Sara Galac, DVM, PhD Assistant Professor Department of Clinical Sciences of Companion Animals Faculty of Veterinary Medicine Universiteit Utrecht Utrecht, The Netherlands Ectopic ACTH Syndrome and FoodDependent Hypercortisolism in Dogs Leana V. Galdjian, DVM Veterinarian Rose City Veterinary Hospital Pasadena, California Veterinarian Warner Center Pet Clinic Woodland Hills, California Pregnancy Diagnosis in Companion Animals

Contributors Tam Garland, DVM, PhD, DABVT Toxicology Section Head Texas A&M Veterinary Medical Diagnostic Laboratory College Station, Texas Aflatoxicosis in Dogs Laurent S. Garosi, DVM, MRCVS, DECVN, RCVS-Recognized Specialist in Veterinary Neurology Head of Neurology/Neurosurgery Service Head Neurology and Neurosurgery Davies Veterinary Specialists Higham Gobion, England Vascular Disease of the Central Nervous System Laura D. Garrett, DVM, DACVIM (Oncology) Clinical Associate Professor Veterinary Clinical Medicine University of Illinois Urbana, Illinois Plasma Cell Neoplasms Anthony T. Gary, DVM, DACVIM Owner/Veterinarian Arkansas Veterinary Internal Medicine Little Rock, Arkansas Evaluation of Elevated Serum Alkaline Phosphatase in Dogs Frédéric P. Gaschen, Dr.med.vet., Dr.habil. M.L. Martin Professor Veterinary Clinical Sciences School of Veterinary Medicine The Louisiana State University Baton Rouge, Louisiana Gastric and Intestinal Motility Disorders Rudayna Ghubash, DVM, DACVD Veterinarian Animal Dermatology Clinic Marina del Rey, California Feline Viral Skin Disease

Urs Giger, PD Dr.med.vet., MS, FVH, DACVIM (Small Animal Internal Medicine), DECVIM-CA (Internal Medicine), DECVCP (Clinical Pathology) Charlotte Newton Sheppard Professor Section of Medical Genetics, School of Veterinary Medicine, and Division of Hematology Senior Faculty Clinician Ryan Veterinary Hospital Director of Metabolic Genetics and Deubler Testing Laboratory (PennGen) Section of Medical Genetics University of Pennsylvania Philadelphia, Pennsylvania Professor of Internal Medicine Department of Small Animal Medicine VetSuisse University of Zurich Zurich, Switzerland Blood Typing and Crossmatching to Ensure Blood Compatibility Margi Gilmour, DVM Associate Professor Veterinary Clinical Sciences Oklahoma State University Stillwater, Oklahoma Canine Nonulcerative Corneal Disease Juliet R. Gionfriddo, DVM, MS, DACVO Professor Clinical Sciences Colorado State University Fort Collins, Colorado Ocular Emergencies Elizabeth A. Giuliano, DVM, MS, DACVO Associate Professor Veterinary Medicine and Surgery University of Missouri Columbia, Missouri Tear Film Disorders in Dogs Richard E. Goldstein, DVM, DACVIM (Small Animal Internal Medicine), DECVIM-CA Chief Medical Officer The Animal Medical Center New York, New York Infectious Causes of Polyarthritis in Dogs Rebecca E. Gompf, DVM, MS Associate Professor of Cardiology Department of Small Animal Clinical Sciences College of Veterinary Medicine The University of Tennessee Knoxville, Tennessee Ventricular Septal Defect

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Jody L. Gookin, DVM, PhD Associate Professor Department of Clinical Sciences North Carolina State University Raleigh, North Carolina Protozoal Gastrointestinal Disease Sonya G. Gordon, DVM, DVSc, DACVIM (Cardiology) Department of Small Animal Clinical Science College of Veterinary Medicine and Biomedical Science Texas A&M University College Station, Texas Canine Heartworm Disease Patent Ductus Arteriosus Carlos M. Gradil, DVM, MS, PhD, DACT Ext. Associate Professor Veterinary and Animal Sciences University of Massachusetts Amherst, Massachusetts Adjunct Associate Professor, Clinical Sciences Tufts University North Grafton, Massachusetts Ovarian Remnant Syndrome in Small Animals Gregory F. Grauer, DVM, MS, DACVIM Professor and Jarvis Chair of Medicine Department of Clinical Sciences Kansas State University Manhattan, Kansas Staff Internist Veterinary Medical Teaching Hospital Kansas State University Manhattan, Kansas Proteinuria/Albuminuria: Implications for Management Deborah S. Greco, DVM, PhD, DACVIM Senior Research Scientist Nestle Purina PetCare St. Louis, Missouri Complicated Diabetes Mellitus Alternatives to Insulin Therapy for Diabetes Mellitus in Cats Craig E. Greene, DVM, MS, DACVIM Emeritus Professor Department of Small Animal Medicine and Surgery College of Veterinary Medicine University of Georgia Athens, Georgia Pet-Associated Illness

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Contributors

Clare R. Gregory, DVM, DACVS Professor Emeritus Surgical and Radiological Sciences School of Veterinary Medicine University of California—Davis Davis, California Staff Surgeon PetCare Animal Hospital Santa Rosa, California Immunosuppressive Agents Joel D. Griffies, DVM DACVD Animal Dermatology Clinic Marietta, Georgia Topical Immunomodulators Carol B. Grindem, DVM, PhD, DACVP Professor of Clinical Pathology Department of Population Health and Pathobiology North Carolina State University Raleigh, North Carolina Thrombocytopenia Amy M. Grooters, DVM, DACVIM Professor, Companion Animal Medicine Veterinary Clinical Sciences The Louisiana State University Baton Rouge, Louisiana Systemic Antifungal Therapy Pythiosis and Lagenidiosis Julien Guillaumin, Doct. Vet. DACVECC Assistant Professor—Clinical Veterinary Clinical Sciences Veterinary Medical Center The Ohio State University Columbus, Ohio Ventilator Therapy for the Critical Patient Lynn F. Guptill, DVM, PhD, DACVIM (SAIM) Associate Professor Veterinary Clinical Sciences Purdue University West Lafayette, Indiana Feline Bartonellosis Amanda Guth, DVM, PhD Research Scientist Animal Cancer Center Clinical Sciences Colorado State University Fort Collins, Colorado Cancer Immunotherapy

Sharon M. Gwaltney-Brant, DVM, PhD, DABVT, DABT Adjunct Instructor Department of Comparative Biosciences University of Illinois College of Veterinary Medicine Urbana, Illinois Toxicology Consultant Veterinary Information Network Davis, California Drugs Used to Treat Toxicoses Lead Toxicosis in Small Animals Timothy B. Hackett, DVM, MS Professor Emergency and Critical Care Medicine Clinical Sciences Colorado State University Fort Collins, Colorado Stabilization of the Patient with Respiratory Distress Transfusion Medicine: Best Practices Susan G. Hackner, BVSc, MRCVS, DACVIM, DACVECC Chief Medical Officer & Chief Operating Officer Cornell University Veterinary Specialists Stamford, Connecticut Pulmonary Thromboembolism Kevin A. Hahn, DVM, PhD, ACVIM (Oncology) Chief Medical Officer Science & Technology Hill’s Pet Nutrition, Inc. Topeka, Kansas Drug Update: Masitinib Pulmonary Neoplasia Annick Hamaide, DVM, PhD, DECVS Associate Professor Department of Clinical Sciences (Companion Animals) School of Veterinary Medicine University of Liege Liege, Belgium Medical Management of Urinary Incontinence and Retention Disorders Ralph E. Hamor, DVM, MS, DACVO Clinical Professor Veterinary Clinical Medicine University of Illinois at Urbana-Champaign Urbana, Illinois Orbital Disease Rita M. Hanel, DVM, DACVIM, DACVECC Assistant Professor of Emergency and Critical Care Department of Clinical Sciences College of Veterinary Medicine North Carolina State University Raleigh, North Carolina Pneumonia

Bernie Hansen, DVM, MS, DACVECC, DACVIM (Internal Medicine) Associate Professor Department of Clinical Sciences North Carolina State University Raleigh, North Carolina Pneumonia William R. Hare Jr., DVM, MS, PhD, DABVT, DABT Veterinary Medical Officer—Retired Animal and Natural Resources Institute USDA-ARS Beltsville, Maryland Urban Legends of Toxicology: Facts and Fiction Katrin Hartmann, Dr.vet.med., Dr. habil., DECVIM-CA Professor Center of Clinical Veterinary Sciences Clinic of Small Animal Medicine Munich, Germany Management of Feline Retrovirus-Infected Cats Andrea M. Harvey, BVSc, DSAM (Feline), DECVIM-CA, MRCVS Feline Specialist Small Animal Specialist Hospital Sydney, New South Wales, Australia Australian Representative International Society of Feline Medicine Feline Primary Hyperaldosteronism Elizabeth A. Hausner, DVM, DABT, DABVT Center for Drug Evaluation and Research United States Food and Drug Administration Silver Spring, Maryland Herbal Hazards Eleanor C. Hawkins, DVM Professor, Internal Medicine Department of Clinical Sciences North Carolina State University College of Veterinary Medicine Raleigh, North Carolina Respiratory Drug Therapy Silke Hecht, Dr.Med.Vet., DACVR, DECVDI Associate Professor Radiology Department of Small Animal Clinical Sciences College of Veterinary Medicine The University of Tennessee Knoxville, Tennessee Applications of Ultrasound in Diagnosis and Management of Urinary Disease

Contributors Romy M. Heilmann, Dr.Med.Vet Veterinary Resident Instructor Small Animal Internal Medicine/ Graduate (PhD) Student Gastrointestinal Laboratory Department of Small Animal Clinical Sciences College of Veterinary Medicine and Biomedical Sciences Texas A&M University College Station, Texas Laboratory Testing for the Exocrine Pancreas Carolyn J. Henry, DVM, MS Professor of Oncology Veterinary Medicine and Surgery Interim Associate Director of Research Internal Medicine Hematology/Oncology Division Ellis Fischel Cancer Center Faculty Facilitator of One Health/One Medicine Office of the Provost Mizzou Advantage Program College of Veterinary Medicine University of Missouri Columbia, Missouri Mammary Cancer Meghan E. Herron, DVM, DACVB Clinical Assistant Professor Veterinary Clinical Sciences The Ohio State University Columbus, Ohio Drugs for Behavior-Related Dermatoses Steve L. Hill, DVM, MS, DACVIM (SAIM) Clinical Associate Faculty Veterinary Medicine Western University of Health Sciences College of Veterinary Medicine Pomona, California Staff Internist, Partner, Hospital Co-Owner Internal Medicine Veterinary Specialty Hospital of San Diego San Diego, California President Comparative Gastroenterology Society (CGS) Feline Hepatic Lipidosis Armando E. Hoet, DVM, PhD, DACVPM Director, Veterinary Public Health Program Veterinary Preventive Medicine Department College of Veterinary Medicine The Ohio State University Columbus, Ohio Disinfection of Environments Contaminated by Staphylococcal Pathogens

Daniel F. Hogan, DVM, DACVIM-Cardiology Associate Professor and Chief, Comparative Cardiovascular Medicine and Interventional Cardiology Veterinary Clinical Sciences College of Veterinary Medicine Purdue University West Lafayette, Indiana Arterial Thromboembolism Steven R. Hollingsworth, DVM, DACVO Associate Professor of Clinical Ophthalmology Department of Surgical and Radiological Sciences School of Veterinary Medicine University of California—Davis Davis, California Diseases of the Eyelids and Periocular Skin Fiona K. Hollinshead, BVSC (Hons), PhD, MACVS, DACT Adjunct Senior Lecturer Veterinary Science The University of Sydney Sydney, New South Wales, Australia Matamata Veterinary Services Matamata, New Zealand Endoscopic Transcervical Insemination David Holt, BVSc, DACVS Professor of Surgery Department of Clinical Studies School of Veterinary Medicine University of Pennsylvania Philadelphia, Pennsylvania Drainage Techniques for the Septic Abdomen Pleural Effusion Heidi A. Hottinger, DVM, DACVS Soft Tissue Surgeon & Practice Partner Surgery, Orthopedics & Neurology Gulf Coast Veterinary Specialists Houston, Texas Canine Biliary Mucocele Geraldine Briony Hunt, DVM Professor of Small Animal Soft Tissue Surgery Veterinary Surgical & Radiological Sciences University of California—Davis Davis, California Nasopharyngeal Disorders Kate Hurley, DVM, MPVM Director, Koret Shelter Medicine Program Center for Companion Animal Health University of California—Davis Davis, California Feline Upper Respiratory Tract Infection

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Toshiroh Iwasaki, DVM, PhD, DAICVD Professor Veterinary Internal Medicine Tokyo University of Agriculture & Technology Fuchu, Tokyo, Japan Interferons Hilary A. Jackson, BVM&S, DVD, DACVD, MRCVS Dermatology Referral Service Honorary Teacher University of Glasgow Veterinary School Glasgow, Scotland, United Kingdom Elimination Diets for Cutaneous Adverse Food Reactions: Principles in Therapy Karl E. Jandrey, DVM, MAS, DACVECC Assistant Professor of Small Animal Emergency & Critical Care Veterinary Surgical & Radiological Sciences University of California—Davis Davis, California William R. Pritchard Veterinary Medical Teaching Hospital Davis, California Thromboelastography Albert E. Jergens, DVM, PhD, DACVIM Professor Veterinary Clinical Sciences Iowa State University Ames, Iowa Current Veterinary Therapy: Antibiotic Responsive Enteropathy Beth M. Johnson, DVM, DACVIM Clinical Assistant Professor of Medicine Department of Small Animal Clinical Sciences College of Veterinary Medicine The University of Tennessee Knoxville, Tennessee Canine Megaesophagus Eileen McGoey Johnson, BS, DVM, MS, PhD Associate Professor Department of Veterinary Pathobiology Oklahoma State University Stillwater, Oklahoma Hepatozoon americanum Infections Valerie Johnson, DVM, DACVECC T32 Fellowship Grant Trainee Microbiology, Immunology, and Pathology Veterinary Teaching Hospital Colorado State University Fort Collins, Colorado Management of Immune-Mediated Hemolytic Anemia in Dogs

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Contributors

Andrea N. Johnston, DVM, DACVIM Clinical Instructor Clinical Sciences College of Veterinary Medicine Cornell University Ithaca, New York Portal Vein Hypoplasia (Microvascular Dysplasia) Debra A. Kamstock, DVM, PhD, DACVP Chief Pathologist and Director KamPath Diagnostics & Investigation Fort Collins, Colorado Faculty Affiliate College of Veterinary Medicine and Biomedical Sciences Colorado State University Fort Collins, Colorado Tumor Biopsy and Specimen Submission Shinichi Kanazono, DVM Veterinary Medicine and Surgery College of Veterinary Medicine University of Missouri Columbia, Missouri Canine Degenerative Myelopathy Margo Karriker, PharmD, FSVHP Clinical Pharmacist University of California Veterinary Medical Center—San Diego San Diego, California University of California—Davis Davis, California Chemotherapeutic Drug Handling and Safety Aarti Kathrani, BVetMed (Hons), PhD, MRCVS Resident Small Animal Internal Medicine Clinical Sciences Cornell University Ithaca, New York Inflammatory Bowel Disease Linda K. Kauffman, BS, DVM Clinician Veterinary Clinical Sciences Iowa State University Ames, Iowa Pregnancy Loss in the Bitch and Queen Bruce W. Keene, DVM, MSc, DACVIM (Cardiology) Professor Department of Clinical Sciences North Carolina State University Raleigh, North Carolina Drugs for Treatment of Heart Failure in Dogs Management of Heart Failure in Dogs

Charlotte B. Keller, Dr.Med.Vet., DACVO, DECVO West Coast Veterinary Eye Specialists New Westminster, British Columbia, Canada Epiphora Robert Allen Kennis, DVM, MS, DACVD Associate Professor Department of Clinical Sciences Auburn University Auburn, Alabama Bilaterally Symmetric Alopecia in Dogs Occult Hyperadrenocorticism: Is It Real? Flea Control in Flea Allergy Dermatitis Michael S. Kent, DVM, MAS, DACVIM (Medical Oncology), DACVR (Radiation Oncology) Associate Professor Surgical and Radiological Sciences School of Veterinary Medicine University of California—Davis Davis, California Oral Tumors Marie E. Kerl, DVM, MPH, DACVIM (SAIM), DACVECC Associate Teaching Professor Veterinary Medicine and Surgery University of Missouri Columbia, Missouri Recognition and Prevention of HospitalAcquired Acute Kidney Injury Peter P. Kintzer, DVM, DACVIM Medical Affairs Manager IDEXX Laboratories Westbrook, Maine Canine Hypoadrenocorticism Differential Diagnosis of Hyperkalemia and Hyponatremia in Dogs and Cats Rebecca Kirby, DVM, DACVIM, DACVECC Animal Emergency Center Glendale, Wisconsin Colloid Fluid Therapy Disseminated Intravascular Coagulation Claudia A. Kirk, DVM, PhD, DACVN, DACVIM (SAIM) Professor and Head Department of Small Animal Clinical Sciences College of Veterinary Medicine The University of Tennessee Knoxville, Tennessee Obesity Deborah W. Knapp, DVM Dolores L. McCall Professor of Comparative Oncology Veterinary Clinical Sciences Purdue University West Lafayette, Indiana Urinary Bladder Cancer

Hans S. Kooistra, DVM, PhD, DECVIM-CA Department of Clinical Sciences of Companion Animals Faculty of Veterinary Medicine Universiteit Utrecht Utrecht, The Netherlands Ectopic ACTH Syndrome and FoodDependent Hypercortisolism in Dogs Peter Hendrik Kook, Dr.Med.Vet., DACVIM, DECVIM Department for Small Animals Clinic for Small Animal Internal Medicine University of Zurich Zurich, Switzerland Gastroesophageal Reflux Bruce G. Kornreich, DVM, PhD, DACVIM (Cardiology) Associate Director for Education and Outreach Cornell Feline Health Center Cardiologist Department of Clinical Sciences College of Veterinary Medicine Cornell University Ithaca, New York Bradyarrhythmias Marc S. Kraus, DVM, DACVIM (Cardiology, Internal Medicine) Senior Lecturer Department of Clinical Sciences College of Veterinary Medicine Cornell University Ithaca, New York Syncope Annemarie T. Kristensen, DVM, PhD, DACVIM-SA, DECVIM-CA (Oncology) Professor, Section Head Internal Medicine and Clinical Pathology Department of Veterinary Clinical and Animal Sciences Faculty of Health and Medical Sciences University of Copenhagen Copenhagen, Denmark Hypercoagulable States Ned F. Kuehn, DVM, MS, DACVIM (SAIM) Chief of Internal Medicine Michigan Veterinary Specialists Southfield, Michigan Rhinitis in Dogs Kate S. KuKanich, DVM, PhD, DACVIM (Internal Medicine) Assistant Professor Department of Clinical Sciences Kansas State University Manhattan, Kansas Surveillance for Asymptomatic and Hospital-Acquired Urinary Tract Infection

Contributors Kenneth W. Kwochka, DVM, DACVD Veterinary Manager Health and Wellness Bayer HealthCare Animal Health Shawnee Mission, Kansas Topical Therapy for Infectious Diseases Mary Anna Labato, DVM, DACVIM (SAIM) Clinical Professor Clinical Sciences Cummings School of Veterinary Medicine Tufts University North Grafton, Massachusetts Medical Management of Nephroliths and Ureteroliths Calcium Oxalate Urolithiasis

Justine A. Lee, DVM, DACVECC, DABT Associate Director of Veterinary Services Pet Poison Helpline, a Division of SafetyCall International Minneapolis, Minnesota Intravenous Lipid Emulsion Therapy Michael S. Leib, DVM, MS C.R. Roberts Professor Small Animal Clinical Sciences Virginia-Maryland Regional College of Veterinary Medicine Virginia Tech Blacksburg, Virginia Gastric Helicobacter spp. and Chronic Vomiting in Dogs

Susan E. Lana, DVM, MS, DACVIM (Oncology) Associate Professor Clinical Sciences Colorado State University Fort Collins, Colorado Lymphocytosis in Dogs and Cats

Jonathan M. Levine, DVM, DACVIM (Neurology) Assistant Professor Neurology/Neurosurgery Small Animal Clinical Sciences Texas A&M University College Station, Texas Canine Intervertebral Disk Herniation

Cathy E. Langston, DVM, DACVIM (SAIM) Staff Veterinarian Nephrology, Urology, and Dialysis Animal Medical Center New York, New York Recognition and Prevention of HospitalAcquired Acute Kidney Injury

Christine C. Lim, DVM, DACVO Assistant Clinical Professor Department of Veterinary Clinical Sciences College of Veterinary Medicine University of Minnesota St. Paul, Minnesota Tear Film Disorders of Cats

Susan M. LaRue, DVM, PhD, DACVS, DACVR (Radiation Oncology) Professor Environmental and Radiological Health Sciences James L. Voss Veterinary Teaching Hospital and the Animal Cancer Center Colorado State University Fort Collins, Colorado Advances in Radiation Therapy for Nasal Tumors

Julius M. Liptak, BVSc, MVetClinStud, FACVSc, DACVS, DECVS Adjunct Professor University of Guelph Guelph, Ontario, Canada Adjunct Professor St. Matthews University Grand Cayman, Cayman Islands Specialist Small Animal Surgeon Alta Vista Animal Hospital Ottawa, Ontario, Canada Soft Tissue Sarcomas

James A. Lavely, DVM, DACVIM Neurology Neurology and Neurosurgery VCA Animal Care Center Rohnert Park, California Priapism in Dogs Eric C. Ledbetter, DVM, DACVO Robert Hovey Udall Assistant Professor of Ophthalmology Clinical Sciences College of Veterinary Medicine Cornell University Ithaca, New York Canine Conjunctivitis

Susan E. Little, DVM, PhD, DACVM (Parasitology) Regents Professor and Chair Veterinary Pathobiology Center for Veterinary Health Sciences Oklahoma State University Stillwater, Oklahoma Hepatozoon americanum Infections Meryl P. Littman, VMD, DACVIM Professor of Medicine Clinical Studies School of Veterinary Medicine University of Pennsylvania Philadelphia, Pennsylvania Borreliosis

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Remo Lobetti, BVSc, MMeVet (Med), PhD, DECVIM Doctor Bryanston Veterinary Hospital Bryanston, South Africa Pneumocystosis Dawn Logas, DVM, DACVD Owner/Staff Dermatologist Veterinary Dermatology Center Maitland, Florida Ear-Flushing Techniques Cheryl A. London, DVM, PhD, ACVIM (Oncology) Associate Professor College of Veterinary Biosciences The Ohio State University Columbus, Ohio Drug Update: Toceranib Catherine A. Loughin, DVM, DACVS, DACCT Staff Surgeon Department of Surgery Long Island Veterinary Specialists Plainview, New York Craniocervical Junction Abnormalities in Dogs Diagnosis and Treatment of Degenerative Lumbosacral Stenosis Virginia Luis Fuentes, MA, VetMB, PhD, CertVR, DVC, MRCVS, DACVIM, DECVIM-CA (Cardiology) Professor of Veterinary Cardiology Department of Veterinary Clinical Sciences and Services The Royal Veterinary College Hatfield, Hertfordshire, United Kingdom Feline Myocardial Disease Jody P. Lulich Professor Co-Director Minnesota Urolith Center University of Minnesota St. Paul, Minnesota Canine Urate Urolithiasis Laser Lithotripsy for Uroliths Katharine F. Lunn, BVMs, MS, PhD, MRCVS, DACVIM Associate Professor Clinical Sciences North Carolina State University Raleigh, North Carolina Leptospirosis John M. MacDonald, MEd, DVM, DACVD Professor of Dermatology Small Animal Hospital Department of Clinical Sciences Auburn University Auburn, Alabama Acral Lick Dermatitis

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Contributors

Kristin A. MacDonald, DVM, PhD, DACVIM (Cardiology) Veterinary Cardiologist VCA—Animal Care Center of Sonoma County Rohnert Park, California Infective Endocarditis Catriona M. MacPhail, DVM, PhD Associate Professor Department of Clinical Sciences College of Veterinary Medicine and Biomedical Sciences Colorado State University Fort Collins, Colorado Laryngeal Diseases Dennis W. Macy, DVM, MS Professor Emeritus Clinical Sciences College of Veterinary Medicine and Biomedical Sciences Colorado State University Fort Collins, Colorado Chief of Medical Oncology Department of Oncology Desert Veterinary Specialist Palm Desert, California Owner Cancer Care Specialist West Flamingo Animal Hospital Las Vegas, Nevada Update on Vaccine-Associated Adverse Effects in Cats David J. Maggs, BVSc, DACVO Professor Department of Surgical and Radiological Sciences University of California—Davis Davis, California Pearls of the Ophthalmic Examination Herbert W. Maisenbacher III, VMD, DACVIM (Cardiology) Clinical Assistant Professor Small Animal Clinical Sciences College of Veterinary Medicine University of Florida Gainesville, Florida Dilated Cardiomyopathy in Dogs Pulmonic Stenosis Giovanni Majolino, DVM Specialist in Small Animal Diseases Reproduction Clinic Majolino-Ranieri Collecchio (Parma), Italy Aspermia/Oligospermia Caused by Retrograde Ejaculation in Dogs

Richard Malik, DVSc, DipVetAn, MVetClinStud, PhD, FASM, FACVSc Adjunct Professor School of Animal & Veterinary Sciences Charles Sturt University Wagga Wagga, New South Wales, Australia Senior Staff Specialist Double Bay Veterinary Clinic Sydney, New South Wales, Australia Valentine Charlton Veterinary Specialist Centre for Veterinary Education University of Sydney Sydney, New South Wales, Australia Nontuberculous Cutaneous Granulomas in Dogs and Cats (Canine Leproid Granuloma and Feline Leprosy Syndrome)

Julie M. Martin, DVM, MS, DACVIM (Cardiology) Veterinary Referral Center of Colorado Rocky Mountain Veterinary Cardiology Englewood, Colorado Cardioversion

Alison C. Manchester, BS Veterinary Student Research Assistant College of Veterinary Medicine Cornell University Ithaca, New York Canine Colitis

Karol A. Mathews, DVM, DVSc, DACVECC Professor Emerita Clinical Studies Ontario Veterinary College University of Guelph Guelph, Ontario, Canada Gastric Dilation-Volvulus

Dominic J. Marino, DVM, DACVS, DACCT, CCRP Long Island Veterinary Specialists Plainview, New York Craniocervical Junction Abnormalities in Dogs Jessica E. Markovich, DVM, DACVIM Department of Clinical Sciences Tufts Cummings School of Veterinary Medicine North Grafton, Massachusetts Internal Medicine and Clinical Nutrition VCA Emergency Animal Hospital & Referral Center San Diego, California Medical Management of Nephroliths and Ureteroliths Stanley L. Marks, BVSc, PhD, DACVIM (Internal Medicine, Oncology), DACVN Professor Department of Medicine and Epidemiology School of Veterinary Medicine University of California—Davis Davis, California Oropharyngeal Dysphagia Rosanna Marsella, DVM, DACVD Professor Small Animal Clinical Sciences University of Florida Gainesville, Florida Pentoxifylline

Linda G. Martin, DVM, MS, DACVECC Associate Professor Critical Care Medicine Department of Veterinary Clinical Sciences Washington State University Pullman, Washington Approach to Critical Illness–Related Corticosteroid Insufficiency Approach to Hypomagnesemia and Hypokalemia

Elizabeth A. Mauldin, DVM, DACVP, DACVD Associate Professor of Dermatopathology, CE Department of Pathobiology School of Veterinary Medicine University of Pennsylvania Philadelphia, Pennsylvania Primary Cornification Disorders in Dogs Glenna E. Mauldin, DVM, MS Western Veterinary Cancer Centre Western Veterinary Specialist and Emergency Centre Calgary, Alberta, Canada Nutritional Support of the Cancer Patient Dianne I. Mawby, DVM, MVSc, DACVIM Clinical Associate Professor Department of Small Animal Clinical Sciences College of Veterinary Medicine The University of Tennessee Knoxville, Tennessee Top Ten Urinary Consult Questions

Contributors Robert J. McCarthy, DVM, MS, DACVS Clinical Associate Professor Veterinary Clinical Sciences Tufts Cummings School of Veterinary Medicine North Grafton, Massachusetts Tufts Foster Hospital Cummings School of Veterinary Medicine North Grafton, Massachusetts Owner Veterinary Surgery of Central Massachusetts Grafton, Massachusetts Emergency Management of Open Fractures Ovarian Remnant Syndrome in Small Animals Mary A. McLoughlin, DVM, MS, DACVS Associate Professor Veterinary Clinical Sciences Small Animal Surgery College of Veterinary Medicine Veterinary Medical Center The Ohio State University Columbus, Ohio Urinary Incontinence: Treatment with Injectable Bulking Agents Erick A. Mears, DVM, DACVIM Medical Director BluePearl Veterinary Partners Specialty & Emergency Medicine for Pets Tampa, Florida Canine Megaesophagus Karelle A. Meleo, DVM, ACVIM, ACVR Chief Oncologist Animal Cancer Specialists Seattle, Washington Treatment of Insulinoma in Dogs, Cats, and Ferrets Colleen L. Mendelsohn, DVM, DACVD Animal Dermatology Clinic Tustin, California Topical Antimicrobials for Otitis Stacy D. Meola, DVM, MS ECC Resident Emergency Wheat Ridge Veterinary Specialists Wheat Ridge, Colorado Emergency Wound Management and Vacuum-Assisted Wound Closure Kathryn M. Meurs, DVM, PhD Professor Department of Clinical Sciences College of Veterinary Medicine North Carolina State University Raleigh, North Carolina Arrhythmogenic Right Ventricular Cardiomyopathy

Vicki N. Meyers-Wallen, VMD, PhD, DACT Associate Professor Baker Institute for Animal Health Cornell University Ithaca, New York Inherited Disorders of the Reproductive Tract in Dogs and Cats Matthew W. Miller, DVM, MS, DACVIM (Cardiology) Professor of Cardiology Small Animal Veterinary Clinical Sciences Senior Research Scientist Texas A&M Institute for Preclinical Studies Charter Fellow Michael E. DeBakey Institute Texas A&M University College Station, Texas Canine Heartworm Disease Patent Ductus Arteriosus Darryl L. Millis, MS, DVM, DACVS, CCRP Associate Professor of Orthopedic Surgery Department of Small Animal Clinical Sciences College of Veterinary Medicine The University of Tennessee Knoxville, Tennessee Physical Therapy and Rehabilitation of Neurologic Patients Leah Ann Mitchell, PhD Research Scientist Department of Clinical Sciences Colorado State University Fort Collins, Colorado Cancer Immunotherapy N. Sydney Moïse, DVM, MS Professor of Medicine (Cardiology) Clinical Sciences College of Veterinary Medicine Cornell University Ithaca, New York Bradyarrhythmias Supraventricular Tachyarrhythmias in Dogs Eric Monnet, DVM, PhD, DACVS, DECVS Professor Clinical Sciences Colorado State University Fort Collins, Colorado Laryngeal Diseases William E. Monroe, DVM, MS, DACVIM (SAIM) Professor, Small Animal Clinical Sciences Department of Small Animal Clinical Sciences Virginia-Maryland Regional College of Veterinary Medicine Virginia Tech Blacksburg, Virginia Canine Diabetes Mellitus

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Hernán J. Montilla, DVM. Assistant Professor Clinical Science Clinical Instructor Theriogenology Veterinary Teaching Hospital Oregon State University Corvallis, Oregon Methods for Diagnosing Diseases of the Female Reproductive Tract Erin Mooney, BVSc, DACVECC Clinical Tutor Department of Emergency and Critical Care University of Melbourne Werribee, Victoria, Australia Pneumothorax Antony S. Moore, BVSc, MVSc, DACVIM (Oncology) Co-Director Veterinary Oncology Consultants Wauchope, New South Wales, Australia Consultant Animal Referral Hospital Homebush, New South Wales, Australia Malignant Effusions George E. Moore, DVM, MS, PhD, DACVIM (SAIM), DACVPM (Epi) Professor School of Veterinary Medicine Comparative Pathobiology Purdue University West Lafayette, Indiana Vaccine-Associated Adverse Effects in Dogs Adam Mordecai, DVM, MS, DACVIM Veterinary Medical Referral Service Veterinary Specialty Center Buffalo Grove, Illinois Rational Use of Glucocorticoids in Infectious Disease Karen A. Moriello, DVM, DACVD Professor of Dermatology American College of Veterinary Dermatology Department of Medical Sciences University of Wisconsin—Madison Madison, Wisconsin Treatment of Dermatophytosis Dermatophytosis: Investigating an Outbreak in a Multicat Environment Daniel O. Morris, DVM, MPH Associate Professor of Dermatology Clinical Studies School of Veterinary Medicine University of Pennsylvania Philadelphia, Pennsylvania Malassezia Infections

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Contributors

Ralf S. Mueller, Dr.Med.Vet., Dr.habil., DACVD, Fellow ANZCVSc, DECVD Professor of Veterinary Dermatology Center of Clinical Veterinary Medicine Chief of Dermatology and Allergy Center of Clinical Veterinary Medicine Ludwig Maximilian University Munich Munich, Germany Canine Demodicosis

Jennifer A. Neel, DVM, DACVP (Clinical) Assistant Professor in Veterinary Clinical Pathology Department of Population Health and Pathobiology College of Veterinary Medicine North Carolina State University Raleigh, North Carolina Thrombocytopenia

Suzanne Murphy, BVM&S, MSc (Clin Onc), DECVIM-CA (Onc), MRCVS Head of Hospital Centre for Small Animal Studies Animal Health Studies Lanwades Park, Kentford, Suffolk, United Kingdom Thyroid Tumors

Reto Neiger, Dr.med.vet., PhD, DECVIM-CA, DACVIM Professor for Small Animal Internal Medicine Justus-Liebig-Universtat-Giessen Small Animal Clinic Giessen, Germany Canine Hyperadrenocorticism Therapy Gastric Ulceration

Russell Muse, DVM, DACVD Animal Dermatology Clinic Tustin, California Diseases of the Anal Sac Anthony J. Mutsaers, DVM, PhD, DACVIM (Oncology) Assistant Professor Department of Clinical Studies Department of Biomedical Sciences Ontario Veterinary College University of Guelph Guelph, Ontario, Canada Metronomic Chemotherapy Kathern E. Myrna, MS, DVM, DACVO Assistant Professor Small Animal Medicine and Surgery University of Georgia Athens, Georgia Feline Retinopathies Masahiko Nagata, DVM, PhD, DAICVD Director Dermatology Service Animal Specialist Center Chofu,Tokyo, Japan Canine Papillomaviruses Larry A. Nagode, DVM, MS, PhD Emeritus Associate Professor Veterinary Biosciences The Ohio State University Columbus, Ohio Treatment of Hypoparathyroidism Jill Narak, DVM, MS, DACVIM (Neurology) Assistant Professor, Neurology & Neurosurgery Department of Small Animal Clinical Sciences College of Veterinary Medicine The University of Tennessee Knoxville, Tennessee Treatment of Intracranial Tumors

O. Lynne Nelson, DVM, MS, DACVIM Associate Professor Veterinary Clinical Sciences Washington State University Pullman, Washington Pericardial Effusion Richard W. Nelson, DVM, DACVIM (Small Animal) Professor Department of Medicine and Epidemiology School of Veterinary Medicine University of California—Davis Davis, California Insulin Resistance Sandra Newbury, DVM Koret Shelter Medicine Program School of Veterinary Medicine University of California—Davis Davis, California Adjunct Assistant Professor Department of Pathobiology University of Wisconsin Madison, Wisconsin Dermatophytosis: Investigating an Outbreak in a Multicat Environment Sandra M. Nguyen, BVSc (Hons I) DACVIM (Oncology) Animal Referral Hospital Sydney, Australia Canine Ocular Neoplasia Feline Ocular Neoplasia Rhett Nichols, DVM, ACVIM The Animal Endocrine Clinic New York City, New York Internal Medicine Consultant Antech Diagnostics Irvine, California Clinical Use of the Vasopressin Analog Desmopressin for the Diagnosis and Treatment of Diabetes Insipidus

Stijn J.M. Niessen, DVM, PhD, DECVIM, PGCVetEd, FHEA, MRCVS Lecturer, Internal Medicine Veterinary Clinical Sciences The Royal Veterinary College North Mymms, Hertfordshire, United Kingdom Research Associate Diabetes Research Group Medical School Newcastle Newcastle-Upon-Tyne, Tyne and Wear, United Kingdom Feline Hypersomatotropism and Acromegaly Benjamin G. Nolan, DVM, PhD, DACVIM (SAIM) Staff Internist Internal Medicine Veterinary Specialty Center Middleton, Wisconsin Calcium Oxalate Urolithiasis Roberto E. Novo, DVM, MS, DACVS Veterinary Surgeon Columbia River Veterinary Specialists Vancouver, Washington Surgical Repair of Vaginal Anomalies in the Bitch Tim Nuttall, BSc, BVSc, CertVD, PhD, CBiol, MSB, MRCVS The Royal (Dick) School of Veterinary Studies The University of Edinburgh Easter Bush Veterinary Centre Roslin, United Kingdom Topical and Systemic Glucocorticoids for Otitis Frederick W. Oehme, DVM, Dr. Med. Vet, PhD Professor Emeritus Diagnostic Medicine/Pathobiology Kansas State University Manhattan, Kansas Urban Legends of Toxicology: Facts and Fiction Thierry Olivry, Dr Vet, PhD, DACVD, DECVD Professor of Immunodermatology Department of Clinical Sciences College of Veterinary Medicine North Carolina State University Raleigh, North Carolina Treatment Guidelines for Canine Atopic Dermatitis Carl A. Osborne, DVM, PhD, DACVIM Veterinary Clinical Sciences Department College of Veterinary Medicine University of Minnesota St. Paul, Minnesota Canine Urate Urolithiasis

Contributors Catherine A. Outerbridge, DVM, MVSc Associate Professor of Clinical Dermatology Department of Veterinary Medicine and Epidemiology William Pritchard Veterinary Medical Teaching Hospital Dermatology Service University of California—Davis Davis, California Diseases of the Eyelids and Periocular Skin Mark A. Oyama, DVM, DACVIM (Cardiology) Professor Department of Clinical Studies University of Pennsylvania Philadelphia, Pennsylvania Ventricular Arrhythmias in Dogs Bradyarrhythmias and Cardiac Pacing Philip Padrid, DVM Associate Professor of Medicine Department of Molecular Medicine University of Chicago Chicago, Illinois Associate Professor of Small Animal Medicine The Ohio State University Columbus, Ohio Regional Medical Director VCA/Antech Los Angeles, California Chronic Bronchitis and Asthma in Cats Lee E. Palmer, DVM Resident, Emergency and Critical Care Small Animal Clinical Sciences Auburn University Small Animal Teaching Hospital Auburn, Alabama Approach to Hypomagnesemia and Hypokalemia Lee Anne Myers Palmer, VMD Office of Surveillance and Compliance FDA Center for Veterinary Medicine Rockville, Maryland Reporting Adverse Events to the Food and Drug Administration—Center for Veterinary Medicine David L. Panciera, DVM, MS Anne Hunter Professor of Small Animal Medicine Department of Small Animal Clinical Sciences Virginia-Maryland Regional College of Veterinary Medicine Virginia Tech Blacksburg, Virginia Complications and Concurrent Conditions Associated with Hypothyroidism in Dogs

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Romain Pariaut, DVM, DACVIM (Cardiology), DECVIM-CA (Cardiology) Assistant Professor of Cardiology Veterinary Clinical Sciences Louisiana State University Baton Rouge, Louisiana Supraventricular Tachyarrhythmias in Dogs

Brenda Phillips, DVM, ACVIM (Oncology) Medical Oncologist Veterinary Specialty Hospital of San Diego San Diego, California Chemotherapeutic Drug Handling and Safety

Edward E. (Ned) Patterson, DVM, PhD, DAVIM Associate Professor Veterinary Clinical Sciences Veterinary Medical Center University of Minnesota St. Paul, Minnesota Methods and Availability of Tests for Hereditary Disorders of Dogs and Cats

Fred S. Pike, DVM, DACVS Clinical Associate Faculty Western University of Health Sciences College of Veterinary Medicine Pomona, California Staff Surgeon and Associate Medical Director Veterinary Specialty Hospital of San Diego San Diego, California Extrahepatic Biliary Tract Disease

Dominique Peeters, DVM, DECVIM-CA Associate Professor Companion Animals Clinical Sciences University of Liège Liège, Belgium Eosinophilic Pulmonary Diseases Simon M. Petersen-Jones, DVetMed, PhD, DVOphthal, DECVO, MRCVS Myers-Dunlap Endowed Chair in Canine Health Department of Small Animal Clinical Sciences Michigan State University East Lansing, Michigan Canine Retinopathies Mark E. Peterson, DVM, DACVIM Director Department of Endocrinology and Nuclear Medicine Animal Endocrine Clinic New York, New York Canine Hypoadrenocorticism Clinical Use of the Vasopressin Analog Desmopressin for the Diagnosis and Treatment of Diabetes Insipidus Differential Diagnosis of Hyperkalemia and Hyponatremia in Dogs and Cats Hyperadrenocorticism in Ferrets Radioiodine for Feline Hyperthyroidism Treatment of Insulinoma in Dogs, Cats, and Ferrets Michael E. Peterson, DVM, MS Staff Veterinarian Reid Veterinary Hospital Albany, Oregon Reproductive Toxicology and Teratogens

Lauren Riester Pinchbeck, DVM, MS, DACVD Veterinary Dermatologist and Partner Northeast Veterinary Dermatology Specialists Shelton, Connecticut New Haven, Connecticut Hopewell Junction, New York Norwalk, Connecticut Yonkers, New York White Plains, New York Systemic Glucocorticoids in Dermatology Simon R. Platt, BVM-S, MRCVS, DECVN, DACVIM (Neurology) Associate Professor Neurology and Neurosurgery Small Animal Medicine and Surgery College of Veterinary Medicine University of Georgia Athens, Georgia Vascular Disease of the Central Nervous System Michael Podell, MSc, DVM, DACVIM (Neurology) Owner Chicago Veterinary Neurology and Neurosurgery Group Chicago, Illinois Ototoxicity Cyrill Poncet, DVM, DECVS Head Department of Soft Tissue Surgery Fregis Hospital Arcueil, Paris, France Brachycephalic Airway Obstruction Syndrome

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Contributors

Robert H. Poppenga, DVM, PhD, DABVT Professor of Diagnostic Veterinary Toxicology California Animal Health and Food Safety Laboratory School of Veterinary Medicine University of California—Davis Davis, California Herbal Hazards Cynthia C. Powell, DVM, MS, DACVO Professor, Veterinary Ophthalmology Clinical Sciences Colorado State University Fort Collins, Colorado Feline Uveitis Pascal Prélaud, DV, DECVD Clinique Veterinaire Advetia Paris, France Treatment Guidelines for Canine Atopic Dermatitis Barrak M. Pressler, DVM, PhD, DACVIM Assistant Professor of Internal Medicine Veterinary Clinical Sciences The Ohio State University Columbus, Ohio Glomerular Disease and Nephrotic Syndrome Jessica M. Quimby, DVM, PhD, DACVIM (Internal Medicine) Clinical Instructor Clinical Sciences Colorado State University Fort Collins, Colorado Immunotherapy for Infectious Diseases Ian K. Ramsey, BVSc, PhD, DSAM, DECVIM-CA, MRCVS Professor of Small Animal Medicine School of Veterinary Medicine University of Glasgow Glasgow, Scotland, United Kingdom Canine Hyperadrenocorticism Therapy Jacquie S. Rand, BVSc, DVSc, MACVS, DACVIM Professor of Companion Animal Health Centre for Companion Animal Health, School of Veterinary Science University of Queensland St. Lucia, Queensland, Australia Feline Diabetes Mellitus Amy J. Rankin, DVM, MS, DACVO Assistant Professor Ophthalmology Clinical Sciences Kansas State University Manhattan, Kansas Feline Glaucoma

Kent R. Refsal, DVM, PhD Professor, Endocrine Section Diagnostic Center for Population and Animal Health Michigan State University Lansing, Michigan Feline Primary Hyperaldosteronism

Wayne S. Rosenkrantz, DVM, ACVD Owner/Partner Animal Dermatology Clinic Tustin, California Topical Therapy for Pruritus House Dust Mites and Their Control Pyotraumatic Dermatitis (“Hot Spots”)

Claudia E. Reusch, Dr. med.vet., DECVIM-CA Professor Clinic for Small Animal Internal Medicine Vetsuisse Faculty University of Zurich Zurich, Switzerland Diabetic Monitoring

Karen L. Rosenthal, DVM, MS Dean and Professor of Exotic Animal Medicine School of Veterinary Medicine St. Matthew’s University Grand Cayman, Cayman Islands Hyperadrenocorticism in Ferrets

Caryn A. Reynolds, DVM, DACVIM (Cardiology) Assistant Professor Department of Veterinary Clinical Sciences Louisiana State University Baton Rouge, Louisiana Ventricular Arrhythmias in Dogs Keith P. Richter, DVM Hospital Director and Staff Internist Internal Medicine Department Veterinary Specialty Hospital of San Diego San Diego, California Feline Gastrointestinal Lymphoma Extrahepatic Biliary Tract Disease Jyothi V. Robertson, DVM Shelter Medicine Consultant Koret Shelter Medicine Program School of Veterinary Medicine University of California—Davis Davis, California Owner-Principal Consultant JVR Shelter Strategies Belmont, California Feline Upper Respiratory Tract Infection Kenita S. Rogers, DVM, MS Associate Dean for Professional Programs & Biomedical Sciences College of Veterinary Medicine Professor of Oncology Small Animal Clinical Sciences Texas A&M University College Station, Texas Collection of Specimens for Cytology Stefano Romagnoli, DVM, MS, PhD, DECAR (European College of Animal Reproduction) Professor Clinical Veterinary Reproduction University of Padova Legnaro, Italy Aspermia/Oligospermia Caused by Retrograde Ejaculation in Dogs

Linda Ross, DVM, MS, DACVIM (SAIM) Associate Professor Clinical Sciences Tufts Cummings School of Veterinary Medicine North Grafton, Massachusetts Medical Management of Acute Kidney Injury Edmund J. Rosser Jr., DVM, DACVD Professor and Head of Dermatology Small Animal Clinical Sciences College of Veterinary Medicine Michigan State University East Lansing, Michigan Therapy for Sebaceous Adenitis Jan Rothuizen, DVM, PhD, DECVIM-CA Clinical Sciences of Companion Animals Faculty of Veterinary Medicine Universiteit Utrecht Utrecht, The Netherlands Copper-Associated Hepatitis Philip Roudebush, DVM, DACVIM Adjunct Professor Department of Clinical Studies College of Veterinary Medicine Kansas State University Manhattan, Kansas Flatulence Elizabeth A. Rozanski, DVM, DACVECC, DACVIM (SAIM) Associate Professor Clinical Sciences Tufts Cummings School of Veterinary Medicine North Grafton, Massachusetts Crystalloid Fluid Therapy Pneumothorax Craig G. Ruaux, BVSc (Hons), PhD, MANZCVSc, DACVIM (SAIM) Assistant Professor Small Animal Internal Medicine Veterinary Clinical Sciences Oregon State University Corvallis, Oregon Treatment of Canine Pancreatitis

Contributors Elke Rudloff, DVM, DACVECC Director of Education Animal Emergency Center and Specialty Services Glendale, Wisconsin President Veterinary Emergency Critical Care Society Colloid Fluid Therapy Disseminated Intravascular Coagulation Wilson K. Rumbeiha, BVM, PhD, DABVT, DABT Professor of Veterinary Toxicology Veterinary Diagnostics and Production Animal Medicine College of Veterinary Medicine Iowa State University Ames, Iowa Parasiticide Toxicoses: Avermectins Nephrotoxicants John E. Rush, DVM, MS Professor Clinical Sciences Tufts Cummings School of Veterinary Medicine North Grafton, Massachusetts Pacing in the ICU Setting Chronic Valvular Heart Disease in Dogs Marco Russo, DVM, PhD, MRCVS Senior Lecturer in Obstetrics and Diagnostic Reproductive Imaging Department of Veterinary Medicine and Animal Sciences University of Naples “Federico II” Naples, Italy Special Lecturer in Veterinary Diagnostic Imaging and Reproduction The School of Veterinary Medicine and Science The University of Nottingham Sutton Bonington Campus Sutton Bonington Leicestershire, England Breeding Management of the Bitch Roberto A. Santilli, DVM, PhD, DECVIM-CA (Cardiology) Chief Cardiology Division Clinica Veterinaria Malpensa Samarate, Varese, Italy Supraventricular Tachyarrhythmias in Dogs Kari Santoro-Beer, BS, DVM Resident Emergency and Critical Care Department of Clinical Studies Matthew J. Ryan Veterinary Hospital University of Pennsylvania Philadelphia, Pennsylvania Shock

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John S. Sapienza, DVM, DACVO Department Chief and Head Ophthalmology Long Island Veterinary Specialists Plainview, New York Canine Glaucoma

Bernard Séguin, DVM, MS, DACVS Associate Professor Animal Cancer Center Colorado State University Fort Collins, Colorado Oral Tumors

Ashley B. Saunders, DVM, DACVIM (Cardiology) Assistant Professor Department of Small Animal Clinical Sciences Texas A&M University College Station, Texas Patent Ductus Arteriosus

Rance K. Sellon, DVM, PhD, DACVIM (Small Animal Internal Medicine; Oncology) Associate Professor Veterinary Clinical Sciences Washington State University Pullman, Washington Rational Use of Glucocorticoids in Infectious Disease

Jimmy H. Saunders, DVM, PhD, DECVDI Professor, Doctor Department of Veterinary Medical Imaging and Small Animal Orthopaedics Ghent University Merelbeke, Belgium Imaging in Diagnosis of Endocrine Disorders Patricia A. Schenck, DVM, PhD Section Chief Endocrine Diagnostic Section Diagnostic Center for Population and Animal Health Michigan State University Lansing, Michigan Assistant Professor Pathobiology and Diagnostic Investigation Michigan State University Lansing, Michigan Feline Idiopathic Hypercalcemia Treatment of Hypoparathyroidism Karsten Eckhard Schober, DVM, PhD, DECVIM (CA) Associate Professor Veterinary Clinical Sciences Department College of Veterinary Medicine The Ohio State University Columbus, Ohio Feline Myocardial Disease Myocarditis J. Catharine R. Scott-Moncrieff, MA, Vet MB, MS Professor Veterinary Clinical Sciences Purdue University West Lafayette, Indiana Canine Hypothyroidism Nutritional Management of Feline Hyperthyroidism Davis M. Seelig, DVM, PhD Assistant Professor Department of Veterinary Clinical Sciences University of Minnesota St. Paul, Minnesota Plasma Cell Neoplasms

G. Diane Shelton, DVM, PhD, DACVIM (Internal Medicine) Professor Department of Pathology School of Medicine University of California—San Diego La Jolla, California Oropharyngeal Dysphagia Treatment of Autoimmune Myasthenia Gravis Treatment of Myopathies and Neuropathies Robert G. Sherding, DVM, DACVIM Professor Emeritus Department of Veterinary Clinical Sciences College of Veterinary Medicine The Ohio State University Columbus, Ohio Respiratory Parasites Traci A. Shreyer, MA Applied Animal Behaviorist-Program Specialist Veterinary Clinical Sciences and Veterinary Preventive Medicine College of Veterinary Medicine The Ohio State University Columbus, Ohio Multimodal Environmental Enrichment for Domestic Cats Deborah C. Silverstein, DVM, DACVECC Assistant Professor of Critical Care Clinical Studies University of Pennsylvania Ryan Veterinary Hospital Philadelphia, Pennsylvania Adjunct Professor Pharmacology Temple School of Pharmacy Philadelphia, Pennsylvania Shock

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Contributors

Kaitkanoke Sirinarumitr Associate Professor Department of Companion Animal Clinical Sciences Faculty of Veterinary Medicine Head of Small Animal Reproduction Clinic Vice Director Kasetsart University Teaching Hospital Kasetsart University Bangkhaen, Bangkok, Thailand Benign Prostatic Hypertrophy and Prostatitis in Dogs D. David Sisson, DVM, DACVIM-Cardiology Professor of Cardiovascular Medicine Department of Clinical Sciences Oregon State University Corvallis, Oregon Bradyarrhythmias and Cardiac Pacing Annette N. Smith, DVM, MS, DACVIM (Oncology & SAIM) Associate Professor Clinical Sciences Auburn University Auburn, Alabama Treatment of Intracranial Tumors Frances O. Smith, DVM, PhD, DACT Owner Smith Veterinary Hospital, Inc. Burnsville, Minnesota President Orthopedic Foundation for Animals, Inc. Columbia, Missouri Pyometra Patricia J. Smith, MS, DVM, PhD, DACVO Animal Eye Care Fremont, California Canine Retinal Detachment Ian Brett Spiegel, VMD, MHS, DACVD Chief of Dermatology and Allergy Veterinary Specialty and Emergency Center Levittown, Pennsylvania Chief of Dermatology and Allergy Animergy Raritan, New Jersey Chief of Dermatology and Allergy Jersey Shore Veterinary Emergency Service Lakewood, New Jersey Cutaneous Adverse Drug Reactions Jörg M. Steiner, Dr.Med.Vet., PhD, DACVIM, DECVIM-CA, AGAF Professor and Director Gastrointestinal Laboratory Department of Small Animal Clinical Sciences Texas A&M University College Station, Texas Laboratory Testing for the Exocrine Pancreas

Janice C. Steinschneider, MA, JD Supervisory Regulatory Counsel Center for Veterinary Medicine Office of Surveillance & Compliance Food and Drug Administration Rockville, Maryland Treatment of Animal Toxicoses: Regulatory Points to Consider Rebecca L. Stepien, DVM, MS Clinical Professor—Cardiology Department of Clinical Sciences School of Veterinary Medicine Staff Cardiologist Chief of Staff Small Animal Services University of Wisconsin Madison, Wisconsin Systemic Hypertension Rachel Sternberg, DVM, DACVIM (Oncology) Medical Oncologist VCA Arboretum View Animal Hospital Downers Grove, Illinois Plasma Cell Neoplasms Rachel A. Strohmeyer, DVM, MS Kingston, Washington Infectious Diseases Associated with Raw Meat Diets Beverly K. Sturges, DVM, DACVIM Radiological & Surgical Sciences University of California—Davis Davis, California Diagnosis and Treatment of Atlantoaxial Subluxation Jan S. Suchodolski, MedVet, DrMedVet, PhD Clinical Assistant Professor Small Animal Clinical Sciences Associate Director Gastrointestinal Laboratory College of Veterinary Medicine Texas A&M University College Station, Texas Probiotic Therapy Lauren Sullivan, DVM, MS, DACVECC Assistant Professor Clinical Sciences Colorado State University Fort Collins, Colorado Stabilization of the Patient with Respiratory Distress Critical Illness–Related Corticosteroid Insufficiency Transfusion Medicine: Best Practices Patricia A. Sura, MS. DVM, DACVS Staff Surgeon BluePearl Veterinary Partners Louisville, Kentucky Minilaparotomy-Assisted Cystoscopy for Urocystoliths

Jane E. Sykes, BVSc(Hons), PhD, DACVIM Professor Medicine & Epidemiology University of California—Davis Davis, California Canine Infectious Respiratory Disease Complex Systemic Antifungal Therapy Harriet M. Syme, BSc, BVM, PhD, DACVIM, DECVIM, MRCVS Senior Lecturer in Small Animal Internal Medicine Department of Veterinary Clinical Sciences The Royal Veterinary College North Mymms, Hatfield, Hertfordshire, United Kingdom Feline Hyperthyroidism and Renal Function Joseph Taboada, DVM, DACVIM Professor Small Animal Internal Medicine Associate Dean Student and Academic Affairs School of Veterinary Medicine Louisiana State University Baton Rouge, Louisiana Systemic Antifungal Therapy Lauren R. Talarico, DVM Neurology/Neurosurgery Resident Department of Clinical Sciences Cornell University Ithaca, New York Treatment of Noninfectious Inflammatory Diseases of the Central Nervous System Patricia Ann Talcott, MS, DVM, PhD, DABVT Professor, Director of Admissions Department of Integrative Physiology and Neuroscience Toxicology Section Head Washington Animal Disease Diagnostic Laboratory College of Veterinary Medicine Washington State University Pullman, Washington Insecticide Toxicoses Séverine Tasker, BSc, BVSc, PhD, DSAM, DECVIM-CA, PGCertHE, MRCVS Senior Lecturer in Small Animal Medicine School of Veterinary Sciences University of Bristol Bristol, North Somerset, United Kingdom Canine and Feline Hemotropic Mycoplasmosis

Contributors John H. Tegzes, MA, VMD, DABVT Professor, Toxicology Director, Year 1 Curriculum College of Veterinary Medicine Western University of Health Sciences Pomona, California Lawn and Garden Product Safety Vincent J. Thawley, VMD Resident in Emergency & Critical Care Clinical Studies Matthew J. Ryan Veterinary Hospital University of Pennsylvania Philadelphia, Pennsylvania Oxygen Therapy Alan P. Théon, Dr Med Vet, MS, PhD, DACR-RO Professor Radiology and Surgery School of Veterinary Medicine Oncology Service Chief Veterinary Medical Teaching Hospital University of California—Davis Davis, California Large Pituitary Tumors in Dogs with Pituitary-Dependent Hyperadrenocorticism Emily K. Thomas, BA, VetMB Emergency and Critical Care Resident Matthew J. Ryan Veterinary Hospital University of Pennsylvania Philadelphia, Pennsylvania Acute Respiratory Distress Syndrome Randall C. Thomas, DVM, DACVD Veterinary Dermatologist Southeast Veterinary Dermatology & Ear Clinic Mt. Pleasant, South Carolina Treatment of Ectoparasitoses William B. Thomas, DVM, MS, DACVIM (Neurology) Associate Professor, Neurology and Neurosurgery Department of Small Animal Clinical Sciences College of Veterinary Medicine The University of Tennessee Knoxville, Tennessee Congenital Hydrocephalus Justin D. Thomason, DVM, DACVIM (Internal Medicine) Assistant Professor of Cardiology Department of Clinical Sciences Veterinary Health Center Kansas State University Manhattan, Kansas Syncope Elizabeth J. Thomovsky, DVM Clinical Assistant Professor Veterinary Clinical Sciences Purdue University West Lafayette, Indiana Drug Incompatibilities and Drug-Drug Interactions in the ICU Patient

Karen M. Tobias, DVM, MS, DACVS Professor, Small Animal Surgery Department of Small Animal Clinical Sciences College of Veterinary Medicine The University of Tennessee Knoxville, Tennessee Portosystemic Shunts Lauren A. Trepanier, DVM, PhD, DACVIM, DACVCP Professor and Director of Clinician Scientist Training Department of Medical Sciences University of Wisconsin—Madison Madison, Wisconsin Medical Treatment of Feline Hyperthyroidism Drug-Associated Liver Disease Gregory C. Troy, DVM, MS, DACVIM Professor Dr. and Mrs. Dorsey Mahin Endowed Professor Department of Small Animal Clinical Sciences Virginia-Maryland Regional College of Veterinary Medicine Virginia Tech Blacksburg, Virginia American Leishmaniasis Michelle M. Turek, DVM, DACVIM (Oncology), DACVR (Radiation Oncology) Assistant Professor Radiation Oncology Veterinary Anatomy and Radiology College of Veterinary Medicine University of Georgia Athens, Georgia Perineal Tumors Shelly L. Vaden, DVM, PhD, DACVIM Professor, Internal Medicine Department of Clinical Sciences College of Veterinary Medicine North Carolina State University Raleigh, North Carolina Glomerular Disease and Nephrotic Syndrome David M. Vail, DVM, DACVIM (Oncology) Professor of Oncology Barbara A. Suran Chair in Comparative Oncology School of Veterinary Medicine University of Wisconsin Madison, Wisconsin Rescue Therapy for Canine Lymphoma Anticancer Drugs: New Drugs Alexandra van der Woerdt, DVM, MS, DACVO, DECVO Staff Ophthalmologist The Animal Medical Center New York, New York Canine Uveitis

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Linda M. Vap, DVM, DACVP Instructor Microbiology, Immunology and Pathology Colorado State University Fort Collins, Colorado Quality Control for the In-Clinic Laboratory Julia K. Veir, DVM, PhD, DACVIM (SAIM) Assistant Professor Clinical Sciences Colorado State University Fort Collins, Colorado Canine Parvoviral Enteritis Carlo Vitale, DVM, ACVD VCA—San Francisco Veterinary Specialists San Francisco, California Methicillin-Resistant Staphylococcal Infections Katrina R. Viviano, DVM, PhD, DACVIM (Internal Medicine) Clinical Assistant Professor Department of Medical Sciences University of Wisconsin Madison, Wisconsin Drug Incompatibilities and Drug-Drug Interactions in the ICU Patient Petra A. Volmer, DVM, MS, DABVT, DABT Manager of Pharmacovigilance Ceva Animal Health Lenexa, Kansas Human Drugs of Abuse and Central Nervous System Stimulants Lori S. Waddell, DVM, DACVECC Adjunct Assistant Professor Critical Care Clinical Studies School of Veterinary Medicine University of Pennsylvania Philadelphia, Pennsylvania Acute Respiratory Distress Syndrome Pleural Effusion Andrea Wang, MA, DVM, DACVIM Small Animal Internal Medicine Resident Veterinary Teaching Hospital University of Georgia Athens, Georgia Pet-Associated Illness Wendy A. Ware, DVM, MS, DACVIM (Cardiology) Professor Departments of Veterinary Clinical Sciences and Biomedical Sciences Staff Cardiologist Lloyd Veterinary Medical Center Iowa State University Ames, Iowa Pericardial Effusion

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Contributors

Erin N. Warren, DVM, MS Small Animal Intern Department of Small Animal Clinical Sciences College of Veterinary Medicine The University of Tennessee Knoxville, Tennessee Treatment of Intracranial Tumors

Chick Weisse, VMD, DACVS Director of Interventional Radiology Staff Surgeon Interventional Radiology/Surgery Animal Medical Center New York, New York Interventional Oncology Tracheal Collapse Interventional Strategies for Urinary Disease

A.D.J. Watson, BVSc, PhD Department of Veterinary Clinical Sciences The University of Sydney Glebe, New South Wales, Australia Chronic Kidney Disease: International Renal Interest Society Staging and Management

Sharon L. Welch, DABVT, DABT, DVM Veterinarian, Toxicologist Pet Poison Helpline Bloomington, Minnesota Toxin Exposures in Small Animals

Penny J. Watson, MA, VetMD, CertVR, DSAM, DECVIM, MRCVS Senior Lecturer in Small Animal Medicine Department of Veterinary Medicine University of Cambridge Cambridge, United Kingdom Chronic Hepatitis Therapy

Elias Westermarck, DVM, PhD, DECVIM Professor Emeritus of Medicine Department of Equine and Small Animal Medicine University of Helsinki Helsinki, Finland Tylosin-Responsive Diarrhea

Craig B. Webb, PhD, DVM Associate Professor Clinical Sciences Colorado State University Fort Collins, Colorado Probiotic Therapy

Jason Wheeler, DVM, MS, DACVS Small Animal Surgeon Virginia Veterinary Specialists Charlottesville, Virginia Emergency Wound Management and Vacuum-Assisted Wound Closure

Cynthia R.L. Webster, DVM, DACVIM (Internal Medicine) Professor Clinical Science Tufts Cummings School of Veterinary Medicine Grafton, Massachusetts Diagnostic Approach to Hepatobiliary Disease Portal Vein Hypoplasia (Microvascular Dysplasia)

Richard Wheeler, DVM, DACT Small Animal Reproduction Veterinary Teaching Hospital College of Veterinary Medicine and Biomedical Sciences Colorado State University Fort Collins, Colorado Vulvar Discharge

Glade Weiser, DVM, DACVP Professor, Special Appointment Department of Microbiology, Immunology & Pathology Colorado State University Fort Collins, Colorado Quality Control for the In-Clinic Laboratory Douglas J. Weiss, DVM, PhD, DACVP Emeritus Professor Department of Veterinary and Biomedical Sciences University of Minnesota St. Paul, Minnesota Nonregenerative Anemias

Maria Wiberg, DVM, PhD Clinical Teacher Department of Equine and Small Animal Medicine Faculty of Veterinary Medicine University of Helsinki Helsinki, Finland Exocrine Pancreatic Insufficiency in Dogs K. Tomo Wiggans, DVM Resident, Comparative Ophthalmology Department of Surgical and Radiological Sciences University of California—Davis Davis, California Ocular Emergencies Bo Wiinberg, DVM, PhD Head of Translational Haemophilia Pharmacology Biopharmaceuticals Research Unit Novo Nordisk A/S Maaloev, Denmark Hypercoagulable States

David A. Wilkie, DVM, MS, ACVO Professor Veterinary Clinical Sciences The Ohio State University Columbus, Ohio Disorders of the Lens Michael D. Willard, DVM, MS, DACVIM Professor Department of Small Animal Clinical Sciences Texas A&M University College Station, Texas Esophagitis Marion S. Wilson, BVMS, MVSc, MRCVS Director TCI Ltd Feilding, New Zealand Endoscopic Transcervical Insemination Tina Wismer, DVM, DABVT, DABT Medical Director ASPCA Animal Poison Control Center Urbana, Illinois ASPCA Animal Poison Control Center Toxin Exposures for Pets Angela Lusby Witzel, DVM, PhD Assistant Clinical Professor Department of Small Animal Clinical Sciences College of Veterinary Medicine The University of Tennessee Knoxville, Tennessee Obesity J. Paul Woods, DVM, MS, DACVIM (Internal Medicine, Oncology) CVMA Certificate of Specialization in Small Animal Internal Medicine Professor Department of Clinical Studies Small Animal Medicine & Oncology Ontario Veterinary College Health Sciences Centre University of Guelph Guelph, Ontario, Canada Small Animal Medicine Thames Valley Veterinary Services The Lawson Research Institute London, Ontario, Canada Feline Cytauxzoonosis Paul A. Worhunsky, DVM Veterinary Resident Clinical Sciences College of Veterinary Medicine Cornell University Ithaca, New York Sage Centers for Veterinary Speciality and Emergency Care Campbell, California Cobalamin Deficiency in Cats

Contributors Panagiotis G. Xenoulis, DVM, Dr.Med.Vet., PhD Gastrointestinal Laboratory Department of Small Animal Clinical Sciences Texas A&M University College Station, Texas Approach to Canine Hyperlipidemia

Vicky K. Yang, DVM, PhD Cardiology Resident Tufts Cummings School of Veterinary Medicine North Grafton, Massachusetts Pacing in the ICU Setting

Debra L. Zoran, DVM, PhD, DACVIM-SAIM Associate Professor and Chief of Medicine Small Animal Clinical Sciences Texas A&M University College Station, Texas Diet and Diabetes Protein-Losing Enteropathies

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To my Dad, Peter J. Bonagura, with admiration and gratitude. JDB

To my wife Liz and my son Ryan for their love and support and to all the animals that make the veterinary profession so worthwhile. DCT

Preface

(Photograph provided by Cornell University.) Robert W. Kirk, DVM, 1922-2011 This 15th volume of Current Veterinary Therapy continues the tradition of presenting practicing veterinarians and students with concise chapters focused on the treatment of medical disorders of dogs and cats. This is the first volume to be published since the passing of Dr. Robert W. Kirk, who founded and edited new editions of this series for nearly three decades. Bob Kirk was a giant in the profession, a man with a remarkable impact on veterinary education and clinical practice. In introducing Current Veterinary Therapy XV, I believe it is appropriate to both remember Dr. Kirk and to consider his intent for creating this book. Therefore this preface will be a bit more personal than usual, as I try to express my admiration for Dr. Kirk and the importance of this clinician-educator to our profession. To that end I will quote Dr. Donald F. Smith, Dean Emeritus of the College of Veterinary Medicine at Cornell University, who has written about Bob’s legacy, and also will include some excerpts from the Preface of Dr. Kirk’s first edition of Current Veterinary Therapy (published as CVT 1964-1965 [i.e., before the Roman numerals were added]). Dr. Smith wrote in his tribute: A 1946 graduate of Cornell, Dr. Kirk was one of the most accomplished clinical veterinarians, authors and educators of the 20th century. His knowledge of general small animal medicine was established through several years in private practice, then honed in his three decades of advanced medical practice, including dermatology, at Cornell University. When he retired in 1985, he was one of the most decorated and widely-known small animal veterinarians in the world. Among his many accomplishments was his famous book, Current Veterinary Therapy, which he edited by himself through its first ten editions. This series of books has sold more than a quarter of a million copies and has been translated into many languages. As a student, I studied from the fourth edition that my friends and I simply knew as Kirk. A native of Stamford, Connecticut, Dr. Kirk came to Cornell in 1943 intent on becoming a large animal veterinarian. The

draw of pet medicine intrigued him, though, and he worked in mixed practices as well as the ASPCA in New York City after graduation. Kirk was recruited in 1952 to .…(help) usher in a new age of pet health care at Cornell. He insisted on the highest quality of medicine but always with a view to practicality and service. Dr. Kirk had an enormous impact on the development of small animal medicine. He was a founding member of the American College of Veterinary Internal Medicine, and also the specialty of veterinary dermatology. His students and residents populated some of the most important university hospitals and private practices in the country. I never had the opportunity to practice alongside Dr. Kirk—he was a faculty member at Cornell, while I have spent most of my career at Ohio State. Nevertheless, his influence on me as a student, trainee, and faculty member was significant. As Dr. Smith remarked, “Dr. Kirk was both professor and practitioner,” and Bob’s ability to teach, publish, and demonstrate practical skills in the clinical arena represented the characteristics I greatly admired in him and in my other mentors. My association with Bob Kirk was actually longer than he ever realized! I spent much of the summer between my second and third years of veterinary school “with Dr. Kirk,” highlighting each chapter in CVT IV (the orange one, for those who know the editions by their colors). I studied Volume V (the yellow cover) and the gigantic sixth volume (with that slightly unnatural green cover) during my residencies. Bob later told me that volume six kept breaking its binding, so he needed to limit the page count in future editions; I still struggle with that issue. As a young faculty member I was asked to write a chapter for CVT VII and can recall how honored I felt. I served as the consulting editor for cardiology for the next three editions and associate editor for CVT X, learning from a distance how Bob managed his textbook. Then one day as we sat on a picnic bench at a New England VMA meeting, Dr. Kirk (and his wife Helen) asked me to assume editorship of CVT. During this conversation, Bob discussed in some detail his vision for future editions of the textbook. This opportunity—to edit what at the time was the best known veterinary textbook— evoked feelings of personal satisfaction but also of daunting obligation to not mess it all up. I have never quite shaken those emotions. Dr. Kirk indicated the purpose of Current Veterinary Therapy in the preface to his first edition, namely “to provide the small animal clinician with easily accessible information on the latest accepted methods of treating medical conditions in a pet practice.” Since assuming editorial duties, I have tried to maintain his focus while adapting the textbook to the remarkable medical advances our profession has witnessed over the past four decades. To control the book size, I have limited the CVT to medical disorders of dogs and cats; when surgical treatments are indicated, the reader is referred to other available sources. Diagnosis is not the focus of CVT, although our authors usually provide basic information regarding diagnostic studies, and a few chapters focus entirely on establishing a correct diagnosis. As Dr. Kirk wrote in the first edition, “the text assumes that a secure diagnosis has been obtained”; achieving that accurate diagnosis is as important today as it was 50 years ago when he wrote his first volume. The organization of the 15th edition of Kirk’s Current Veterinary Therapy will be familiar to long-time users. Sections are devoted to multisystem specialties of critical care medicine, endocrine and metabolic disorders, hematology and oncology, infectious diseases, and toxicology. Sections that focus on

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specific organ systems detail cardiovascular, dermatologic and otic, gastrointestinal, neurologic, ophthalmologic, respiratory, reproductive, and urinary system diseases. There are a total of 365 chapters, with 279 chapters in the textbook and 86 chapters on the companion website and in all electronic versions of CVT XV. Some of the appendices have been moved to the website to gain page space, but the often-copied Table of Common Drugs: Approximate Dosages is still found in both electronic and print versions of the book. When navigating CVT, most readers find the Table of Contents, which is divided into individual sections, and the Index to be their best guide. The chapters also have been extensively cross referenced. We continue our policy of integrating this new volume with the “still current” chapters from Volume XIV of Current Veterinary Therapy. These chapters have been updated by the authors and are reprinted because of their clinical importance. Others have been updated and appear on the companion website. CVT XV is available for today’s veterinary students and practitioners both as a print book and as an e-book accessible on any mobile device (eReader, tablet, or laptop). I firmly believe that the student or first-time reader of “Kirk” who holds only this current volume will find the information so useful as to forgive the occasional omission of a topic, or be convinced to go online when that subject is covered only in the electronic version of the book. Owing to the large number of potential chapters, we have elected not to reprint some chapters in which new information is minimal or where we simply could not allocate the page space. The organization and overall editing of this new volume has been shared with Dr. David Twedt, Professor of Clinical Sciences at Colorado State University. I first met Dave when he tried to train me during my internship at the Animal Medical Center in New York, and from that point on I have admired his intellect, common sense, clinical acumen, sense of humor, and kindness. David is an internist and gastroenterologist of extraordinary skill and experience, as evidenced by his publications, his world travel as an invited lecturer, and his recent receipt of the ACVIM Distinguished Service Award. This is a capstone award bestowed on one individual annually and marks a distinguished career of service to veterinary internal medicine; Dr. Twedt is a most deserving recipient. CVT is so much better with David’s input and I am thankful for his collaboration and friendship. Dr. Kirk knew that the quality of the textbook depended mainly on the recruitment of authors with expertise and clinical experience, and we have been fortunate to enlist over 300 outstanding clinicians and clinical scientists to help with CVT XV. As with Dr. Kirk’s first CVT volume, we have asked our contributors to provide what the “author regards as the best treatment at present,” accepting that some will be “traditional,” whereas others are “just emerging” and will require more definition. We practice in an era in which clinical trial evidence is considered the standard; however, definitive trial data are often lacking due to a variety of factors (including insufficient research funding and insufficient numbers of clinical scientists in veterinary schools). We ask our authors to inform us about evidence-based treatments, but also ask them to explain how they manage their own patients in practical terms, even in the absence of definitive studies. Our contributors have done a tremendous job of summarizing available therapies within the confines of relatively

short chapters, and both Dr. Twedt and I are highly appreciative of their efforts. These chapter submissions have been guided and reviewed by our Consulting Editors, with one or two experts overseeing each of the 13 textbook sections. Collectively, these clinical specialists have evaluated each chapter in CVT, offering their perspective and providing oversight for content accuracy and currency. We are truly grateful to each of these outstanding clinicians for their guidance, editorial input, and time. Ultimately, our readers—practicing veterinarians and veterinary students studying clinical science—decide the fate of a textbook. Too many books become ornaments on shelves (or now pretty pictures on digital devices). We certainly hope that readers will find the volumes of CVT useful to their practices. No single textbook can cover the vast subject of veterinary medicine, and thus we have maintained our niche, focusing (as Dr. Kirk directed) on medical therapies of canine and feline diseases. There are a large number of textbooks addressing diagnosis and other volumes detailing subspecialty medicine and surgery. It is our hope that CVT will find a useful place between these other resources and be a first choice when managing patients in your clinical practice. Extraordinary efforts have been made to ensure accuracy in treatment recommendations, especially in the dosing of drugs (as so many are used in an extralabel manner). We are very interested in hearing from readers about things they like about CVT, as well as suggestions for improvement. Should a potential error be encountered, I would be indebted to any reader willing to take the time to notify me or the publisher of their concern. I would like to close by reiterating that Dr. Kirk was a role model as an academic clinician. He practiced, contributed to scientific discovery, and disseminated what he learned himself and from others through his teaching and writings. He recognized talent in others and collaborated with many outstanding clinicians and scientists during his career. Although he was a pioneer of our profession in so many ways, to me he was foremost a clinician-educator and mentor. In this regard, I would like to briefly acknowledge and thank three other veterinarians who have greatly influenced my career. Dr. Robert Hamlin has taught me cardiology continuously, with brilliance, imagination, and enthusiasm for over 40 years. His helpfulness and impact on educating veterinary students and future cardiologists around the world cannot be overestimated. Bob inspired me to an academic career, and I will forever be thankful for his example. Dr. William Kay was still a practicing neurologist when he taught and mentored me during my internship at the Animal Medical Center (and later during my professional career). Bill taught me how to approach all sorts of difficult, complicated, and challenging situations in a forthright manner. I am indebted to him for these lessons. Dr. Stephen Ettinger was a great friend to Bob Kirk, and he stands as another giant of our profession. His textbooks, Canine Cardiology and Textbook of Veterinary Internal Medicine, were highly influential to me as a clinician and author. I have learned even more by talking to Steve and observing his intellect, innovation, passion, and persistence. Along with Dr. Kirk, these mentors have offered me guidance, support, and opportunities throughout my career; without their help and friendship, someone else would likely be writing this preface.

Acknowledgments In addition to our contributors, David and I would like to thank everyone at Elsevier who worked so hard to bring this new edition to publication. Shelly Stringer, Content Manager, was our daily go-to person. Shelly patiently listened to all of my excuses, managed thousands of details, and kept us moving toward the target with grace and helpfulness. David Stein, Senior Production Manager at Elsevier, was superb while wearing multiple hats as senior copy editor and production leader. He carried the book through edited manuscript and page proofs while fixing hundreds of my errors with aplomb. Whitney Noble was often working behind the scenes in various aspects of organization, communication, website structure, and textbook production. I’ve no doubt she performed many other essential tasks, but

largely under the radar of the authors and editors. Once again the overall supervision and guidance of CVT was managed most capably by Content Strategy Director Penny Rudolph. Penny knew when we needed her insight and direction and otherwise supported us throughout the creation of this new volume. Special thanks are extended to Dr. Debra Primovic, a practicing veterinarian, for indexing yet another volume of CVT with care and clinical perspective. Dr. Twedt and I would like to thank each of these individuals, along with others at Elsevier who worked to bring Current Veterinary Therapy XV to publication. John D. Bonagura, DVM Columbus, Ohio

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Contents Section I: Critical Care

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Crystalloid Fluid Therapy, 2 John D. Anastasio, Daniel J. Fletcher, and Elizabeth A. Rozanski Colloid Fluid Therapy, 8 Elke Rudloff and Rebecca Kirby Catecholamines in the Critical Care Patient, 14 Edward S. Cooper Shock, 18 Kari Santoro-Beer and Deborah C. Silverstein Cardiopulmonary Resuscitation, 26 Daniel J. Fletcher and Manuel Boller Drug Incompatibilities and Drug-Drug Interactions in the ICU Patient, 32 Katrina R. Viviano and Elizabeth J. Thomovsky Nutrition in Critical Care, 38 Daniel L. Chan Stabilization of the Patient with Respiratory Distress, 44 Timothy B. Hackett and Lauren Sullivan Acute Respiratory Distress Syndrome, 48 Emily K. Thomas and Lori S. Waddell Oxygen Therapy, 52 Vincent J. Thawley and Kenneth J. Drobatz Ventilator Therapy for the Critical Patient, 55 Julien Guillaumin Analgesia of the Critical Patient, 59 Nigel Campbell Anesthesia for the Critical Care Patient, 63 Derek Flaherty Hyperthermia and Heat-Induced Illness, 70 Elisa M. Mazzaferro Thromboelastography, 74 Karl E. Jandrey and Benjamin M. Brainard Critical Illness–Related Corticosteroid Insufficiency, 78 Lauren Sullivan and Jamie M. Burkitt Creedon Evaluation of Canine Orthopedic Trauma, 80 Randall B. Fitch Emergency Management of Open Fractures, 83 Robert J. McCarthy Emergency Wound Management and Vacuum-Assisted Wound Closure, 87 Stacy D. Meola and Jason Wheeler Chapter 1 Acid-Base Disorders, e1 Helio Autran de Morais and Stephen P. DiBartola Chapter 2 Drainage Techniques for the Septic Abdomen, e9 Adrienne Bentley and David Holt Chapter 3 Gastric Dilation-Volvulus, e13 Karol A. Mathews Chapter 4 Pacing in the ICU Setting, e21 John E. Rush and Vicky K. Yang

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Drugs Used to Treat Toxicoses, 101 Sharon M. Gwaltney-Brant Intravenous Lipid Emulsion Therapy, 106 Justine A. Lee and Alberto L. Fernandez Mojica Human Drugs of Abuse and Central Nervous System Stimulants, 109 Petra A. Volmer Antidepressants and Anxiolytics, 112 Ahna G. Brutlag Over-the-Counter Drug Toxicosis, 115 David C. Dorman Top Ten Toxic and Nontoxic Household Plants, 121 A. Catherine Barr Herbal Hazards, 122 Elizabeth A. Hausner and Robert H. Poppenga Lawn and Garden Product Safety, 130 John H. Tegzes Rodenticide Toxicoses, 133 Michael J. Murphy Insecticide Toxicoses, 135 Patricia Ann Talcott Pesticides: New Vertebrate Toxic Agents for Pest Species, 142 Rhian Cope Parasiticide Toxicoses: Avermectins, 145 Wilson K. Rumbeiha Human Foods with Pet Toxicoses: Alcohol to Xylitol, 147 Eric K. Dunayer Automotive Toxins, 151 Karyn Bischoff Lead Toxicosis in Small Animals, 156 Sharon M. Gwaltney-Brant Aflatoxicosis in Dogs, 159 Karyn Bischoff and Tam Garland Chapter 5 Nephrotoxicants, e29 Wilson K. Rumbeiha and Michael J. Murphy Chapter 6 Reporting Adverse Events to the Food and Drug Administration—Center for Veterinary Medicine, e35 Susan J. Bright-Ponte and Lee Anne Myers Palmer Chapter 7 Respiratory Toxicants of Interest to Pet Owners, e43 Janice A. Dye Chapter 8 Small Animal Poisoning: Additional Considerations Related to Legal Claims, e49 Michael J. Murphy Chapter 9 Sources of Help for Toxicosis, e53 Michael J. Murphy Chapter 10 Treatment of Animal Toxicoses: Regulatory Points to Consider, e54 Michael J. Murphy, Susan J. Bright-Ponte, and Janice C. Steinschneider

Section II: Toxicologic Diseases   20

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ASPCA Animal Poison Control Center Toxin Exposures for Pets, 92 Tina Wismer Toxin Exposures in Small Animals, 93 Colleen M. Almgren and Sharon L. Welch Urban Legends of Toxicology: Facts and Fiction, 97 Frederick W. Oehme and William R. Hare Jr.

Section III: Endocrine and Metabolic Diseases   39   40

Bilaterally Symmetric Alopecia in Dogs, 164 Robert Allen Kennis Imaging in Diagnosis of Endocrine Disorders, 167 Jimmy H. Saunders

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Approach to Critical Illness–Related Corticosteroid Insufficiency, 174 Linda G. Martin Canine Hypothyroidism, 178 J. Catharine R. Scott-Moncrieff Feline Hyperthyroidism and Renal Function, 185 Harriet M. Syme Canine Diabetes Mellitus, 189 William E. Monroe Diabetic Monitoring, 193 Claudia E. Reusch Diet and Diabetes, 199 Debra L. Zoran Insulin Resistance, 205 Richard W. Nelson Feline Diabetes Mellitus, 208 Jacquie S. Rand Feline Hypersomatotropism and Acromegaly, 216 Stijn J.M. Niessen and David B. Church Occult Hyperadrenocorticism: Is It Real? 221 Ellen N. Behrend and Robert Allen Kennis Canine Hyperadrenocorticism Therapy, 225 Ian K. Ramsey and Reto Neiger Ectopic ACTH Syndrome and Food-Dependent Hypercortisolism in Dogs, 230 Sara Galac and Hans S. Kooistra Canine Hypoadrenocorticism, 233 Peter P. Kintzer and Mark E. Peterson Feline Primary Hyperaldosteronism, 238 Kent R. Refsal and Andrea M. Harvey Feline Idiopathic Hypercalcemia, 242 Joao Felipe de Brito Galvao, Dennis J. Chew, and Patricia A. Schenck Approach to Hypomagnesemia and Hypokalemia, 248 Lee E. Palmer and Linda G. Martin Obesity, 254 Angela Lusby Witzel and Claudia A. Kirk Approach to Canine Hyperlipidemia, 261 Panagiotis G. Xenoulis Chapter 11 Hypercalcemia and Primary Hyperparathyroidism in Dogs, e69 Edward C. Feldman Chapter 12 Clinical Use of the Vasopressin Analog Desmopressin for the Diagnosis and Treatment of Diabetes Insipidus, e73 Rhett Nichols and Mark E. Peterson Chapter 13 Complicated Diabetes Mellitus, e76 Deborah S. Greco Chapter 14 Complications and Concurrent Conditions Associated with Hypothyroidism in Dogs, e84 David L. Panciera Chapter 15 Large Pituitary Tumors in Dogs with Pituitary-Dependent Hyperadrenocorticism, e88 Alan P. Théon and Edward C. Feldman Chapter 16 Differential Diagnosis of Hyperkalemia and Hyponatremia in Dogs and Cats, e92 Peter P. Kintzer and Mark E. Peterson Chapter 17 Hyperadrenocorticism in Ferrets, e94 Karen L. Rosenthal and Mark E. Peterson Chapter 18 Interpretation of Endocrine Diagnostic Test Results for Adrenal and Thyroid Disease, e97 Robert J. Kemppainen and Ellen N. Behrend Chapter 19 Medical Treatment of Feline Hyperthyroidism, e102 Lauren A. Trepanier Chapter 20 Nutritional Management of Feline Hyperthyroidism, e107 J. Catharine R. Scott-Moncrieff

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Web Chapter 21 Radioiodine for Feline Hyperthyroidism, e112 Mark E. Peterson and Michael R. Broome Web Chapter 22 Treatment of Hypoparathyroidism, e122 Joao Felipe de Brito Galvao, Dennis J. Chew, Larry A. Nagode, and Patricia A. Schenck Web Chapter 23 Treatment of Insulinoma in Dogs, Cats, and Ferrets, e130 Karelle A. Meleo and Mark E. Peterson Web Chapter 24 Alternatives to Insulin Therapy for Diabetes Mellitus in Cats, e135 Deborah S. Greco

Section IV: Oncology and Hematology   59   60

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Immunosuppressive Agents, 268 Clare R. Gregory Management of Immune-Mediated Hemolytic Anemia in Dogs, 275 Valerie Johnson and Steven Dow Thrombocytopenia, 280 Jennifer A. Neel, Adam J. Birkenheuer, and Carol B. Grindem von Willebrand Disease and Hereditary Coagulation Factor Deficiencies, 286 Marjorie B. Brooks Disseminated Intravascular Coagulation, 292 Elke Rudloff and Rebecca Kirby Hypercoagulable States, 297 Bo Wiinberg and Annemarie T. Kristensen Lymphocytosis in Dogs and Cats, 301 Susan E. Lana, Christine S. Olver, and Anne Avery Quality Control for the In-Clinic Laboratory, 306 Glade Weiser and Linda M. Vap Transfusion Medicine: Best Practices, 309 Lauren Sullivan and Timothy B. Hackett Bone Marrow Dyscrasias, 314 Christine S. Olver Talking to Clients about Cancer, 318 Douglas H. Thamm Tumor Biopsy and Specimen Submission, 322 Debra A. Kamstock and Nicholas J. Bacon Chemotherapeutic Drug Handling and Safety, 326 Andrea Flory, Brenda Phillips, and Margo Karriker Treatment of Adverse Effects from Cancer Therapy, 330 Dennis B. Bailey Cancer Immunotherapy, 334 Leah Ann Mitchell, Amanda Guth, and Steven Dow Advances in Radiation Therapy for Nasal Tumors, 338 James T. Custis III and Susan M. LaRue Malignant Effusions, 341 Antony S. Moore Interventional Oncology, 345 William T.N. Culp and Chick Weisse Nutritional Support of the Cancer Patient, 349 Glenna E. Mauldin Metronomic Chemotherapy, 354 Anthony J. Mutsaers Drug Update: Toceranib, 358 Cheryl A. London Drug Update: Masitinib, 360 Kevin A. Hahn Oral Tumors, 362 Michael S. Kent and Bernard Séguin Perineal Tumors, 366 Michelle M. Turek Urinary Bladder Cancer, 370 Deborah W. Knapp

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Mammary Cancer, 375 Carolyn J. Henry Rescue Therapy for Canine Lymphoma, 381 David M. Vail Plasma Cell Neoplasms, 384 Rachel Sternberg, Davis M. Seelig, and Laura D. Garrett Osteosarcoma, 388 Nicole P. Ehrhart and Timothy M. Fan Canine Hemangiosarcoma, 392 Craig A. Clifford and Louis-Philippe de Lorimier Thyroid Tumors, 397 Suzanne Murphy Chapter 25 Anticancer Drugs: New Drugs, e139 Douglas H. Thamm and David M. Vail Chaptre 26 Blood Typing and Crossmatching to Ensure Blood Compatibility, e143 Urs Giger Chapter 27 Soft Tissue Sarcomas, e148 Tania Ann Banks and Julius M. Liptak Chapter 28 Collection of Specimens for Cytology, e153 Kenita S. Rogers Chapter 29 Nasal Tumors, e157 Lisa J. Forrest Chapter 30 Nonregenerative Anemias, e160 Douglas J. Weiss Chapter 31 Pulmonary Neoplasia, e165 Kevin A. Hahn and Sandra M. Axiak-Bechtel Chapter 32 Surgical Oncology Principles, e168 James P. Farese

Section V: Dermatologic and Otic Diseases   90   91   92   93   94   95   96

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Diagnostic Criteria for Canine Atopic Dermatitis, 403 Claude Favrot Treatment Guidelines for Canine Atopic Dermatitis, 405 Thierry Olivry and Pascal Prélaud Cyclosporine Use in Dermatology, 407 Andrew Hillier Allergen-Specific Immunotherapy, 411 Douglas J. DeBoer Systemic Glucocorticoids in Dermatology, 414 Lauren Riester Pinchbeck Topical Therapy for Pruritus, 419 Wayne S. Rosenkrantz Elimination Diets for Cutaneous Adverse Food Reactions: Principles in Therapy, 422 Hilary A. Jackson Flea Control in Flea Allergy Dermatitis, 424 Robert Allen Kennis and Andrew Hillier Treatment of Ectoparasitoses, 428 Randall C. Thomas Canine Demodicosis, 432 Ralf S. Mueller Staphylococci Causing Pyoderma, 435 Linda A. Frank Treatment of Superficial Bacterial Folliculitis, 437 Andrew Hillier Topical Therapy for Infectious Diseases, 439 Kenneth W. Kwochka Methicillin-Resistant Staphylococcal Infections, 443 Carlo Vitale Nontuberculous Cutaneous Granulomas in Dogs and Cats (Canine Leproid Granuloma and Feline Leprosy Syndrome), 445 Anne Fawcett, Janet A.M. Fyfe, and Richard Malik Treatment of Dermatophytosis, 449 Karen A. Moriello and Douglas J. DeBoer

106 Dermatophytosis: Investigating an Outbreak in a Multicat Environment, 452 Sandra Newbury and Karen A. Moriello 107 Disinfection of Environments Contaminated by Staphylococcal Pathogens, 455 Armando E. Hoet 108 Principles of Therapy for Otitis, 458 Lynette K. Cole 109 Topical and Systemic Glucocorticoids for Otitis, 459 Tim Nuttall 110 Topical Antimicrobials for Otitis, 462 Colleen L. Mendelsohn 111 Systemic Antimicrobials for Otitis, 466 Lynette K. Cole 112 Ototoxicity, 468 Michael Podell and Cecilia Friberg 113 Ear-Flushing Techniques, 471 Dawn Logas 114 Primary Cornification Disorders in Dogs, 475 Elizabeth A. Mauldin 115 Alopecia X, 477 Rosario Cerundolo 116 Actinic Dermatoses and Sun Protection, 480 Amanda K. Burrows 117 Drugs for Behavior-Related Dermatoses, 482 Meghan E. Herron 118 Superficial Necrolytic Dermatitis, 485 Kevin Byrne 119 Cutaneous Adverse Drug Reactions, 487 Ian Brett Spiegel Web Chapter 33 Acral Lick Dermatitis, e172 John M. MacDonald Web Chapter 34 Avermectins in Dermatology, e178 Amanda K. Burrows Web Chapter 35 Canine Papillomaviruses, e184 Masahiko Nagata Web Chapter 36 Diseases of the Anal Sac, e187 Russell Muse Web Chapter 37 Feline Demodicosis, e191 Karin M. Beale Web Chapter 38 Feline Viral Skin Disease, e194 Rudayna Ghubash Web Chapter 39 House Dust Mites and Their Control, e197 Wayne S. Rosenkrantz Web Chapter 40 Interferons, e200 Toshiroh Iwasaki Web Chapter 41 Pentoxifylline, e202 Rosanna Marsella Web Chapter 42 Pyotraumatic Dermatitis (“Hot Spots”), e206 Wayne S. Rosenkrantz Web Chapter 43 Therapy for Sebaceous Adenitis, e209 Edmund J. Rosser Jr. Web Chapter 44 Malassezia Infections, e212 Daniel O. Morris Web Chapter 45 Topical Immunomodulators, e216 Joel D. Griffies

Section VI: Gastrointestinal Diseases 120 Feline Caudal Stomatitis, 492 Linda J. DeBowes 121 Oropharyngeal Dysphagia, 495 Stanley L. Marks 122 Gastroesophageal Reflux, 501 Peter Hendrik Kook 123 Antacid Therapy, 505 Alexa M.E. Bersenas

Contents 124 Gastric Helicobacter spp. and Chronic Vomiting in Dogs, 508 Michael S. Leib 125 Gastric and Intestinal Motility Disorders, 513 Frédéric P. Gaschen 126 Current Veterinary Therapy: Antibiotic Responsive Enteropathy, 518 Albert E. Jergens 127 Cobalamin Deficiency in Cats, 522 Kenneth W. Simpson and Paul A. Worhunsky 128 Probiotic Therapy, 525 Craig B. Webb and Jan S. Suchodolski 129 Protozoal Gastrointestinal Disease, 528 Jody L. Gookin and Michael R. Lappin 130 Canine Parvoviral Enteritis, 533 Julia K. Veir 131 Inflammatory Bowel Disease, 536 Karin Allenspach and Aarti Kathrani 132 Protein-Losing Enteropathies, 540 Debra L. Zoran 133 Feline Gastrointestinal Lymphoma, 545 Keith P. Richter 134 Canine Colitis, 550 Kenneth W. Simpson and Alison C. Manchester 135 Laboratory Testing for the Exocrine Pancreas, 554 Romy M. Heilmann and Jörg M. Steiner 136 Exocrine Pancreatic Insufficiency in Dogs, 558 Maria Wiberg 137 Treatment of Canine Pancreatitis, 561 Craig G. Ruaux 138 Feline Exocrine Pancreatic Disorders, 565 Marnin A. Forman 139 Diagnostic Approach to Hepatobiliary Disease, 569 Cynthia R.L. Webster and Johanna C. Cooper 140 Drug-Associated Liver Disease, 575 Lauren A. Trepanier 141 Acute Liver Failure, 580 Sharon A. Center 142 Chronic Hepatitis Therapy, 583 Penny J. Watson 143 Copper Chelator Therapy, 588 Allison Bradley and David C. Twedt 144 Ascites and Hepatic Encephalopathy Therapy for Liver Disease, 591 Nick Bexfield 145 Portosystemic Shunts, 594 Karen M. Tobias 146 Portal Vein Hypoplasia (Microvascular Dysplasia), 599 Andrea N. Johnston and Cynthia R.L. Webster 147 Extrahepatic Biliary Tract Disease, 602 Keith P. Richter and Fred S. Pike 148 Idiopathic Vacuolar Hepatopathy, 606 David C. Twedt 149 Feline Hepatic Lipidosis, 608 Steve L. Hill and P. Jane Armstrong 150 Feline Cholangitis, 614 David C. Twedt, P. Jane Armstrong, and Kenneth W. Simpson Web Chapter 46 Canine Biliary Mucocele, e221 Heidi A. Hottinger Web Chapter 47 Canine Megaesophagus, e224 Beth M. Johnson, Robert C. DeNovo, and Erick A. Mears Web Chapter 48 Copper-Associated Hepatitis, e231 Hille Fieten and Jan Rothuizen Web Chapter 49 Esophagitis,e237 Michael D. Willard and Elizabeth A. Carsten

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Web Chapter 50 Evaluation of Elevated Serum Alkaline Phosphatase in Dogs, e242 Anthony T. Gary and David C. Twedt Web Chapter 51 Flatulence, e247 Philip Roudebush Web Chapter 52 Gastric Ulceration, e251 Reto Neiger Web Chapter 53 Hepatic Support Therapy, e255 David C. Twedt Web Chapter 54 Oropharyngeal Dysphagia, e259 G. Diane Shelton Web Chapter 55 Tylosin-Responsive Diarrhea, e262 Elias Westermarck

Section VII: Respiratory Diseases 151 Respiratory Drug Therapy, 622 Eleanor C. Hawkins and Mark G. Papich 152 Feline Upper Respiratory Tract Infection, 629 Jyothi V. Robertson and Kate Hurley 153 Canine Infectious Respiratory Disease Complex, 632 Jane E. Sykes 154 Rhinitis in Dogs, 635 Ned F. Kuehn 155 Rhinitis in Cats, 644 Lynelle R. Johnson and Vanessa R. Barrs 156 Brachycephalic Airway Obstruction Syndrome, 649 Cyrill Poncet and Valérie Freiche 157 Nasopharyngeal Disorders, 653 Susan F. Foster and Geraldine Briony Hunt 158 Laryngeal Diseases, 659 Catriona M. MacPhail and Eric Monnet 159 Tracheal Collapse, 663 Brian A. Scansen and Chick Weisse 160 Chronic Bronchial Disorders in Dogs, 669 Lynelle R. Johnson 161 Chronic Bronchitis and Asthma in Cats, 673 Philip Padrid 162 Pneumonia, 681 Rita M. Hanel and Bernie Hansen 163 Eosinophilic Pulmonary Diseases, 688 Cécile Clercx and Dominique Peeters 164 Pleural Effusion, 691 David Holt and Lori S. Waddell 165 Pneumothorax, 700 Elizabeth A. Rozanski and Erin Mooney 166 Pulmonary Thromboembolism, 705 Susan G. Hackner 167 Pulmonary Hypertension, 711 Michele Borgarelli Web Chapter 56 Interstitial Lung Diseases, e266 Brendan M. Corcoran Web Chapter 57 Respiratory Parasites, e269 Robert G. Sherding

Section VIII: Cardiovascular Diseases 168 Nutritional Management of Heart Disease, 720 Lisa M. Freeman 169 Systemic Hypertension, 726 Rebecca L. Stepien 170 Bradyarrhythmias, 731 Bruce G. Kornreich and N. Sydney Moïse 171 Supraventricular Tachyarrhythmias in Dogs, 737 Romain Pariaut, Roberto A. Santilli, and N. Sydney Moïse 172 Ventricular Arrhythmias in Dogs, 745 Mark A. Oyama and Caryn A. Reynolds

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Contents

173 Feline Cardiac Arrhythmias, 748 Étienne Côté 174 Congenital Heart Disease, 756 Brian A. Scansen, Richard E. Cober, and John D. Bonagura 175 Drugs for Treatment of Heart Failure in Dogs, 762 John D. Bonagura and Bruce W. Keene 176 Management of Heart Failure in Dogs, 772 Bruce W. Keene and John D. Bonagura 177 Chronic Valvular Heart Disease in Dogs, 784 John E. Rush and Suzanne M. Cunningham 178 Dilated Cardiomyopathy in Dogs, 795 Amara H. Estrada and Herbert W. Maisenbacher III 179 Arrhythmogenic Right Ventricular Cardiomyopathy, 801 Kathryn M. Meurs 180 Feline Myocardial Disease, 804 Virginia Luis Fuentes and Karsten Eckhard Schober 181 Arterial Thromboembolism, 811 Daniel F. Hogan 182 Pericardial Effusion, 816 O. Lynne Nelson and Wendy A. Ware 183 Feline Heartworm Disease, 824 Clarke E. Atkins 184 Canine Heartworm Disease, 831 Matthew W. Miller and Sonya G. Gordon Web Chapter 58 Arrhythmogenic Right Ventricular Cardiomyopathy in Cats, e277 Philip R. Fox Web Chapter 59 Bradyarrhythmias and Cardiac Pacing, e281 Mark A. Oyama and D. David Sisson Web Chapter 60 Cardioversion, e286 Janice M. Bright and Julie M. Martin Web Chapter 61 Infective Endocarditis, e291 Kristin A. MacDonald Web Chapter 62 Mitral Valve Dysplasia, e299 Barret J. Bulmer Web Chapter 63 Myocarditis, e303 Karsten Eckhard Schober Web Chapter 64 Patent Ductus Arteriosus, e309 Matthew W. Miller, Sonya G. Gordon, and Ashley B. Saunders Web Chapter 65 Pulmonic Stenosis, e314 Amara H. Estrada and Herbert W. Maisenbacher III Web Chapter 66 Subaortic Stenosis, e319 Jonathan A. Abbott Web Chapter 67 Syncope, e324 Marc S. Kraus, Justin D. Thomason, and Clay A. Calvert Web Chapter 68 Tricuspid Valve Dysplasia, e332 Darcy B. Adin Web Chapter 69 Ventricular Septal Defect, e335 Rebecca E. Gompf and John D. Bonagura

Section IX: Urinary Diseases 185 Applications of Ultrasound in Diagnosis and Management of Urinary Disease, 840 Silke Hecht 186 Recognition and Prevention of Hospital-Acquired Acute Kidney Injury, 845 Marie E. Kerl and Cathy E. Langston 187 Proteinuria/Albuminuria: Implications for Management, 849 Gregory F. Grauer 188 Glomerular Disease and Nephrotic Syndrome, 853 Shelly L. Vaden and Barrak M. Pressler

189 Chronic Kidney Disease: International Renal Interest Society Staging and Management, 857 Jonathan Elliott and A.D.J. Watson 190 Use of Nonsteroidal Antiinflammatory Drugs in Kidney Disease, 863 Scott A. Brown 191 Medical Management of Acute Kidney Injury, 868 Linda Ross 192 Continuous Renal Replacement Therapy, 871 Mark J. Acierno 193 Surveillance for Asymptomatic and Hospital-Acquired Urinary Tract Infection, 876 Kate S. KuKanich 194 Persistent Escherichia coli Urinary Tract Infection, 880 Julie R. Fischer 195 Interventional Strategies for Urinary Disease, 884 Allyson Berent and Chick Weisse 196 Medical Management of Nephroliths and Ureteroliths, 892 Jessica E. Markovich and Mary Anna Labato 197 Calcium Oxalate Urolithiasis, 897 Benjamin G. Nolan and Mary Anna Labato 198 Canine Urate Urolithiasis, 901 Jody P. Lulich, Carl A. Osborne, and Hasan Albasan 199 Minilaparotomy-Assisted Cystoscopy for Urocystoliths, 905 Joseph W. Bartges, Patricia A. Sura, and Amanda Callens 200 Multimodal Environmental Enrichment for Domestic Cats, 909 Traci A. Shreyer and C.A. Tony Buffington 201 Medical Management of Urinary Incontinence and Retention Disorders, 915 Annick Hamaide 202 Mechanical Occluder Devices for Urinary Incontinence, 919 Christopher A. Adin 203 Top Ten Urinary Consult Questions, 923 Dianne I. Mawby, Amanda Callens, and Joseph W. Bartges Web Chapter 70 Laser Lithotripsy for Uroliths, e340 Jody P. Lulich, Larry G. Adams, and Hasan Albasan Web Chapter 71 Urinary Incontinence: Treatment with Injectable Bulking Agents, e345 Julie K. Byron, Dennis J. Chew, and Mary A. McLoughlin

Section X: Reproductive Diseases 204 Breeding Management of the Bitch, 930 Gary C.W. England and Marco Russo 205 Methods for Diagnosing Diseases of the Female Reproductive Tract, 936 Hernán J. Montilla 206 Endoscopic Transcervical Insemination, 940 Marion S. Wilson and Fiona K. Hollinshead 207 Pregnancy Diagnosis in Companion Animals, 944 Dana R. Bleifer, Leana V. Galdjian, and Cindy Bahr 208 Dystocia Management, 948 Autumn P. Davidson 209 Postpartum Disorders in Companion Animals, 957 Michelle Anne Kutzler 210 Nutrition in the Bitch and Queen During Pregnancy and Lactation, 961 David A. Dzanis 211 Pyometra, 967 Frances O. Smith 212 Vulvar Discharge, 969 Richard Wheeler

Contents 213 Surgical Repair of Vaginal Anomalies in the Bitch, 974 Roberto E. Novo 214 Early Age Neutering in Dogs and Cats, 982 Michelle Anne Kutzler 215 Estrus Suppression in the Bitch, 984 Patrick W. Concannon 216 Medical Termination of Pregnancy, 989 Bruce E. Eilts 217 Inherited Disorders of the Reproductive Tract in Dogs and Cats, 993 Vicki N. Meyers-Wallen 218 Ovarian Remnant Syndrome in Small Animals, 1000 Carlos M. Gradil and Robert J. McCarthy 219 Pregnancy Loss in the Bitch and Queen, 1003 Linda K. Kauffman and Claudia J. Baldwin 220 Benign Prostatic Hypertrophy and Prostatitis in Dogs, 1012 Kaitkanoke Sirinarumitr 221 Methods and Availability of Tests for Hereditary Disorders of Dogs and Cats, 1015 Edward E. (Ned) Patterson 222 Reproductive Oncology, 1022 Shay Bracha 223 Reproductive Toxicology and Teratogens, 1026 Michael E. Peterson 224 Acquired Nonneoplastic Disorders of the Male External Genitalia, 1029 Michelle Anne Kutzler Web Chapter 72 Aspermia/Oligospermia Caused by Retrograde Ejaculation in Dogs, e350 Stefano Romagnoli and Giovanni Majolino Web Chapter 73 Priapism in Dogs, e354 James A. Lavely

Section XI: Neurologic Diseases 225 Congenital Hydrocephalus, 1034 William B. Thomas 226 Intracranial Arachnoid Cysts in Dogs, 1038 Curtis W. Dewey 227 Treatment of Intracranial Tumors, 1039 Erin N. Warren, Jill Narak, Todd W. Axlund, and Annette N. Smith 228 Metabolic Brain Disorders, 1047 Cristian Falzone 229 New Maintenance Anticonvulsant Therapies for Dogs and Cats, 1054 Curtis W. Dewey 230 Treatment of Cluster Seizures and Status Epilepticus, 1058 Daniel J. Fletcher 231 Treatment of Noninfectious Inflammatory Diseases of the Central Nervous System, 1063 Lauren R. Talarico 232 Peripheral and Central Vestibular Disorders in Dogs and Cats, 1066 Starr Cameron and Curtis W. Dewey 233 Canine Intervertebral Disk Herniation, 1070 Jonathan M. Levine 234 Canine Degenerative Myelopathy, 1075 Joan R. Coates and Shinichi Kanazono 235 Diagnosis and Treatment of Atlantoaxial Subluxation, 1082 Beverly K. Sturges 236 Diagnosis and Treatment of Cervical Spondylomyelopathy, 1090 Ronaldo Casimiro da Costa

xxxvii

237 Craniocervical Junction Abnormalities in Dogs, 1098 Curtis W. Dewey, Dominic J. Marino, and Catherine A. Loughin 238 Diagnosis and Treatment of Degenerative Lumbosacral Stenosis, 1105 Catherine A. Loughin 239 Treatment of Autoimmune Myasthenia Gravis, 1109 G. Diane Shelton 240 Treatment of Myopathies and Neuropathies, 1113 G. Diane Shelton 241 Vascular Disease of the Central Nervous System, 1119 Laurent S. Garosi and Simon R. Platt Web Chapter 74 Physical Therapy and Rehabilitation of Neurologic Patients, e357 Darryl L. Millis

Section XII: Ophthalmologic Diseases 242 Pearls of the Ophthalmic Examination, 1128 David J. Maggs 243 Evaluation of Blindness, 1134 Anne J. Gemensky Metzler 244 Canine Conjunctivitis, 1138 Eric C. Ledbetter 245 Tear Film Disorders in Dogs, 1143 Elizabeth A. Giuliano 246 Corneal Ulcers, 1148 Amber Labelle 247 Canine Nonulcerative Corneal Disease, 1152 Margi Gilmour 248 Feline Corneal Disease, 1156 Cheryl L. Cullen 249 Canine Uveitis, 1162 Alexandra van der Woerdt 250 Feline Uveitis, 1166 Cynthia C. Powell 251 Canine Glaucoma, 1170 John S. Sapienza 252 Feline Glaucoma, 1177 Amy J. Rankin 253 Disorders of the Lens, 1181 David A. Wilkie 254 Canine Retinopathies, 1188 Simon M. Petersen-Jones 255 Feline Retinopathies, 1193 Kathern E. Myrna 256 Orbital Disease, 1197 Ralph E. Hamor 257 Canine Ocular Neoplasia, 1201 Sandra M. Nguyen and Amber Labelle 258 Feline Ocular Neoplasia, 1207 Sandra M. Nguyen and Amber Labelle Web Chapter 75 Diseases of the Eyelids and Periocular Skin, e363 Catherine A. Outerbridge and Steven R. Hollingsworth Web Chapter 76 Canine Retinal Detachment, e370 Patricia J. Smith Web Chapter 77 Epiphora, e374 Charlotte B. Keller Web Chapter 78 Ocular Emergencies, e377 K. Tomo Wiggans and Juliet R. Gionfriddo Web Chapter 79 Tear Film Disorders of Cats, e384 Christine C. Lim Web Chapter 80 Anisocoria and Abnormalities of the Pupillary Light Reflex: The Neuro-ophthalmic Examination, e388 Nancy B. Cottrill

xxxviii

Contents

Section XIII: Infectious Diseases 259 Infectious Agent Differentials for Medical Problems, 1212 Michael R. Lappin 260 Rational Empiric Antimicrobial Therapy, 1219 Patricia M. Dowling 261 Infectious Causes of Polyarthritis in Dogs, 1224 Richard E. Goldstein and Michael R. Lappin 262 Immunotherapy for Infectious Diseases, 1229 Steven Dow and Jessica M. Quimby 263 Systemic Antifungal Therapy, 1234 Jane E. Sykes, Amy M. Grooters, and Joseph Taboada 264 Infectious Diseases Associated with Raw Meat Diets, 1239 Rachel A. Strohmeyer 265 Pet-Associated Illness, 1244 Andrea Wang and Craig E. Greene 266 Vaccine-Associated Adverse Effects in Dogs, 1249 George E. Moore 267 Update on Vaccine-Associated Adverse Effects in Cats, 1252 Dennis W. Macy and Michael R. Lappin 268 Treatment of Canine Babesiosis, 1257 Adam J. Birkenheuer 269 Canine Bartonellosis, 1261 Pedro Paulo Vissotto de Paiva Diniz 270 Feline Bartonellosis, 1267 Lynn F. Guptill 271 Borreliosis, 1271 Meryl P. Littman 272 Management of Feline Retrovirus-Infected Cats, 1275 Katrin Hartmann 273 Hepatozoon americanum Infections, 1283 Kelly E. Allen, Eileen McGoey Johnson, and Susan E. Little

274 Leptospirosis, 1286 Katharine F. Lunn 275 Neospora caninum, 1290 Jeanne E. Ficociello 276 Canine and Feline Monocytotropic Ehrlichiosis, 1292 Susan M. Eddlestone 277 Toxoplasmosis, 1295 Michael R. Lappin 278 Rational Use of Glucocorticoids in Infectious Disease, 1299 Adam Mordecai and Rance K. Sellon 279 Feline Infectious Peritonitis Virus Infections, 1303 Michael R. Lappin Web Chapter 81 American Leishmaniasis, e396 Gregory C. Troy Web Chapter 82 Canine and Feline Hemotropic Mycoplasmosis, e398 Séverine Tasker Web Chapter 83 Canine Brucellosis, e402 Autumn P. Davidson Web Chapter 84 Feline Cytauxzoonosis, e405 J. Paul Woods Web Chapter 85 Pneumocystosis, e409 Remo Lobetti Web Chapter 86 Pythiosis and Lagenidiosis, e412 Amy M. Grooters Appendix I Table of Common Drugs: Approximate Dosages, 1307 Mark G. Papich Appendix II Treatment of Parasites, 1335 Lora R. Ballweber Index, 1339

SECTION I Critical Care Chapter Chapter Chapter Chapter Chapter Chapter

1: 2: 3: 4: 5: 6:

Chapter 7: Chapter 8: Chapter 9: Chapter 10: Chapter 11: Chapter 12: Chapter 13: Chapter 14: Chapter 15: Chapter 16: Chapter 17: Chapter 18: Chapter 19:

Crystalloid Fluid Therapy Colloid Fluid Therapy Catecholamines in the Critical Care Patient Shock Cardiopulmonary Resuscitation Drug Incompatibilities and Drug-Drug Interactions in the ICU Patient Nutrition in Critical Care Stabilization of the Patient with Respiratory Distress Acute Respiratory Distress Syndrome Oxygen Therapy Ventilator Therapy for the Critical Patient Analgesia of the Critical Patient Anesthesia for the Critical Care Patient Hyperthermia and Heat-Induced Illness Thromboelastography Critical Illness–Related Corticosteroid Insufficiency Evaluation of Canine Orthopedic Trauma Emergency Management of Open Fractures Emergency Wound Management and Vacuum-Assisted Wound Closure

2 8 14 18 26 32 38 44 48 52 55 59 63 70 74 78 80 83 87

The following web chapters can be found on the companion website at www.currentveterinarytherapy.com Web Web Web Web

Chapter Chapter Chapter Chapter

1: 2: 3: 4:

Acid-Base Disorders Drainage Techniques for the Septic Abdomen Gastric Dilation-Volvulus Pacing in the ICU Setting

1

CHAPTER 

1 

Crystalloid Fluid Therapy JOHN D. ANASTASIO, Malvern, Pennsylvania DANIEL J. FLETCHER, Ithaca, New York ELIZABETH A. ROZANSKI, North Grafton, Massachusetts

C

rystalloids are water-based solutions containing electrolyte and nonelectrolyte solutes and are capable of entering all body compartments. They are the most common fluid type used therapeutically in veterinary medicine. The major goals of crystalloid fluid therapy are restoration of intravascular volume (in shock), replacement of interstitial fluid deficits (in dehydration), and provision of maintenance fluid needs for dogs or cats at risk of dehydration. Fluid therapy is not warranted in cases in which heart failure cannot be excluded, as in the hypothermic tachypneic cat, and it should be used with caution if anuria is a possibility. The route of fluid administration is determined based on the goals of fluid therapy and the likelihood that these goals may be reasonably met with the planned therapeutic approach. The authors assume that most practitioners employ fluid therapy on a regular basis, and thus the purpose of this chapter is to highlight some controversial and emerging aspects of fluid therapy.

Types of Crystalloid Fluids Crystalloids are classified as isotonic, hypotonic, or hypertonic in relation to plasma osmolality. Isotonic crystalloids are by far the most commonly used fluid type in veterinary medicine (Table 1-1). Also known as replacement fluids, isotonic crystalloids are used to replace fluid deficits that may have developed from excessive loss. The electrolyte composition of isotonic fluid is typically similar to that of plasma. These solutions may also be classified as acidifying (e.g., normal saline) or buffering (e.g., lactated Ringer’s solution [LRS], Normosol-R, PlasmaLyte 148) solutions. Buffering solutions are considered balanced due to an electrolyte composition that is roughly equal to plasma. Normal saline is not a balanced solution and is acidifying due to a relatively high concentration of chloride and a lack of buffer, both of which decrease plasma bicarbonate. The clinical relevance of isotonic fluid choice is perhaps less important than commonly believed, although it is reasonable to closely evaluate the electrolyte composition of the fluid choice in relation to the patient’s needs. For example, 0.9% saline might be preferred in cases of head trauma, hypercalcemia, or metabolic alkalosis caused by gastrointestinal (GI) obstruction. Some believe that LRS administration to patients with hepatic dysfunction is contraindicated. A recent study in healthy dogs found that LRS given at a rate of 2

180 ml/kg/hr resulted in a significant increase in plasma lactate concentration within 10 minutes of infusion. However, the clinical significance of this finding is uncertain, especially considering the extreme fluid rates needed to raise the plasma lactate. Additionally, the impact of lactate-containing solutions has never been investigated in patients with liver disease. In the absence of fulminant low-output hepatic failure, the benefits of using LRS for treatment of hypovolemia and metabolic acidosis likely outweigh the risks. Alternatively, balanced isotonic crystalloids with acetate or gluconate may be considered. However, these molecules also require hepatic metabolism to bicarbonate (albeit less than LRS) to exert their buffering effects. Hypotonic crystalloids have a lower tonicity relative to plasma and contain additional free water. These solutions may be termed maintenance fluids. Hypotonic fluids are primarily used when volume replacement is adequate but ongoing fluid therapy is deemed necessary, such as for a dog recovering from maxillary fracture that is not yet eating. When fluid therapy is needed in the patient with cardiac failure, hypotonic solutions also may be preferable. Hypertonic crystalloids (e.g., 7.5% saline) can be used for short-term, rapid resuscitation and intravascular volume expansion, as well as for treatment of head trauma. These solutions pull water from the interstitium down the concentration gradient into the intravascular space. They are preferred in euhydrated but hypovolemic patients. These fluids cause interstitial and intracellular dehydration and therefore must be followed by administration of isotonic crystalloids. The addition of electrolytes and dextrose may increase the tonicity of isotonic fluids to a hyperosmolar range (see Table 1-1). Hypertonic crystalloids are not intended for long-term use.

Fluid Management of Hypovolemic Shock Hypovolemic shock can occur in dogs and cats in association with trauma, massive gastrointestinal hemorrhage, spontaneous hemoperitoneum (e.g., ruptured splenic mass), untreated gastrointestinal disease (e.g., parvovirus infection), gastric dilation-volvulus (GDV), diabetic ketoacidosis, and renal failure. Fluid administration is a mainstay of shock management. The term shock dose of fluids has been popularized in emergency and critical care medicine. Twenty years ago it was commonly recommended to give a specific dose of fluids to animals in shock (generally 90 ml/kg in dogs and

CHAPTER  1  Crystalloid Fluid Therapy

3

TABLE 1-1  Composition of Commonly Used Fluids* Fluid

Glucose (g/L)

Na+ (mEq/L)

Cl− (mEq/L)

K+ (mEq/L)

Ca2+ (mEq/L)

Mg2+ (mEq/L)

Buffer (mEq/L)

Osmolarity (mOsm/L)

Cal/L

pH

5% Dextrose

50

0

0

0

0

0

0

252

170

4.0

10% Dextrose

100

0

0

0

0

0

0

505

340

4.0

2.5% Dextrose in 0.45% NaCl

25

77

77

0

0

0

0

280

85

4.5

5% Dextrose in   0.45% NaCl

50

77

77

0

0

0

0

406

170

4.0

5% Dextrose in   0.9% NaCl

50

154

154

0

0

0

0

560

170

4.0

0.45% NaCl

0

77

77

0

0

0

0

154

0

5.0

0.9% NaCl

0

154

154

0

0

0

0

308

0

5.0

3% NaCl

0

513

513

0

0

0

0

1026

0

5.0

7.5% NaCl

0

1283

1283

0

0

0

0

2567

0

5.0

23.4% NaCl

0

4004

4004

0

0

0

0

8008

0

5.0

Ringer’s lactated solution

0

130

109

4

3

0

28 (L)

272

9

6.5

2.5% Dextrose in Ringer’s lactated solution

25

130

109

4

3

0

28 (L)

398

94

5.0

5% Dextrose in Ringer’s lactated solution

50

130

109

4

3

0

28 (L)

524

179

5.0

2.5% Dextrose in half-strength Ringer’s lactated solution

25

65.5

55

2

1.5

0

14 (L)

263

89

5.0

Normosol M in 5% dextrose

50

40

40

13

0

3

16 (A)

364

175

5.5

Normosol R

0

140

98

5

0

3

27 (A) 23 (G)

294

18

6.4

Plasma-Lyte A

0

140

98

5

0

3

27 (A) 23 (G)

294

17

7.4

Plasma-Lyte 148

0

140

98

5

0

3

27 (A) 23 (G)

294

17

5.5

50

40

40

13

0

3

16 (A)

363

170

5.5

Procalamine

0

35

41

24.5

3

0

47 (A)

735

0

8.8

20% Mannitol

0

0

0

0

0

0

0

1099

0

7.5% NaHCO3

0

893

0

0

0

0

893 (B)

1786

0

8.4% NaHCO3

0

1000

0

0

0

0

1000 (B)

2000

0

10% CaCl2

0

0

2720

0

1360

0

0

4080

0

0

0

2000

2000

0

0

0

4000

0

500

0

0

0

0

0

0

2780

1700

Plasma-Lyte 56 in 5% dextrose

14.9% KCl 50% Dextrose

L, Lactate; A, acetate; G, gluconate; B, bicarbonate; Cal, calorie. *Please see text for more explanation.

4.2

4

SECTION  I  Critical Care

60 ml/kg in cats). The volume was set to replace an entire blood volume with crystalloids administered over a period of 1 hour or less. Similarly, administration of shock volumes of fluids was considered the norm in human patients until publication of the landmark study investigating immediate versus delayed fluid resuscitation for hypotensive patients (Bickell et al, 1994). The results of that study challenged the idea that if some fluids are good, more must be better. Multiple experimental studies and clinical trials in people have subsequently demonstrated that excessive crystalloid or synthetic colloid fluid therapy is associated with dilutional coagulopathy, decreased wound healing, increased risk of sepsis, and acute lung injury leading to acute respiratory distress syndrome (ALI/ARDS). Current resuscitation efforts in massively traumatized humans have focused on treatment with blood and blood products. It is unlikely that most veterinary hospitals have a blood bank with sufficient resources to resuscitate all dogs and cats with blood, but this may become a therapeutic possibility in the future. So what do these studies mean for the clinician treating a patient in hypovolemic shock? Intravascular fluid support is clearly indicated to restore or maintain circu­ lating blood volume. However, the dose of fluid should not be a specific volume but rather a quantity titrated to restore perfusion parameters such as heart rate, mucous membrane color, and peripheral pulse quality to normal values. Blood pressure (BP) is maintained in most cases of shock owing to compensatory mechanisms. Normal BP does not exclude hypovolemia and should be interpreted with caution in patients with other signs of shock. Lactate is a useful surrogate marker of inadequate tissue perfusion, with increased lactate (>2.5 mmol/L) associated most commonly with hypoperfusion. It should be recognized that blood lactate may increase with patient struggling, with excessive muscle activity, in association with metabolic alternations (e.g., neoplasia), and with some medications, most notably prednisone (Boysen et al, 2009). A reasonable starting point for fluid administration is 15 to 20 ml/kg of crystalloids over 10 to 15 minutes with reassessment of patient parameters, especially those of perfusion. Additionally, attention should be directed to the underlying cause of the hypovolemic shock so that the cause can be treated directly through surgical or other medical therapy. If a patient is not responding rapidly to initial fluid therapy, urgent response is needed to reverse shock. It helps to know the average response time for a specific disease and to understand other comorbidities that may accompany the specific injury. For example, if stabilization is not occurring, major differentials include ongoing bleeding into the abdomen, thorax, or fracture site (femur/pelvis) or possibly pneumothorax. Other useful monitoring parameters include heart rate, respiratory rate, pulse quality, lactate, packed cell volume, total solids, urine production, and attitude. Goals for fluid therapy in shock are restoration of circulating plasma volume to reverse oxygen debt and normalization of the above parameters. Fluid therapy may be tapered over several hours if the resuscitation goals have been met and the patient remains stable.

Fluids should be given as a bolus in the patient with evidence of intravascular volume depletion, as suggested by tachycardia, dull mentation, pale mucous membranes, or hypotension. If vomiting and diarrhea are associated with extreme hemoconcentration, such as a packed cell volume of greater than 60% in non-greyhound dogs (or > 70% in greyhounds), a fluid bolus also may be used to decrease blood viscosity and improve hemodynamics. A fluid bolus is not needed in a pet that is simply dehydrated.

Hypotensive or Low-Volume Resuscitation Extrapolating from medicine, limited-volume resuscitation (also know as low-volume or hypotensive resuscitation) has gained some momentum in veterinary medicine. The goal of low-volume resuscitation is administration of fluid volumes sufficient to achieve a mean arterial BP of 60 to 80 mm Hg, ensuring adequate tissue and organ perfusion while preventing clot disruption. This method, used for people with uncontrolled cavitary hemorrhage requiring surgical stabilization, aims to have patients in the operating room within an hour of first response to minimize the time that they are hypotensive. Short transitions from the emergency room to the operating room can be difficult to attain in the veterinary setting. Although surgical intervention is usually unnecessary for traumatic hemoabdomen, other causes of hemoabdomen, such as ruptured neoplasia, are likely to require surgery. In this latter setting, low-volume resuscitation may be beneficial for the patient earmarked for surgery. However, this approach requires careful patient monitoring so that prolonged hypotension and the complications of poor tissue perfusion and organ dysfunction are avoided. Occasionally, there is confusion between low-volume resuscitation and resuscitation with hypertonic saline (HTS) and colloids. One popular method is to mix 43 ml of hetastarch with 17 ml of 23.4% hypertonic saline in a 60-ml syringe and then dose this at 4 to 5 ml/kg over 10 to 15 minutes. Although HTS and colloids represent a smaller volume of fluid than an equivalent dose of crystalloids and may be infused more rapidly than an isotonic crystalloid, the approaches are not interchangeable. Use of HTS and colloid results in a higher plasma volume than administered due to an interstitial fluid shift to the vascular space. In one small unpublished study of nontraumatic hemoabdomen, dogs randomized to hypertonic saline and hetastarch showed a more rapid time to stabilization than did dogs randomized to crystalloids; however, no differences were noted in either outcome or transfusion needs.*

Fluids for Rehydration Isotonic crystalloids are commonly used for rehydration and may be administered subcutaneously (SC [or SQ]) or intravenously (IV). Fluid therapy for rehydration is typically based on the formula *Tara Hammond, DVM, DACVECC, personal communication.

CHAPTER  1  Crystalloid Fluid Therapy

TABLE 1-2  Historical and Physical Examination Findings Relative to Estimated Dehydration % Dehydration

Historical Findings

Physical Examination Findings

12%

Collapsed, long-standing or severe fluid losses

Hypovolemic shock; other findings are typically present but due to severity of signs may not be appreciated

Maintenance needs + percent dehydration + ongoing losses = Volume to be infused 24 Hours Maintenance fluid is usually calculated at 40 to 60 ml/kg/ day, with calculations ideally based on lean body weight. Smaller animals tend to need more fluids per day, while larger animals require a smaller amount on a non-linear per kilogram basis. Dehydration percentage can be calculated many ways, most commonly based on a combination of historical and physical examination findings (Table 1-2). Clinical signs of dehydration include tacky or dry mucous membranes, increased skin turgor, eyes sunken within orbits, and weight loss. Moisture of mucous membranes and skin turgor, however, are at best crude estimates of dehydration. Patients who pant excessively may have dry mucous membranes, and young or obese patients with dehydration may be assessed as having normal skin turgor due to a large amount of SC water or fat. Conversely, older euhydrated patients may be assessed as dehydrated due to a lack of SC fat and elastin. Ongoing fluid losses should be estimated and reassessed over the first 12 to 24 hours of fluid therapy. As an example, a 20-kg dog with severe vomiting and diarrhea is estimated to be 10% dehydrated; one approach to fluid therapy might be:

5

1. Calculate maintenance fluids: 60 ml/kg/day × 20 kg = 1200 ml/day. 2. Calculate dehydration fluids: 20 kg × 0.1 × 1000 = 2000 ml (percentage dehydration may be converted to a decimal, and the result multiplied by 1000 to determine ml). 3. Estimate ongoing losses: This is harder to do, but one might guess 250 ml. The sum of 1200 + 2000 + 250 = 3450 ml or approximately 144 ml/hr infused over 24 hours to rehydrate the patient. For this example fluid rate would likely be rounded to 150 ml/hr. Some clinicians prefer to rehydrate over 12 hours and then decrease fluid rates based on the patient’s response. Acute changes in body weight also can be used to judge fluid loss, with 1 gm roughly equal to 1 ml of fluid. Fluids are sometimes dosed in “multiples of main­ tenance” such as twice maintenance fluids. Twice maintenance fluids is basically the same as maintenance fluids plus 5% dehydration deficits; thus this may be used if preferred or if easier for calculation purposes. However, an animal with polyuria/polydipsia (PU/PD) may have higher than average maintenance needs, and this method may underestimate the patient’s actual needs. Conversely, some disorders can make a patient intolerant of an otherwise reasonable volume of crystalloid. This is more likely when there is enhanced potential for sodium and water retention as can occur with advanced cardiac disease, hyperthyroidism, hypoproteinemia, and moderate-to-severe anemia. No matter which formula is used to calculate fluid rates, the patient should be evaluated at regular intervals. Parameters to reassess include the physical examination findings, urine production, heart rate, attitude, and body weight. Jugular venous pressure is an oftenoverlooked estimate of volume status, especially in cats. Onset of tachypnea also may indicate circulatory overload. The patient should be evaluated for evidence of overhydration or ongoing dehydration. Additionally, patients should be observed for improvement in the clinical signs that caused the dehydration, such as vomiting or polyuria. Daily weights and in-house laboratory testing such as packed cell volumes and total solids are also helpful, as is following serum electrolytes and acidbase status. Fluid rates should be assessed and altered as needed, at least twice a day, and the fluid therapy discontinued as soon as the patient is recovered. In patients with ongoing renal disease or in situations in which it is unclear if the patient can drink enough to maintain hydration, it helps to taper fluids over 24 to 48 hours. In animals with resolved disorders, such as acute gastroenteritis, fluid therapy may be abruptly stopped.

Fluid Therapy in Special Cases Crystalloid therapy is one of the most important treatments available to critically ill veterinary patients. Certain diseases require specific considerations, and fluid plans should be tailored to meet individual needs. Some important examples follow.

6

SECTION  I  Critical Care

Polyuria/Polydipsia Fluid therapy in conditions of PU/PD can be challenging. As illness progresses, the animal may be drinking large amounts (>50 ml/kg/day) of fluids; after dehydration develops, the patient needs much higher than anticipated fluid volume replacements in order to achieve rehydration. It helps to recall the common diseases that usually result in loss of urine concentrating ability, including renal diseases, hyperthyroidism, hypercalcemia, hypoadrenocorticism, hepatic shunts, and diabetes insipidus. Also, other common conditions can result in dilute urine including unregulated or poorly regulated diabetes mellitus and hyperadrenocorticism, as well as exogenous glucocorticoid therapy, phenobarbital therapy, and treatment with diuretics. It is especially difficult to know the pre­ renal contribution to azotemia in a dehydrated patient who has been receiving furosemide. Additionally, post­ obstructive diuresis, as follows urethral obstruction, may create large volumes of dilute urine. Dogs that pant or vocalize excessively may also have increased fluid needs, a finding that may be underappreciated. Some of these patients lose so much free water with panting and vocalizing that hypernatremia may develop.

Pulmonary Contusion Patients with pulmonary contusions (as well as some other parenchymal injuries such as noncardiogenic pulmonary edema) have altered vascular permeability and increased lung water at the site of the contusion. Fluid therapy, especially colloids, can extravasate and exacerbate the functional lung injury, worsening ventilation (V)/perfusion (Q) mismatch and gas exchange. However, many traumatized animals are also hypovolemic and require some IV fluids to restore circulating intravascular volume and support arterial BP. This leads to a dilemma: deciding to volume resuscitate these patients with pulmonary lesions versus fluid-restricting to prevent worsening of the lung injury. Guidelines advanced by some criticalists are to err on the conservative side for crystalloid fluid resuscitation (e.g., 10 to 25 ml/kg as a bolus) and to avoid colloids. Additionally, pneumothorax commonly accompanies lung contusion, so if the patient is showing respiratory compromise, further diagnostic imaging or diagnostic thoracocentesis is recommended.

Head Trauma Patients with head trauma commonly present in hypovolemic shock; to maintain cerebral perfusion and reduce cerebral ischemia, fluid therapy should be implemented to restore and maintain normal mean arterial BP (80 to 100 mm Hg). To prevent fluid therapy from contributing to cerebral edema, patients without electrolyte disturbances should be administered 0.9% saline. Water is able to freely cross the blood-brain barrier (BBB), but sodium is not. Because it has the highest sodium concentration of the isotonic crystalloids, 0.9% saline is least likely to contribute to cerebral edema. Additionally, some euhydrated patients with hypotension due to hypovolemia and clinical signs of increased

intracranial pressure (altered mentation, cranial nerve deficits, abnormal postures) can be treated with 7% hypertonic saline (2 to 4 ml/kg over 15 to 20 minutes). The high osmolarity of this solution draws water across the BBB as well as from the interstitium, reducing cerebral edema. This solution also has beneficial rheologic effects, increases cardiac contractility, and reduces edema and dysfunction of the BBB. As described earlier, a mixture of 23.4% hypertonic saline and a synthetic colloid will have similar effects, with the added benefit of prolonged volume expansion compared with administration of a crystalloid alone (see Chapter 2).

Cardiopulmonary Arrest Administration of IV fluids in euvolemic or hypervolemic patients with cardiopulmonary arrest (CPA) does not increase cardiac output and, due to the resulting increase in venous pressure, commonly reduces tissue blood flow and perfusion. Coronary artery perfusion pressure is defined as the diastolic aortic pressure minus right atrial pressure; thus increasing right atrial pressure will decrease coronary artery perfusion pressure. However, administration of IV fluids during cardiopulmonary resuscitation (CPR) is reasonable in patients with documented or suspected hypovolemia, although it is wise to use conservative doses of isotonic crystalloids (20 ml/kg over 15 to 20 minutes) during CPR. In the postarrest period, hemodynamic optimization targeted at restoring adequate oxygen delivery and tissue perfusion is essential. Crystalloid fluid therapy helps restore intravascular volume and compensate for the peripheral vasodilation that commonly occurs due to acidemia (from respiratory and metabolic acidosis), hypoxic endothelial damage, and ischemia-reperfusion injury. Ideally, intravascular volume status should be assessed objectively in these patients using central venous pressure with a target of 6 to 10 cm H2O. In patients without central lines, indirect measures such as extent of jugular vein filling, oral mucous membrane color, and capillary refill time may be helpful. Due to the high incidence of postarrest cerebral edema, 0.9% saline (or 7% hypertonic saline in euhydrated patients) is preferred. For further information on goal-directed postarrest care, see Chapter 5.

Potassium Supplementation Potassium supplementation to crystalloids is warranted in hypokalemic therapy and in patients at risk for potassium depletion. Risk factors for hypokalemia include anorexia, PU/PD, diuretic therapy, hypomagnesemia, metabolic alkalosis, insulin therapy, β-agonist toxicity, and catecholamine therapy. Some clinicians routinely use a sliding scale (Table 1-3) to help determine the amount of potassium to add to the fluids. Animals with marked potassium deficits can be PU/PD patients (e.g., diabetic patients or patients with chronic renal failure) and require larger volumes of crystalloids for maintenance or they can be dehydrated cardiac patients receiving diuretic therapy necessitating fluid rates that are more conservative. Potassium supplementation rates should be adjusted accordingly in these individuals. The reported maximum

CHAPTER  1  Crystalloid Fluid Therapy

TABLE 1-3  Sliding Scale for Addition of Potassium to IV Fluids (Originally Proposed by Dr. Richard Scott)* Serum Potassium (mEq/L)

Millequivalents of KCl to Add to 1 L Fluids

Maximal Fluid Infusion Rate (ml/kg/hr)

60 mEq/L of potassium to decrease the likelihood of phlebitis.

potassium that should be administered to non-oliguric patients is 0.5 mEq/kg/hr (0.5 mmol/kg/hr), although some patients with severe polyuria and cellular potassium depletion (e.g., diabetic ketoacidosis) may require higher rates in rare instances. High concentrations (>60 mEq/L) of potassium in fluids irritate the peripheral vessels and should ideally be given through a central catheter. Two examples may be instructive. In the first an elderly 4-kg cat has chronic renal failure, anorexia, and serum potassium of 2.7 mmol/L. He is approximately 10% dehydrated, and his fluid replacement needs are calculated to be 28 ml/hr owing to his degree of dehydration and preexisting PU/PD. If we chose to correct his potassium deficits at one half the maximal allowable supplementation rate (see above), the dose would be 1 mEq KCl per hr, with a total volume infusion of 30 ml/hr. This supplementation would represent the addition of 35 mEq of KCl per liter of isotonic crystalloid. In the second example, a cat of identical age and body weight is diagnosed with congestive heart failure due to hypertrophic cardiomyopathy. He was treated aggressively with furosemide, is currently out of heart failure, but is slightly dehydrated and persistently anorexic, with a serum potassium of 2.8 mEq/L. If a conservative crystalloid fluid rate of 5 ml/ hr is selected and again supplemented with potassium at one half the maximal allowable infusion rate, a concentration of 200 mEq of KCl per liter of crystalloid would be required. This concentration would be irritating to the vessels, and thus ideally a central line might be used. Alternatively, it may be preferable to decrease the added potassium to 60 mEq/L (or less) and supplement potassium orally.

7

goals of fluid therapy and the preferences of both the clinician and the client. IV fluid therapy is the standard for hospitalized patients and in urgent situations. Some solutions, such as hypertonic solutions or those supplemented with high concentrations of potassium, only should be administered IV. However, SC fluids may be more practical in some situations and the following comments pertain to this route of administration. SC fluids are warranted in smaller animals that are dehydrated or at risk of dehydration (e.g., patients with chronic renal failure). For hospitalized pets or those treated as outpatients, SC fluids can be administered and then permitted to absorb slowly. The rate of fluid absorption depends on the volume administered, the patient’s hydration status, and the perfusion to the SC space. Some elderly cats take a long time to absorb fluids, and fluids may migrate to gravity-dependent areas such as the limbs. Most clients can be taught to administer SC fluids at home, and this treatment is often well tolerated. For some clients, long-term SC fluid therapy is most easily accomplished with the placement of a SC port,* which prevents the need to “stick” the patient. In most cases, the standard needle, dripset, and fluid bag are preferred. Overall, complications from SC fluids are uncommon. However, potential complications include failure to absorb fluids adequately and SC pooling. Rarely, injection site infections or abscesses have been observed, most frequently in the immunocompromised patient (e.g., a puppy with parvoviral enteritis). Only isotonic fluids should be given SC; 20 mEq/L KCl may be added, but no other additives. Hypotonic and hypertonic fluids should never be administered SC. Dosage for SC fluids depends on patient size, underlying renal function, the size of the SC, and the degree of dehydration. The single most important determinate of fluid dosing in dehydration is the presence or absence of a PU/PD condition (see earlier). A cat with chronic renal failure may benefit from 150 to 250 ml/cat per day for months, whereas a cat with moderate GI upset may be adequately rehydrated with a single dose of 100 ml.

References and Suggested Reading

Fluids may be administered SC, intraosseously (IO),* or IV. Older textbooks describe intraperitoneal fluid therapy, but this route is rarely used. The route of fluid reflects the

Bickell WH et al: Immediate versus delayed fluid resuscitation for hypotensive patients with penetrating torso injuries, N Engl J Med 331(17):1105-1109, 1994. Boysen SR et al: Effects of prednisone on blood lactate concen­ trations in healthy dogs, J Vet Intern Med 23(5):1123-1125, 2009. DiBartola SP, Bateman S: Introduction to fluid therapy. In Fluid, electrolyte, and acid-base disorders in small animal practice, ed 4, St Louis, 2012, WB Saunders. Drobatz KJ, Cole SG: The influence of crystalloid type on acidbase and electrolyte status of cats with urethral obstruction, Vet Emerg Crit Care 18:355-361, 2008. Hammond TN, Holm JL: Limited fluid volume resuscitation, Compend Contin Educ Vet 31(7):309-321, 2009. Pachtinger GE, Drobatz K: Assessment and treatment of hypovolemic states, Vet Clin North Am Small Anim Pract 38(3):629-643, 2008.

*EX-IO, Vidacare, San Antonio, TX.

*GIF tube, PractiVet, Phoenix, AZ.

Route of Fluid Administration

CHAPTER 

2 

Colloid Fluid Therapy ELKE RUDLOFF, Glendale, Wisconsin REBECCA KIRBY, Glendale, Wisconsin

S

evere intravascular volume depletion associated with conditions such as hemorrhage, trauma, systemic inflammatory response syndrome (SIRS) diseases, and various metabolic diseases ultimately results in poor tissue perfusion, tissue hypoxia, and cellular energy depletion. As a consequence, vascular tone can be lost and capillary permeability can be increased, leading to maldistribution of fluid between fluid compartments. Timely and appropriate intravascular fluid resuscitation becomes the mainstay of treatment to restore perfusion and oxygen delivery. The goals of resuscitation and maintenance fluid therapy in the critically ill animal are to restore and maintain perfusion and hydration without causing volume overload and complications caused by pulmonary, peripheral, or brain edema. By using colloid fluids in conjunction with crystalloid fluids (see Chapter 1), goal-driven resuscitation (also known as end-point resuscitation) can be achieved more rapidly and with less fluid volume compared with crystalloid fluids alone. Maintaining an effective circulating volume can be challenging when there is vascular leakage, vasodilation, excessive vasoconstriction, inadequate cardiac function, hypoalbuminemia, or ongoing fluid loss. Whether a fluid administered intravenously remains in the intravascular compartment or moves into the interstitial or intracellular spaces depends on the dynamic forces that affect fluid movement between body fluid compartments.

Fluid Dynamics The body fluids are distributed between three major compartments: intracellular, intravascular, and interstitial. The cellular membrane defines the intracellular space and is freely permeable only to water. Most ions must enter the cell by specific mechanisms such as channels, solvent drag, carriers, or pumps. Intracellular ions help retain water within the cell by osmosis. The intravascular space is contained within a vascular semipermeable “membrane” composed of a single thin glycocalyx surface lining the endothelium. Fluid and nutrient exchange between the blood and the tissues occur primarily at the level of the capillary membrane. Larger molecules such as the plasma proteins (albumin, fibrinogen, and globulins) are too large to freely cross this semipermeable membrane. The modified Starling-Landis equation defines the forces that control the rate of the flow of fluid between the capillary and interstitium as: 8

V = k [(HPc − HPi ) − σ (COPc − COPgc )] − Q where V = filtered volume, k = filtration coefficient, HP = hydrostatic pressure, c = capillary, i = interstitial fluid, gc = subendothelial glycocalyx, σ = membrane pore size, COP = colloid osmotic pressure, and Q = lymph flow. The main components that control intravascular fluid volume include intravascular colloid osmotic pressure (COP) and hydrostatic pressure (HP) (Figure 2-1). Eighty percent of the COP is produced by albumin, which is the most abundant extracellular protein. The pressure generated by albumin is augmented by its negative charge, which attracts cations (e.g., sodium) and water around its core structure. This unique dynamic is termed the GibbsDonnan effect. Vascular permeability to ion species, ionic concentration gradients, and electrochemical charges influence the movement of ions such as sodium, potassium, and chloride. Capillary membrane pore size and the filtration coefficient control the ease with which larger molecules such as albumin leave the intravascular space. Pore size varies from tissue to tissue (e.g., continuous capillaries in the brain and fenestrated capillaries in the liver). The filtration coefficient is variable and partly dependent on the amount of albumin in the intravascular space and within the interendothelial cleft. The dynamics of normal fluid movement across the capillary membrane can change with certain diseases. Fluid moves from the intravascular to the interstitial or third-space compartment under certain conditions (Figure 2-2 and Table 2-1). Plasma COP can increase with water loss (hemoconcentration), remain the same when there is acute hemorrhage, or decrease with protein loss. In addition to capillary dynamics, the composition of intravenously administered fluids determines how these fluids are distributed across fluid compartments.

Basic Colloid Fluid Pharmacology The two major categories of intravenous fluids are crystalloids (see Chapter 1) and colloids. A crystalloid fluid is a water-based solution with small molecules permeable to the capillary membrane. A colloid fluid is a crystalloidbased solution that contains large molecules that do not easily cross normal capillary membranes. When large volumes are needed for intravascular fluid resuscitation, crystalloids alone may fail to provide effective intravascular volume support without causing interstitial volume overload and edema. Ultimately the selection of a colloid or a combin­ ation of a colloid with a crystalloid for intravenous

CHAPTER  2  Colloid Fluid Therapy Intravascular compartment

Interstitial compartment

9

TABLE 2-1  Examples of Conditions That Result in Movement of Fluid Out of the Intravascular Space

HP

COP

Colloid molecule Cations and water molecule

Figure 2-1  The main components of the Starling-Landis equa-

tion that affect intravascular water content include intravascular hydrostatic pressure (HP) and colloid osmotic pressure (COP). The intravascular HP is a result of intravascular volume, cardiac output (CO), and systemic vascular resistance (SVR). Under normal conditions the HP favors the movement of fluid from the vessel into the interstitium. The COP is the force that opposes intravascular HP, supporting intravascular water retention. The COP is generated by the presence of large molecules (primarily proteins) that do not readily pass the capillary membrane and create an osmotic effect.

Intravascular compartment CO

Interstitial compartment

SVR

HP

COP

Colloid molecule Cations and water molecule

Figure 2-2  Fluid can pass out of the intravascular space under

several conditions listed in Table 2-1: increased intravascular hydrostatic pressure (HP), increased capillary permeability, decreased filtration coefficient, and decreased intravascular colloid osmotic pressure (COP). These conditions lead to the consequences of peripheral edema and hypovolemia.

Condition

Example

Plasma to interstitial HP gradient increases over the COP gradient

Hypertension Fluid overload

Capillary membrane pore size becomes larger

SIRS-associated diseases • Pancreatitis • Peritonitis • Sepsis • Severe gastroenteritis • Burns • Multitrauma • Vasculitis

The filtration coefficient changes

Burns Hypoalbuminemia Hypervolemia

Intravascular COP falls below interstitial COP

Hypoalbuminemia • SIRS disease • Liver dysfunction • Protein-losing nephropathy/ enteropathy

COP, Colloid osmotic pressure; HP, hydrostatic pressure; SIRS, systemic inflammatory response syndrome.

resuscitation and maintenance is based on the pharmacology of the fluid and the disorder that requires treatment. Each colloid solution is unique, and knowledge of the composition and pharmacology of the fluid is needed to make an appropriate colloid selection for an individual patient’s needs (Table 2-2). Differences in macromolecular structure and weight dictate the colloid osmotic effect, method of excretion, and half-life of the colloid solution. The larger the number of small molecules per unit volume of the colloid, the greater will be the initial colloid osmotic effect and plasma volume expansion. When the number of large molecules per unit volume of colloid is high, the colloid is retained longer within the vascular space. Solutions that contain naturally produced proteins such as albumin (whole blood, plasma products, and concentrated human and canine albumin solutions) or hemoglobin (hemoglobin-based oxygen carriers [HBOCs]) are referred to as natural colloids. Solutions that contain synthetically derived colloid particles such as hydroxyethyl starches (HESs) (hetastarch and tetrastarch) are referred to as synthetic colloids. Large-volume fluid resuscitation decreases the con­ centration of coagulation proteins in the plasma and can cause a dilutional coagulopathy. Synthetic colloids are not a substitute for blood products when albumin, hemoglobin, antithrombin, or coagulation proteins are needed. At the present time, albumin products and HESs are the most readily available and commonly used colloids in the United States. Although HBOCs are not available for clinical use at this time, they are being

307 308 326

6% Hetastarch 670/0.75 (Hextend)

6% Tetrastarch 130/0.4 (VetStarch)

10% Pentastarch 260/0.45 (Pentaspan)

COP, Colloid osmotic pressure.

310

6% Hetastarch 600/0.7 (Hespan)

Synthetic

5.0

4-6.5

5.9

5.5

7.8

154

154

143

154

150

0

Oxyglobin

300

140

Lyophilized canine albumin

Variable

140

Na+ (mEq/L)

0

300

Frozen plasma

Variable

pH

25% Human albumin

300

Osmolarity (mOsm/L)

Whole blood

Natural

Colloid

Characteristics of Colloid Fluids

TABLE 2-2 

154

154

124

154

118

0

0

110

100

Cl– (mEq/L)

0

0

3

0

4

0

0

4

4

K+ (mEq/L)

0

0

0.9

0

0

0

0

0

0

Mg2+ (mEq/L)

0

0

5

0

0

0

0

0

0

Ca2+ (mEq/L)

0

0

0.99

0

0

0

0

0-4

0-4

Dextrose (g/L)

None

None

Lactate

None

Lactate

None

None

None

None

Buffer

66

36

31

32

40

200

20

20

COP (mm Hg)

C2 : C6 = 4.5 : 1

C2 : C6 = 9 : 1

C2 : C6 = 4 : 1

C2 : C6 = 4-5 : 1

Miscellaneous

10 SECTION  I  Critical Care

CHAPTER  2  Colloid Fluid Therapy continuously evaluated in experimental studies and are expected to be reintroduced in the near future.

Albumin Albumin, the most abundant colloid molecule in plasma, can be administered through plasma transfusions, canine lyophilized albumin, or concentrated (25%) human albumin. Allogeneic blood products contain approximately 2.5% albumin. The size of the albumin molecule is constant, and the higher the concentration of albumin, the greater the colloid osmotic effect per milliliter of solution. Plasma transfusions have an albumin concentration equal to that of plasma and may not increase intravascular COP significantly when administered as the sole colloid solution. Availability of plasma in an unfrozen form (i.e., liquid plasma) reduces the time to administration; refrigerated liquid plasma is also advocated by some for use during resuscitation of coagulopathic animals. Because of its high concentration of albumin and high COP (200 mm Hg), 25% human albumin has the greatest capability for increasing plasma COP. When capillary permeability is normal, 25% albumin can be an effective colloid for rapid intravascular volume expansion. It also can be used to minimize interstitial edema in animals with hypoalbuminemia caused by inadequate albumin production or renal and gastrointestinal albumin loss. However, when increased capillary permeability allows plasma albumin to pass into the interstitium, the initial intravascular COP benefits of albumin infusion are temporary and increased interstitial COP and edema may result. Human albumin has physiochemical properties that differ from canine and feline albumin, and complications appear to occur at a higher rate (about 20%) with human albumin administration in dogs than with allogeneic transfusions. This risk is reduced when the solution is diluted to a 5% concentration with 0.9% saline and administered over 10 to 24 hours. Acute and delayed immune-mediated reactions have been reported after the administration of human albumin, allogeneic plasma, and blood, requiring vigilant monitoring for allergic reactions when any of these colloids are used. Accordingly, these colloids are administered slowly for the first hour, with careful monitoring for adverse reactions, before increasing to standard recommended rates of infusion. A 5-g lyophilized canine albumin (www.ABRInt.net) recently has been developed for use as a replacement colloid in the treatment of hypoalbuminemia in dogs. It is stored in a dehydrated powder form and reconstituted with isotonic saline to a desired concentration. Information on its clinical use is limited to albumin replacement in dogs with hypoalbuminemia and septic peritonitis, but not for volume replacement.

Hemoglobin-Based Oxygen Carrier Solutions The hemoglobin contained in HBOC solutions binds with oxygen, transporting it to the tissues. Because of their

11

small size, HBOC molecules sometimes can pass through the microcirculation more effectively than red blood cells. Their colloidal properties, oxygen-carrying capacity, and low antigenicity may make HBOC solutions an ideal fluid for animals with severe anemia, hypotension, or hypovolemia. Oxyglobin (Dechra) is a stroma-free, ultrapure bovineorigin polymerized hemoglobin solution approved by the Food and Drug Administration for therapeutic use in dogs with anemia. Oxygen is bound to hemoglobin by a chloride-dependent process, facilitating its release at the capillary. In addition to acting as a temporary oxygencarrying substitute for red blood cells, the product maintains osmotic pressure and exerts a vasoconstricting effect that can reduce the volume required for resuscitation. It can be stored at room temperature with a 3-year shelf life if unopened, making it more readily available and transportable than whole blood; has universal compatibility; and is unlikely to transmit hematogenous diseases. Oxyglobin is excreted in the urine and bile. Limitations include a short half-life (40 hours) once administered, interferences with enzyme-based chemistry analyses, and requirements for red blood cell replacement if significant anemia is present. Side effects occur most commonly in euvolemic patients and include pulmonary edema, vomiting and diarrhea, and hypertension. These can be minimized by slow administration of small quantities, titrated to effect.

Hydroxyethyl Starch HES, the parent name of a synthetic polymer of glucose (98% amylopectin), is made from a waxy species of plant starch (either maize or sorghum). It is a highly branched polysaccharide that closely resembles glycogen and is formed by the reaction between ethylene oxide and amylopectin in the presence of an alkaline catalyst. The molecular weight and molar substitution can be adjusted by replacing hydroxyl groups with hydroxyethyl groups at the C2, C3, and C6 positions on the glucose molecule. The greater the substitution on position C2 in relation to C6 (the C2 : C6 ratio), the slower the degradation of the molecule by amylase. Renal function has been shown to decline after infusion of hetastarch with molar substitutions greater than 0.62 in human patients undergoing surgery and receiving 10% (hyperoncotic) solutions. This adverse effect has not been identified in animals. Renal effects of lower molar substitutions and 6% solutions are currently under evaluation. The number-averaged molecular weight (Mn) is the arithmetic mean of the molecular weights of the polymers in solution. Weight-averaged molecular weight (Mw) is the sum of the number of molecules at each Mn divided by the total of all molecules. This weight is generally larger when larger polymers are present in a solution. The classification of different HES products includes the ratio of the Mw and the degree of substitution. There are three HES products clinically available in the United States at this time: hetastarch (0.7-degree substitution), pentastarch (0.5-degree substitution), and tetrastarch (0.4-degree substitution). Hetastarch can be purchased in 0.9% saline (Hespan; Mw of 450 kD) or in lactated Ringer’s

12

SECTION  I  Critical Care

solution (LRS) (Hextend; Mw of 670 kD). The electrolyte and buffer compositions of Hextend may reduce the incidence of hyperchloremic acidosis. Hextend also contains 0.45 mmol/L of magnesium and 99 mg/dl (0.99%) of dextrose. A tetrastarch, VetStarch (Mw of 130 kD), is new to the U.S. veterinary market; this solution’s higher C2 : C6 ratio (9 : 1) increases its half-life compared with the hetastarch solutions. Pentaspan is a 10% pentastarch solution (Mw of 200 kD) that has a lower average molecular weight than hetastarch. Although HES can adversely affect von Willebrand’s factor, factor VIII, and platelet function, as well as reduce fibrin polymerization, clinical evidence of bleeding has not been reported in animals receiving 6% HES 450/0.7 (Hespan) at doses up to 20 ml/kg/day. The use of 6% hetastarch in LRS (Hextend) may be associated with fewer coagulation abnormalities when compared with 6% hetastarch in saline (Hespan) because it contains calcium, which can become depleted in coagulopathic states. Because of a lower Mw and degree of substitution, the use of 6% HES 130/0.4 is associated with few coagulation abnormalities, and doses up to 50 ml/kg have been recommended. A differential charge may exist between administered HES molecules and the capillary pore, blocking the passage of HES molecules into the interstitium. This property is independent of molecular size. HESs may also down-regulate and decrease expression of endothelial surface adhesion molecules, which has been reported to decrease cytokine release, inflammation, endothelial injury, and leukocyte migration into the interstitium. HESs have been shown to reverse changes in microvascular permeability caused by oxygen-free radicals during reperfusion injury. This may explain why HES molecules remain in the vascular space in the septic patient when albumin does not (Marx et al, 2002).

Smaller HES molecules are filtered through the glomerulus and excreted in the urine, excreted through the bile, or passed into the interstitium and ingested by macrophages. Larger molecules are degraded by α-amylase into smaller HES molecules. Ongoing studies will better define the safety of various HES solutions on renal function. The authors have observed signs of nausea, occasional vomiting, and hypotension with rapid infusion of hetastarch in cats. Slow administration of small-volume increments has eliminated these side effects in cats.

Clinical Use Goals for colloid administration include increasing intravascular volume and improving systemic blood flow while maintaining intravascular COP. Selection of a specific colloid or colloids is based on individual traits of the product and the disease under treatment (Tables 2-2 and 2-3). In hypercoagulable animals, the hetastarch solutions may be more useful, whereas in hypocoagulable animals, the tetrastarches may be more suitable for volume expansion. Because at least 75% of the volume of isotonic crystalloid administered into the intravascular fluid compartment translocates into the interstitial fluid compartment within 45 minutes, there is an increased risk for formation of interstitial edema in clinical settings of moderate to severe hypovolemia or systemic inflammation (see Figure 2-2). The 6% HES solutions are effective for expanding intravascular volume while minimizing interstitial edema. The 10% HES solutions are considered hyperoncotic and can increase intravascular volume by 175%. When there is a coexistent coagulopathy, VetStarch may be the colloid of choice for acute volume replacement. If large volumes of HES are required to restore perfusion, plasma or whole blood transfusions may be

TABLE 2-3  Colloid Choices and Resuscitation Goals Used Based on Hypovolemic Condition in Dogs* Condition

Resuscitation Colloid

Resuscitation Goal

Hypovolemic and/or traumatic shock

6% HES Oxyglobin

MAP 60-80 mm Hg HR normal CVP 8-10 cm H2O

Trauma or edema in the brain or lungs

6% HES Oxyglobin

MAP 60 mm Hg† HR 90% protein binding) that have a narrow therapeutic range. In these cases, low albumin levels lead to more pharmacologically active free drug at standard dosing, increasing the risk of toxicity. Examples of common drugs with high protein binding include nonsteroidal antiinflammatory drugs (NSAIDs) and benzodiazepines (see Table 6-2).

Kidney Disease The kidneys are involved in clearance of many watersoluble (hydrophilic) drugs. Drug clearance is compromised either due to decreased drug delivery to the kidneys (as with massive vasodilation, decreased perfusion, or severe dehydration) or if intrinsic renal disease is present. In human patients the standard recommendation is that dosage adjustments for drugs primarily eliminated by the kidney should occur when 67% of renal function (i.e., when urine concentrating ability) is lost. Creatinine clearance is the best guide for drug dosage adjustments because functional tubular secretion and creatinine clearance decrease at parallel rates. For drugs excreted in the urine, the elimination half-life remains stable until the creatinine clearance is reduced by 30% to 40%. Unfortunately, creatinine clearance is not readily available in dogs and cats; therefore the patient’s serum creatinine may be used to estimate creatinine clearance and thus aid in proportionally adjusting the dosages of those drugs primarily excreted by the kidneys. However, this approach has limitations because the relationship between serum creatinine and creatinine clearance is linear only up to a serum creatinine of about 4 mg/dl. Therefore clinically monitoring the patient’s response following dosage adjustment remains important. Table 6-2 outlines drugs in which dosage adjustments are recommended for patients with kidney disease. Due to the potential for direct renal toxicity, nephrotoxic drugs (e.g., NSAIDs) should be completely avoided in patients with kidney disease. Serum creatinine can be used to reduce the dose or to adjust the dosing interval. Drugs commonly adjusted by dose are those with relatively high safety margins that require a minimum drug concentration during the dosing interval. Examples include time-dependent antibiotics such as penicillins and cephalosporins, anticonvulsants, and cardiac drugs. The new drug dose is calculated using the following equation:

New dose = Standard dose ×

Normal serum creatinine Patient’s serum creatinine

Interval adjustment is most appropriate for drugs that remain effective at low concentrations or have a long elimination half-life. These include the concentrationdependent antibiotics with postantibiotic effects such as aminoglycosides and fluoroquinolones, as well as glucocorticoids. The new dosing interval is calculated using the following equation: New interval Normal serum creatinine  = Standard interval ×  1 ÷   Patient’s serum creatinine  Uremic patients are also at increased risk for drug toxicities due to altered tissue receptors, changes in protein binding, or electrolyte abnormalities. For example, acidic drugs such as NSAIDs, penicillins, furosemide, and anticonvulsants have decreased protein binding, increased concentration of free active drug, and increased clearance in uremic patients. Basic drugs such as diazepam, propranolol, and prazosin have increased protein binding, decreased concentrations of free drug, and decreased clearance in uremic patients. The clinical significance of altered protein binding of acidic and basic drugs is difficult to predict based on the compensatory changes in drug clearance in association with the increase or decrease in free drug available for metabolism and elimination. Dosage adjustments should be made on an individual basis.

Cardiovascular Disease The most common form of cardiac disease seen in the ICU setting is cardiac failure, primarily due to left-sided congestive heart failure (CHF). In CHF there is an increase in total body water as well as a decrease in the effective perfusion of tissues. Together these alter the distribution of drugs to common sites such as skeletal muscle or reduce the delivery to sites of drug clearance such as the liver and kidney. For example, clearance of drugs dependent on hepatic blood flow (lidocaine, propranolol, calcium channel blockers, and opioids) may be reduced, resulting in accumulation or toxicity. Similarly impaired renal perfusion can lead to toxicosis of drugs requiring renal elimination such as digoxin and potentially atenolol. Dosage adjustments should therefore be considered in CHF patients for drugs that have significant distribution to skeletal muscle as well as for those cleared by the liver or kidney. For example, digoxin has significant distribution to skeletal muscle and therefore should be dosed on lean body weight (see Table 6-2). Diuretics such as furosemide alter the amount of total body water, which further impacts drug distribution while potentially increasing the clearance of some drugs by the kidneys, provided renal perfusion is not markedly diminished from volume contraction. Furosemide also significantly alters serum potassium and magnesium concentrations, and these electrolyte disturbances can alter the action of some drugs. For example, hypokalemia

CHAPTER  6  Drug Incompatibilities and Drug-Drug Interactions in the ICU Patient increases the risk of digoxin toxicity and decreases the efficacy of lidocaine (see Table 6-2). Other cardiovascular conditions seen in the ICU are of concern. The patient with either a tachyarrhythmia or bradyarrhythmia may experience reductions of cardiac output and blood delivery of drugs to the kidney and liver. Systemic hypertension can impair cardiac output and more importantly cause end-organ damage to the kidneys.

Gastrointestinal Disease Patients are often treated for gastrointestinal (GI) disease in the ICU. Typically, the GI tract manifests disease as inflammation, bleeding, or alterations in motility. GI disease can be the primary condition or secondary to another disease (e.g., GI bleeding associated with sloughing of the gut lining due to hypoperfusion). Changes in motility can be transient (e.g., as with anesthetic-related events), secondary to the effects of other medications, or a result of the patient’s primary disease. GI drug absorption is a function of GI pH, motility, epithelial permeability, surface area, and blood flow. In the critically ill patient, changes in GI motility and blood flow can influence the rate and extent of absorption of orally administered drugs. This can cause prolonged time for oral drug absorption and delay the drug’s onset of action. In addition, opioid administration negatively impacts GI motility. In the critically ill patient intravenous drugs are often indicated to remove any questions about compromised oral absorption or peripheral hypoperfusion. Once the patient is stabilized hemodynamically and has resumed eating, oral, subcutaneous, or intramuscular drug administration can be reintroduced. Table 6-2 lists some of the common therapies used in patients with GI disease and associated with clinically significant drug-drug interactions. Additional clinically significant drug interactions associated with GI therapies involve drugs that modify gastric pH (especially cimetidine), sucralfate, and NSAIDs. Drugs that raise gastric pH such as the H2 blockers and proton pump inhibitors may impact the oral absorption of some drugs, as well as exert other effects on drug metabolism. Cimetidine is a particularly notable H2 blocker with CYP 450 inhibition, which alters the disposition of substrate drugs such as theophylline, cyclosporine, and verapamil, leading to drug-drug interactions (see Table 6-3). Among other H2 blockers, famotidine and ranitidine do not inhibit CYP 450 and therefore are preferred in small animal patients when H2 blockers are used to treat gastric ulceration. However, these drugs—as well as the proton pump inhibitors related to omeprazole (Prilosec)—increase gastric pH, enhancing absorption of drugs that are weak bases and impairing absorption of drugs that are weak acids. For example, some of the drugs used in critically ill patients that are weak acids include aspirin, diazepam, furosemide, ketoconazole, and itraconazole (Reynolds, 1990). To optimize oral absorption of these drugs, H2 blockers or proton pump inhibitors should be discontinued. Alternatively in cases of GI disease, the clinician can choose drugs whose oral absorption is not altered by gastric pH (e.g., fluconazole).

37

Other drugs used to manage GI ulceration include aluminum-containing antacids and sucralfate. These drugs prevent the oral absorption of drugs that can chelate with aluminum including fluoroquinolones, tetracyclines, and digoxin. If sucralfate is indicated in a patient concurrently treated with oral fluoroquinolones, tetracyclines, or digoxin, the recommendation is to administer the other drugs 2 hours prior to the administration of sucralfate to optimize drug absorption. NSAIDs inhibit cyclooxygenase (COX-1 and/or COX-2) and glucocorticoids inhibit phospholipase A2. The net effect of each drug class is to decrease prostaglandin production and lead to clinically significant GI ulceration and bleeding. The concurrent administration of NSAIDs and glucocorticoids is contraindicated due to the high risk of GI ulceration and perforation.

Sepsis/Infection/Systemic Inflammation Septic patients suffer from complex and multifactorial disease processes (see Chapter 4). However, in cases of significant inflammation (whether idiopathic or resulting from generalized or localized infection) most patients develop some degree of vasodilation and injury to vascular endothelium. In both situations, blood flow to the liver and kidneys is decreased and this can impair drug elimination. Other organs are often ineffectively perfused, which can lead to reduced efficacy in organs targeted by specific drugs. Significant inflammation leads to reduced albumin production by the liver, often causing dramatic reductions in albumin levels (see Table 6-2). Drug dosage adjustments are recommended in septic patients with third-spacing or peripheral edema. Lipidsoluble drugs such as fluoroquinolones should be dosed based on lean body weight. Water-soluble drugs like aminoglycosides will distribute to areas of edema and decrease drug plasma concentrations; they are best dosed using an accurate current body weight. In addition, drugs with a narrow therapeutic window that carry a high risk of toxicity should be dosed on lean body weight. However, although dehydration or volume contraction can increase the plasma concentration of drugs, drug dosage adjustments are NOT recommended in critical patients that are volume contracted; instead therapy should focus on fluid resuscitation prior to administration of drugs.

Neurologic Disease Many ICU patients are hospitalized for treatment of neurologic disease. The most common diseases include seizures, inflammatory brain disease, brain tumors, head trauma, and disorders increasing intracranial pressure (ICP). In the majority of situations, aside from traumatically induced increased ICP, these patients are systemically normal. Therefore the concerns of treatment largely relate to the effects of the medications themselves or their interactions with other drugs. For example, phenobarbital accelerates the elimination half-life of drugs like digoxin, propranolol, and phenobarbital through CYP 450 induction. Furosemide increases bromide excretion, effectively decreasing potassium bromide plasma levels.

38

SECTION  I  Critical Care

References and Suggested Reading Bowman L, Carlstedt BC, Black CD: Incidence of adverse drug reactions in adult medical inpatients, Can J Hosp Pharm 47:209-216, 1994. Close SL: Clopidogrel pharmacogenetics: metabolism and drug interactions, Drug Metabol Drug Interact 26:45-51, 2011. Ogilvie BW et al: The proton pump inhibitor, omeprazole, but not lansoprazole or pantoprazole, is a metabolism-dependent inhibitor of CYP2C19: implications for coadministration with clopidogrel, Drug Metab Dispos 39(11):2020-2033, 2011. Quimby JM et al: Studies on the pharmacokinetics and pharmacodynamics of mirtazapine in healthy young cats, J Vet Pharmacol Ther 34:388-396, 2011.

CHAPTER 

Quimby JM et al: The pharmacokinetics of mirtazapine in cats with chronic kidney disease and in age-matched control cats, J Vet Intern Med 25:985-989, 2011. Reynolds JC: The clinical importance of drug interactions with antiulcer therapy, J Clin Gastroenterol 12:S54-S63, 1990. WHO Collaborating Centre for International Drug Monitoring: Safety monitoring of medicinal products: guidelines for setting up and running a pharmacovigilance centre, London, UK, 2000, Uppsala Monitoring Centre, EQUUS.

7 

Nutrition in Critical Care DANIEL L. CHAN, Hertfordshire, United Kingdom

C

ritical illness in animals induces unique metabolic changes that put them at high risk for malnutrition and its deleterious effects. The rationale for providing nutritional support in critical illness is based on a number of pathophysiologic factors. In diseased states the inflammatory response triggers alterations in cytokine and hormone concentrations and shifts metabolism toward a catabolic state. In the absence of adequate food intake, the predominant energy source for the host is derived from accelerated proteolysis. Thus the animal may preserve fat deposits in the face of loss of lean muscle tissue. Consequences of malnutrition include negative effects on wound healing, immune function, strength (both skeletal and respiratory), and ultimately the overall prognosis. An important point with regard to nutritional support of hospitalized patients is that the immediate goal is not to achieve “weight gain,” per se, which mostly likely reflects shift in water balance, but rather to minimize further loss of lean body mass. Reversal of malnutrition hinges on resolution of the primary underlying disease. Provision of nutritional support is aimed at restoring nutrient deficiencies and providing key substrates for healing and repair.

Patient Selection As with any intervention in critically ill animals, nutritional support carries some risk of complications. This risk likely increases with the severity of the disease, and the clinician must therefore consider many factors in deciding when to institute nutritional support. Of utmost importance is the patient’s cardiovascular status, which must be stable before initiation of any nutritional support.

Processes such as gastrointestinal motility, digestion, and nutrient assimilation are altered when perfusion is reduced. Feeding under such circumstances is likely to result in complications. Other issues that should be addressed before nutritional support begins include patient hydration, electrolyte imbalances, and abnormalities in acid-base status. In animals that have been stabilized, careful consideration must be given to the appropriate time to initiate nutritional support. A previously held notion that nutritional support is unnecessary until 10 days of inadequate nutrition have elapsed is outdated. Commencing nutritional support within 3 days of hospitalization (sometimes as early as within the first 12 hours), even before determining the diagnosis of the underlying disease, is a more appropriate goal in most cases; however, other factors should also be considered as discussed in the next section.

Nutritional Assessment Indicators of malnutrition in animals that have been proposed include unintentional weight loss (typically greater than 10% of body weight), poor hair coat quality, muscle wasting, signs of inadequate wound healing, and hypoalbuminemia. However, these abnormalities are not specific to malnutrition and often occur as late complications of a variety of systemic diseases. A greater emphasis is placed on evaluating overall body condition rather than simply noting body weight. Body condition scores (BCSs) have been shown to be reproducible, reliable, and clinically useful in nutritional assessment. Fluid shifts may significantly impact body weight, but BCSs are not affected

CHAPTER  7  Nutrition in Critical Care by fluid shifts and therefore are helpful in assessing critically ill animals. More recently, lean muscle loss has also been evaluated in cats and this may become a component of nutritional assessment in small animals (Michel et al, 2011). In light of the limitations to assessing nutritional status, it is crucial to identify early risk factors that may predispose patients to malnutrition such as anorexia of greater than 5-days’ duration, serious underlying disease (e.g., severe trauma, sepsis, peritonitis, acute pancreatitis), and large protein losses (e.g., protracted diarrhea, draining wounds, burns). Nutritional assessment also identifies factors that can impact the nutritional plan such as specific electrolyte abnormalities; hyperglycemia, hypertriglyceridemia, or hyperammonemia; or comorbid illnesses such as renal, cardiac, or hepatic disease, including various forms of neoplasia. In the presence of such abnormalities the nutritional plan should be adjusted accordingly to limit acute exacerbations of any preexisting condition. Finally, since many of the techniques required for implementation of nutritional support (e.g., placement of most feeding tubes, intravenous catheters for parenteral nutrition) necessitate sedation or anesthesia, the patient must be properly evaluated and stabilized first. When the patient is deemed too unstable for general anesthesia, temporary measures of nutritional support that do not require anesthesia (e.g., nasoesophageal tube placement, placement of peripheral catheters for parenteral nutrition) should be considered.

Nutritional Plan Nutrition should be provided as soon as it is feasible, with careful consideration of the most appropriate route of nutritional support. Providing nutrition via a functional digestive system is the preferred route of feeding, and particular care should be taken to evaluate if the patient can tolerate enteral feedings. Even if the patient can only tolerate small amounts of enteral nutrition, this route of feeding should be pursued and supplemented or augmented with parenteral nutrition (PN) as necessary to meet the patient’s nutritional needs. However, if an animal demonstrates complete enteral feeding intolerance, some form of PN should be provided. Implementation of the devised nutritional plan also should be gradual, with the goal of reaching target level of nutrient delivery within 48 to 72 hours. Adjustments to the nutritional plan are made on the basis of frequent reassessment and the development of any complications.

Calculating Nutritional Requirements Based on indirect calorimetry studies in dogs, there has been a recent trend toward formulating nutritional support simply to meet resting energy requirements (RERs) rather than more generous illness energy requirements (IERs). For many years clinicians used to multiply the RER by an illness factor between 1.1 and 2 to account for purported increases in metabolism associated with different disease states. However, now less emphasis is being placed on these extrapolated factors, and the current recommendation is to use more conservative

39

energy estimates (i.e., start with the animal’s RER) to avoid overfeeding and its associated complications. Examples of complications resulting from overfeeding include gastrointestinal intolerance, hepatic dysfunction, and increased carbon dioxide production. Although several formulas are proposed to calculate the RER, a widely used allometric formula can be applied to both dogs and cats of all weights. The formula most commonly used by the author is: RER = 70 × (current body weight in kilograms )0.75 Alternatively, for animals weighing between 3 and 25 kg, the following may be used: RER = (30 × current body weight in kilograms ) + 70 Hospitalized dogs should be supported with 4 to 6 g of protein per 100 kcal (15% to 25% of total energy requirements), whereas cats are usually supported with 6 g or more of protein per 100 kcal (25% to 35% of total energy requirements). In most cases estimation of protein requirements is based on clinical judgment and recognition that in certain disease states (e.g., peritonitis, draining wounds) protein requirements are markedly increased.

Parenteral Nutritional Support PN, formerly referred to as total PN (TPN) or partial PN (PPN), is the intravenous delivery of nutrients (e.g., dextrose, amino acids, lipid emulsion, vitamins, minerals, electrolytes) to patients. This can be achieved via a central vein (central PN [CPN]) or a peripheral vein (peripheral PN [PPN]). Factors that influence how PN should be administered include feasibility of central venous access and the osmolarity of the PN solution, with the recommendation to use the central route when the osmolarity of solution exceeds 850 mOsm/L. Crystalline amino acid solutions are an essential component of PN. The importance of supplying amino acids relates to the maintenance of positive nitrogen balance and repletion of lean body tissue, which may be vital in the recovery of critically ill patients. Supplementation of amino acids may support protein synthesis and spare tissue proteins from being catabolized via gluconeogenesis. The most commonly used amino acid solutions (e.g., Travasol, Aminosyn II) contain most of the essential amino acids for dogs and cats, with the exception of taurine. However, because PN is typically not used beyond 10 days, the lack of taurine does not become a problem in most circumstances. Amino acid solutions are available in different concentrations from 4% to 15%, but the most commonly used concentration is 8.5%. Amino acid solutions are also available with and without electrolytes. Lipid emulsions are the calorically dense component of PN and a source of essential fatty acids. Lipid emulsions are isotonic and available in 10% to 30% solutions (e.g., Intralipid, Liposyn III). These commercially available lipid emulsions are made primarily of soybean and safflower oil and provide predominantly long-chain polyunsaturated fatty acids, including linoleic, oleic, palmitic, and stearic acids. The emulsified fat particles are comparable in size to chylomicrons and are removed from the

40

SECTION  I  Critical Care

circulation via the action of peripheral lipoprotein lipase. Side effects attributed to lipid emulsions include liver dysfunction and immune suppression. Newer lipid emulsions with fewer side effects have been developed, and one such product composed of soybean oil, medium chain triglycerides, olive oil, and fish oil (i.e., SMOF lipid) is available in Europe and may become more widely distributed in the future (Goulet et al, 2010). There is a persistent misconception regarding the use of lipids in cases of pancreatitis. Although hypertriglyceridemia may be a risk factor for pancreatitis, infusions of lipids have not been shown to increase pancreatic secretion or worsen pancreatitis and therefore are considered safe. However, the one exception is in cases in which serum triglyceride concentrations are severely increased, indicating a clear failure of triglyceride clearance. Although specific data regarding the maximal safe level of lipid administration in veterinary patients are not available, it would seem prudent to maintain normal serum triglyceride concentrations in patients receiving PN. Another concern surrounding the use of lipids in PN is their purported immunosuppressive effects via impairment of the reticuloendothelial system, particularly in PN solutions containing a high percentage of lipids. Despite in vitro evidence supporting the notion that lipid infusions can also suppress neutrophil and lymphocyte function, studies have not yet correlated lipid use and increased rates of infectious complications. Electrolytes, vitamins, and trace elements also may be added to the PN formulation. Depending on the hospital and the individual patient, electrolytes can be added to the admixture, included as part of the amino acid solution, or left out altogether and managed separately. Because B vitamins are water soluble, they are more likely to become deficient in patients with high-volume diuresis (e.g., renal failure, diabetes mellitus), and supplementation could be considered. Since most animals receive PN for only a short duration, fat-soluble vitamins usually are not limiting; therefore supplementation is not typically required. The exception is in obviously malnourished animals in which supplementation may be necessary. Trace elements serve as cofactors in a variety of enzyme systems and can become deficient in malnourished patients as well. In people receiving PN, zinc, copper, manganese, and chromium are routinely added to the PN admixture. These are sometimes added to PN admixtures for malnourished animals, but their compatibility with the solution must be verified. The addition of other parenteral medications to the PN admixture is possible; however, their compatibility also must be verified. Drugs that are known to be compatible and sometimes added to PN include heparin, insulin, potassium chloride, and metoclopramide. Although the addition of insulin to PN is often necessary in people, the hyperglycemia seen in veterinary patients with PN usually does not require insulin administration, except for patients with known diabetes mellitus.

7-1 and 7-2. For CPN (see Box 7-1) the first step is the calculation of the patient’s RER. Protein requirements (grams of protein required per day) are then calculated, taking into consideration factors such as excessive protein losses or severe hepatic or renal disease. The energy provided from amino acids is accounted for in the energy calculations and subtracted from the daily RER to estimate the total nonprotein calories required. Some protocols do not account for the energy provided by amino acids in the calculations, which may lead to overfeeding in critically ill animals. The nonprotein calories are usually provided as a 50 : 50 mixture of lipids and dextrose; however, this ratio can be adjusted in cases of persistent hyperglycemia or hypertriglyceridemia (e.g., a higher proportion of calories would be given from lipids in an animal with hyperglycemia). The calories provided from each component (amino acids, lipids, and dextrose) are then divided by their respective caloric density, and the exact amounts of each component are added to the PN bags in an aseptic fashion. The amount of CPN delivered often provides less than the patient’s daily fluid requirement. Additional fluids can either be added to the PN bag at the time of compounding or be provided as a separate infusion. For formulation of PPN, Box 7-2 provides a step-bystep protocol in which patients of various sizes can receive 70% of their RER and approximately meet their daily maintenance fluid requirement. In very small animals (≤3 kg), the amount of PPN will exceed the maintenance fluid requirement and increase the risk for fluid overload; thus adjustments may need to be made. Also, in animals requiring conservative fluid administration (e.g., congestive heart failure), these calculations for PPN may provide more fluid than would be safe. This formulation has been designed so that the proportion of each PN component depends on the weight of the patient, such that a smaller animal (between 3 and 5 kg) receives proportionally more calories from lipids compared with a large dog (>30 kg) that receives more calories in the form of carbohydrates. This allows the resulting formulation to approximate the patient’s daily fluid requirement. Ideally, compounding of PN should be done aseptically under a laminar flow hood using a semiautomated, closedsystem PN compounder (e.g., Automix compounder). If the appropriate facilities and equipment are not available, it may be preferable to have a local human hospital, compounding pharmacy, or human home health care company compound PN solutions using the formulations listed in Boxes 7-1 and 7-2. Alternatively, commercial ready-to-use preparations of glucose or glycerol and amino acids suitable for (peripheral or central) intravenous administration are available (e.g., ProcalAmine). Although ready-to-use preparations are convenient, they provide only 30% to 50% of caloric requirements when administered at maintenance fluid rates and as a result should only be used for interim nutritional support or to supplement low-dose enteral feedings.

Parenteral Nutrition Compounding

Parenteral Nutrition Administration

Based on the nutritional assessment and plan, PN can be formulated according to the worksheets found in Boxes

The high osmolarity of CPN solutions (often > 1200  mOsm/L) requires its administration through a

CHAPTER  7  Nutrition in Critical Care

41

BOX 7-1  Worksheet for Calculating a Central Parenteral Nutrition Formulation 1. Resting energy requirement (RER) 70 × (current body weight in kg)0.75 = kcal/day or for animals 3-25 kg, can also use: 30 × (current body weight in kg) + 70 = kcal/day RER = _________ kcaal/day 2. Protein requirements

Canine

Feline

Standard

5 g/100 kcal

6-7 g/100 kcal

Decreased requirements (hepatic/renal failure)

3 g/100 kcal

3-4 g/100 kcal

Increased requirements (protein-losing conditions)

6-7 g/100 kcal

6-7 g/100 kcal

(RER ÷ 100) × _______________ g/100 kcal = _______________ g of protein required per day (protein req) 3. Volumes of nutrient solutions required each day a. 8.5% amino acid solution = 0.085 g of protein per milliliter _______________ g of protein per day required ÷ 0.085 g/ml = _______________ ml of amino acids per day b. Nonprotein calories: The calories supplied by protein (4 kcal/g) are subtracted from the RER to get total nonprotein calories needed:  _______________ g of protein required per day × 4 kcal/g = _______________ kcal provided by protein RER − kcal provided by protein = _______________ nonprotein kcal needed per day c. Nonprotein calories are usually provided as a 50 : 50 mixture of lipid and dextrose. However, if the patient has a preexisting condition (e.g., diabetes, hypertriglyceridemia), this ratio may need to be adjusted. *20% lipid solution = 2 kcal/ml

To supply 50% of nonprotein kcal _______________ lipid kcal required ÷ 2 kcal/ml = _______________ ml of lipid *50% dextrose solution = 1.7 kcal/ml To supply 50% of nonprotein kcal _______________ dextrose kcal required ÷ 1.7 kcal/ml = _______________ ml of dextrose 4. Total daily requirements _______________ ml of 8.5% amino acid solution _______________ ml of 20% lipid solution _______________ ml of 50% dextrose solution _______________ ml total volume of total parenteral nutrition solution 5. Administration rate Day 1: _______________ ml/hr Day 2: _______________ ml/hr Day 3: _______________ ml/hr *Be sure to adjust the patient’s other fluids accordingly!

central venous (jugular) catheter, whereas PPN solutions can be administered through either a jugular catheter or catheters placed in peripheral veins. The concern with high osmolarity is that it may increase the incidence of thrombophlebitis, although this has not been well characterized in veterinary patients. The adminis­ tration of any PN requires a dedicated catheter used solely for PN administration that is placed using aseptic technique. In most cases this requires placement of additional catheters because PN should not be administered through existing catheters that were placed for reasons other than PN. Long catheters composed of silicone, polyurethane, or tetrafluoroethylene are recommended for use with any type of PN to reduce the risk of thrombophlebitis. Multilumen catheters are often recommended for CPN because they can remain in place for long periods and separate ports can also be used for blood sampling and administration of additional fluids

and intravenous medications without the need for separate catheters placed at other sites. Injections into the PN catheter infusion port or administration lines should be strictly prohibited. Because of the various metabolic derangements associated with critical illness, PN should be instituted gradually over 48 hours. Administration of PN is typically initiated at 50% of the RER on the first day and increased to the targeted amount by the second day. In most cases PPN can be started without gradual increase. It is also important to adjust the rates of other fluids being concurrently administered. For both forms of PN, the animal’s catheter and infusion lines must be handled aseptically at all times to reduce the risk of PN-related infections. PN should be administered as continuous-rate infusions over 24 hours via fluid infusion pumps. Inadvertent delivery of massive amounts of PN can result if administration is not regulated properly. Once a bag of PN is set

42

SECTION  I  Critical Care

BOX 7-2  Worksheet for Calculating a Peripheral Parenteral Nutrition Formulation 1. Resting energy requirement (RER) 70 × (current body weight in kg)0.75 = kcal/day or for animals 3-25 kg, can also use: 30 × (current body weight in kg) + 70 = kcal/day RER = _______________ kcal/day 2. Partial energy requirement (PER) Plan to supply 70% of the animal’s RER with peripheral parenteral nutrition (PPN): PER = RER × 0.70 = _______________ kcal/day 3. Nutrient composition (NOTE: For animals ≤3 kg, the formulation will provide a fluid rate higher than maintenance fluid requirements. Be sure that the animal can tolerate this volume of fluids) a. Cats and dogs 3-5 kg: PER × 0.20 =_______________ kcal/day from carbohydrate PER × 0.20 =_______________ kcal/day from protein PER × 0.60 =_______________ kcal/day from lipid b. Cats and dogs 6-10 kg: PER × 0.25 =_______________ kcal/day from carbohydrate PER × 0.25 =_______________ kcal/day from protein PER × 0.50 =_______________ kcal/day from lipid c. Dogs 11-30 kg: PER × 0.33 =_______________ kcal/day from carbohydrate PER × 0.33 =_______________ kcal/day from protein PER × 0.33 =_______________ kcal/day from lipid d. Dogs >30 kg: PER × 0.50 =_______________ kcal/day from carbohydrate PER × 0.25 =_______________ kcal/day from protein PER × 0.25 =_______________ kcal/day from lipid 4. Volumes of nutrient solutions required each day a. 5% dextrose solution = 0.17 kcal/ml _______________ kcal from carbohydrate ÷ 0.17 kcal/ml = _______________ml of dextrose per day b. 8.5% amino acid solution = 0.085 g/ml = 0.34 kcal/ml _______________ kcal from protein ÷ 0.34 kcal/ml = _______________ml of amino acids per day c. 20% lipid solution = 2 kcal/ml _______________ kcal from lipid ÷ 2 kcal/ml = _______________ ml of lipid per day 5. Total daily requirements _______________ ml of 5% dextrose solution _______________ ml of 8.5% amino acid solution _______________ ml of 20% lipid solution _______________ ml of total volume of PPN solution 6. Administration rate This formulation provides an approximate maintenance fluid rate. _______________ ml/hour of PPN solution Be sure to adjust the patient’s other fluids accordingly!

up for administration, it is not disconnected from the patient even for walks or diagnostic procedures—the drip regulator is decreased to a slow drip and accompanies the patient throughout the hospital. Administration of PN through a 1.2-micron in-line filter (e.g., 1.2-micron downstream filter) is also recommended and is attached at the time of setup. This setup process is performed daily with each new bag of PN. Each bag should only hold 1 day’s worth of PN, and the accompanying fluid administration sets and in-line filter are changed at the same time using aseptic technique. PN should be discontinued when the animal resumes consuming an adequate amount of calories of at least 50% of RER. CPN should be discontinued gradually over a 6- to 12-hour period, but PPN can be discontinued without weaning.

Enteral Nutritional Support In critically ill animals with a functional gastrointestinal tract, feeding tubes are the standard mode of nutritional support. As discussed previously, a key decision is determining whether the patient can undergo general anesthesia for placement of feeding tubes. In animals with surgical disease requiring laparotomy, placement of gastrostomy or jejunostomy feeding tubes should receive particular consideration. Feeding tubes commonly used in critically ill animals are nasoesophageal, esophagostomy, gastrostomy, and jejunostomy. Newer techniques available in some institutions include fluoroscopy-guided jejunal tubes. The decision to choose one tube over another is based on the anticipated duration of nutritional support (e.g., days

CHAPTER  7  Nutrition in Critical Care versus months), the need to circumvent certain segments of the gastrointestinal tract (e.g., oropharyngeal injury, esophagitis, pancreatitis), clinician experience, and suitability of patient to withstand anesthesia (very critical animals may only tolerate placement of nasoesophageal feeding tubes). Another consideration for choosing the most appropriate tube is the expectation of how well the animal will tolerate enteral feedings. Nasoesophageal and esophagostomy feeding tubes may not be ideal in animals that have persistent vomiting or regurgitation and that are also mostly recumbent. In these animals, gastrostomy or jejunal tubes may be preferable.

Monitoring for Complications Because the development of complications in critically ill animals can have serious consequences, close monitoring is an important aspect of nutritional support. With implementation of enteral nutrition, possible complications include vomiting, diarrhea, fluid overload, electrolyte imbalances, feeding tube malfunction, and infectious complications associated with the feeding tube insertion site. Metabolic complications are more common with PN and include the development of hyperglycemia, lipemia, azotemia, hyperammonemia, and electrolyte abnormalities. Rarely nutritional support can be associated with severe abnormalities that are sometimes referred to as the refeeding syndrome. Strategies to reduce risk of complications include observing aseptic techniques when placing feeding tubes and intravenous catheters, using con­servative estimates of energy requirements (i.e., RER), and careful patient monitoring. Parameters that should be monitored during nutritional support include body temperature; respiratory rate and effort; signs of fluid overload (e.g., chemosis, tachypnea, pulmonary crackles, increased body weight); and serum concentrations of glucose, triglycerides, electrolytes, blood urea nitrogen, and creatinine. Detection of any abnormality should prompt full reassessment.

Pharmacologic Agents in Nutritional Support Since critically ill animals are often anorexic, there is the temptation to use appetite stimulants to increase food intake. Unfortunately appetite stimulants are generally unreliable and seldom result in adequate food intake in critically ill animals. Pharmacologic stimulation of appetite is often short-lived and only delays true nutritional support. This author does not believe that appetite stimulants have a place in the management of hospitalized animals when more effective measures of nutritional support such as placement of feeding tubes are more appropriate. Appetite stimulants may be considered in recovering animals once they are home in their own environment, since ideally the primary reason for loss of ap­­ petite should be reversed by time of hospital discharge.

Future Directions in Critical Care Nutrition The current state of veterinary critical care nutrition revolves around proper recognition of animals in need of

43

nutritional support and implementation of strategies to best provide nutritional therapies. Important areas that need further evaluation in critically ill animals include the optimal composition and caloric target of nutritional support and strategies to minimize complications and optimize outcome. Recent findings implicating development of hyperglycemia with poor outcome in critically ill humans have led to more vigilant monitoring and stricter control of blood glucose, with obvious implications for nutritional support. Evidence of a similar relationship in dogs and cats is mounting, and ongoing studies are focusing on the possible consequences of hyperglycemia. Until further studies suggest otherwise, efforts to reduce the incidence of hyperglycemia in critically ill animals, especially those receiving nutritional support, should be strongly pursued. Other exciting areas of clinical nutrition in critically ill humans include the use of special nutrients that possess immunomodulatory properties such as glutamine, arginine, and n-3 fatty acids. In specific popu­ lations these agents used singly or in combination have demonstrated promising results, even in severely affected people. However, results have not been consistent, and ongoing trials continue to evaluate their efficacy. To date there is limited information on the use of these nutrients to specifically modulate disease in clinically affected animals. Future studies should focus on whether manipulation of such nutrients offer any benefit in animals.

References and Suggested Reading Brunetto MA et al: Effects of nutritional support on hospital outcome in dogs and cats, J Vet Emerg Crit Care 20:224, 2010. Buffington T, Holloway C, Abood A: Nutritional assessment. In Buffington T, Holloway C, Abood S, editors: Manual of veterinary dietetics, St Louis, 2004, Saunders, p 1. Chan DL: Nutritional requirements of the critically ill patient, Clin Tech Small Anim Pract 19:1, 2004. Freeman LM, Chan DL: Total parenteral nutrition. In DiBartola SP, editor: Fluid, electrolyte, and acid-base disorders in small animal practice, ed 3, St Louis, 2006, Saunders, p 584. Goulet O et al: A new intravenous fat emulsion containing soybean oil, medium-chain triglycerides, olive oil, and fish oil: a single-center, double-blind randomized study on efficacy and safety in pediatric patients receiving home parenteral nutrition, J Parenter Enteral Nutr 34:485, 2010. Michel KE et al: Correlation of a feline muscle mass score with body composition determined by dual-energy x-ray absorptiometry, Br J Nutr 106:S57, 2011. Novak F et al: Glutamine supplementation in serious illness: a systematic review of the evidence, Crit Care Med 30:2022, 2002. Pyle SC, Marks SL, Kass PH: Evaluation of complications and prognostic factors associated with administration of total parenteral nutrition in cats: 75 cases (1994-2001), J Am Vet Med Assoc 255:242, 2004. Torre DM, deLaforcade AM, Chan DL: Incidence and significance of hyperglycemia in critically ill dogs, J Vet Intern Med 21:971, 2007. Van den Berghe G et al: Intensive insulin therapy in critically ill patients, N Engl J Med 345:1359, 2001. Walton RS, Wingfield WE, Ogilvie GK: Energy expenditure in 104 postoperative and traumatically injured dogs with indirect calorimetry, J Vet Emerg Crit Care 6:71, 1998.

CHAPTER 

8 

Stabilization of the Patient with Respiratory Distress TIMOTHY B. HACKETT, Fort Collins, Colorado LAUREN SULLIVAN, Fort Collins, Colorado

R

espiratory distress in small animals presents a therapeutic dilemma. By the time owners identify a problem, their animal may be so severely compromised that diagnostic testing and treatment could stress the pet to the point of respiratory and cardiac arrest. Thus diagnostic testing may be delayed or restricted to avoid placing the patient at further risk. In these circumstances, the clinician must quickly develop a rational list of differential diagnoses and treatments, while providing basic supportive care. Initial steps toward stabilization of the respiratory system, such as oxygen supplementation, thoracocentesis, and possibly airway control via endotracheal intubation or temporary tracheotomy, may be necessary before proceeding with diagnostics. This chapter reviews the pathophysiologic mechanisms behind respiratory distress and provides guidance on anatomic localization of the disease, recommendations for initial stabilization, and appropriate sequencing of diagnostic tests.

Pathophysiology of Respiratory Distress Work of breathing, or the effort required for effective pulmonary gas exchange, depends mainly on two forces within the respiratory system: (1) airway resistance, which opposes airflow during inspiration and expiration and (2) elastic recoil, which is the tendency for the lungs to collapse following inspiration. In animals with respiratory tract pathology, additional energy and effort may be required to overcome these forces. The clinician who is faced with managing respiratory distress requires greater understanding of airway resistance and elastic recoil, as well as their contributions to overall work of breathing. Airway resistance is the pressure difference between the alveoli and the mouth divided by flow rate. Airway caliber is critical in determining resistance. If the radius of the airway is halved, resistance increases sixteenfold; in comparison, doubling airway length only increases resistance by a factor of two. Therefore small changes in airway caliber can lead to noticeable clinical signs. The major site of airway resistance in healthy animals is the medium-sized bronchi. Airway resistance is determined by lung volume, bronchial smooth muscle tone, and dynamic airway compression. At reduced lung volumes, radial traction supporting the bronchi is lost and airway caliber is reduced. Similarly, bronchial muscle 44

contraction narrows airways and increases resistance. Bronchoconstriction is mediated by reflex stimulation of irritant receptors in the upper airways or increased parasympathetic activity. Dynamic airway collapse is seen with forceful respiration. Sudden changes in intrathoracic pressure can affect the diameter of large airways. Intrathoracic and extrathoracic airway collapse, airway foreign bodies, and mass lesions also result in increased airway resistance. The resting lung volume is a balance between the elastic properties of the lung (favoring alveolar collapse) and the elastic properties of the chest wall (favoring alveolar expansion). This resting lung volume, understood as the volume of air remaining in the lungs at the end of a normal breath, is called the functional residual capacity (FRC). At the normal FRC, the lung is very compliant. Compliance or stiffness is the change in lung volume for any given applied pressure. In a healthy state with compliant lungs, small changes in intrapleural pressure cause a large change in lung volume, subsequently drawing fresh air into the respiratory tract. A pressure-volume curve of the lung shows the change in the work of breathing at normal and reduced lung volumes (Figure 8-1). Most common pulmonary parenchymal diseases (e.g., pulmonary edema, pneumonia) increase FRC, flatten the pressure-volume curve, and decrease compliance. Significant pleural space disease resulting in lung collapse (e.g., pneumothorax, diaphragmatic hernia) produces similar changes in lung compliance and FRC.

Respiratory Failure Impaired respiration occurs secondary to inadequate ventilation or inadequate gas exchange. If sufficiently severe, this impairment can progress to respiratory failure, a lifethreatening situation that often necessitates aggressive intervention. Failure of ventilation is the inability to move fresh air into the pulmonary alveoli, resulting in high blood carbon dioxide levels (hypercarbia) and low blood oxygen levels (hypoxemia). Failure of gas exchange occurs at the level of the blood-air barrier, resulting in hypoxemia with or without hypercarbia. In cases of impaired gas exchange, the hypoxemic patient initially hyperventilates in an effort to improve oxygenation. This results in low blood carbon dioxide levels and a respiratory alkalosis. With progression of disease and onset of respiratory

Volume (Percent)

CHAPTER  8  Stabilization of the Patient with Respiratory Distress

Work of breathing Vt Normal FRC Vt Reduced FRC R Distending Pressure

Figure 8-1  Pulmonary compliance equals the slope of the pres-

sure volume curve at the functional residual capacity (FRC) or resting volume of the lung. The x-axis, R, is the pressure required to move a volume of air (shown in the y-axis). With a reduced FRC, a greater distending pressure is required to move an equal tidal volume. This requires more work and therefore more energy. Vt, Tidal volume.

failure, effective exchange of both oxygen and carbon dioxide is lost, resulting in hypoxemia and hypercarbia. Appropriate differentiation of the type of respiratory failure is critical when moving forward with proper medical intervention. Close observation of respiratory pattern and physical examination findings are especially helpful in determining the likely cause and appropriate therapeutic interventions (Table 8-1).

Physical Examination Due to the fragile nature of most animals in respiratory distress, physical restraint for close examination, radiography, or intravenous catheterization may need to wait until the patient is less anxious and breathing more comfortably. In such cases, determination of the problem underlying respiratory distress often can be accomplished with observation alone. There are several key observations that optimize the information gained and help the clinician tailor treatment to the most likely underlying disease. One of the more common descriptors used by clinicians when observing an animal in respiratory distress is the term dyspneic. Dyspnea is frequently used in veterinary medicine to designate animals with difficult or labored breathing, whereas in human medicine the term describes the sensation of an unpleasant sensory experience. In human medicine not all dyspneic patients have increased respiratory efforts, nor do all patients with labored breathing have the sensation of dyspnea. Dyspnea can be subjective and difficult to assess in nonverbal patients, thus making identification of these sensations particularly challenging in veterinary medicine. The sensation of air hunger is often stressful. The results of this stress are a more rapid breathing pattern

45

and increased levels of circulating catecholamines, which only further increase the animal’s oxygen requirements. Clinical signs associated with the underlying disease are frequently exacerbated when these patients increase their respiratory rate or effort. For example, disorders characterized by dynamic airway narrowing (e.g., laryngeal paralysis, tracheal collapse, bronchitis) become more severe when airflow velocity increases due to reduced pressure within the airway lumen. This further compromises the airway cross-sectional area and illustrates how increasing oxygen demand, coupled with impaired respiratory function, can have additive consequences. This is one reason why sedatives/tranquilizers that reduce this stress response can help the dyspneic animal breathe more efficiently and why these drugs are often imperative to successful management of respiratory distress (Table 8-2). Identification and treatment of dyspnea are im­­ portant first steps before moving on to the physical examination. When in distress, animals adopt a respiratory pattern to minimize their work of breathing. Characterization of the breathing pattern can be helpful in anatomic localization of the disease. Specific points to evaluate include the phase of respiration affected and the overall breathing pattern (see Table 8-1). The first step is to determine if the increased work of breathing is occurring on inspiration, expiration, or both. Increased work of breathing on inspiration often localizes the problem to the upper airways (e.g., laryngeal paralysis, extrathoracic tracheal collapse), whereas increased work of breathing on expiration indicates intrathoracic or lower airway disease (e.g., intrathoracic tracheal collapse, bronchitis). Increased work of breathing on both inspiration and expiration suggests a fixed lesion within the airway (e.g., airway foreign bodies, intraluminal masses, external compression of the airway). Following anatomic localization of the respiratory pathology, further characterization of the respiratory pattern can help narrow down the differential diagnoses (see Table 8-1). Animals with airway obstruction generally breathe slower and deeper to minimize the resistance to airflow. Loud respiratory noise may be evident without a stethoscope. A rapid, shallow respiratory pattern, also known as a restrictive pattern, is observed in animals with pulmonary parenchymal disease (e.g., pneumonia, pulmonary edema) and in some animals with pleural space diseases. A third breathing pattern, known as an inverse or asynchronous pattern, might also be evident with pleural space disease. This pattern is characterized by paradoxical movement of the chest wall on inspiration (the thorax collapses in) and on expiration (the thorax expands out), which is the reverse of normal chest wall movement. Upper airway and thoracic auscultation can be highly beneficial in the initial evaluation and can be accomplished without stressing the patient. An obvious heart murmur or gallop sound may indicate congestive heart failure. In many cases of airway obstruction, noise that is loudest over the obstruction can be heard during slow breathing. Wheezing with prolonged expiration suggests either bronchial narrowing (bronchitis or asthma) or obstruction/collapse of a principal bronchus. When

46

SECTION  I  Critical Care

TABLE 8-1  Common Causes of Respiratory Distress in Dogs and Cats Problem

Phase Affected/Respiratory Pattern

Emergency Treatment

Laryngeal paralysis

Inspiratory/Obstructive

O2, sedation, antiinflammatory, +/− tracheostomy

Extrathoracic tracheal collapse

Inspiratory/Obstructive

O2, sedation, antitussive

Airway mass lesion

Fixed/Obstructive

O2, sedation, +/− tracheostomy

Airway foreign body

Fixed/Obstructive

O2, sedation, Heimlich maneuver

Laryngeal stenosis

Fixed/Obstructive

O2, sedation, +/− tracheostomy

Intrathoracic tracheal collapse

Expiratory/Obstructive

O2, sedation, antitussive

Bronchitis

Expiratory/Obstructive

O2, sedation, antiinflammatory, bronchodilator

Airway mass lesion

Fixed/Obstructive

O2, sedation

Airway foreign body

Fixed/Obstructive

O2, sedation, Heimlich maneuver

Pneumonia

Inspiratory/Restrictive

O2, IV fluids, antibiotic, physical therapy

Cardiogenic pulmonary edema

Inspiratory/Restrictive

O2, sedation, fluid restriction/diuretics

Noncardiogenic pulmonary edema

Inspiratory/Restrictive

O2, sedation

Pulmonary hemorrhage

Inspiratory/Restrictive

O2, sedation, FFP

Pulmonary neoplasia

Inspiratory/Restrictive

O2, sedation

Chylothorax

Inspiratory/Restrictive/Inverse

O2, thoracocentesis

Pneumothorax

Inspiratory/Restrictive/Inverse

O2, thoracocentesis

Pyothorax

Inspiratory/Restrictive/Inverse

O2, thoracocentesis

Pleural hemorrhage

Inspiratory/Restrictive/Inverse

O2, FFP, thoracocentesis

Diaphragmatic hernia

Inspiratory/Restrictive/Inverse

O2, sedation, surgical correction

Pulmonary Thromboembolism

Hyperventilation

O2, sedation, thrombolytic, anticoagulation

Upper Airway Obstruction

Lower Airway Obstruction

Pulmonary Parenchymal Disease

Pleural Space Disease

Phase affected describes either inspiratory or expiratory dyspnea, with increased effort and time devoted to that phase of respiration. Fixed obstructive pattern will have increased effort during both phases of respiration. Obstructive pattern is generally deeper with a loud stridor. Restrictive pattern breathing is rapid and shallow. O2, Oxygen supplemented by face mask, blow-by, nasal cannula, oxygen cage, oxygen tent, or positive pressure ventilation. FFP, fresh frozen plasma. Physical therapy consists of nebulization and coupage to loosen airway secretions.

attempting to differentiate pleural space disease from parenchymal diseases particular attention should be directed to identification of a pleural fluid line (muffled breath sounds ventrally) or pulmonary crackles (indicating diffuse small airway or lung parenchymal disease). Unfortunately, an absence of crackles does not exclude the presence of pulmonary parenchymal disease. Initial interventions (e.g., oxygen supplementation, minimization of stress and sedation) are often performed concurrently with observation and brief thoracic auscultation. Once these steps are complete, a more thorough physical examination is warranted. This should include close monitoring of vital signs, assessment of cardiovascular status, and a thorough thoracic auscultation if not already done. Following the physical examination, additional interventions may be required (e.g., thoracocentesis, temporary tracheotomy) or definitive diagnostics can be performed.

Diagnostics Radiography Radiography is typically indicated for animals presenting with respiratory signs because radiographic changes or patterns can help further determine the cause of the distress. As indicated earlier, radiography should be delayed until the patient is more stable. Thoracic and cervical radiographs can be used to diagnose collapsing trachea, tracheal or laryngeal foreign bodies, and mass lesions. It is possible to assess airway dynamics by taking inspiratory and expiratory views of the trachea or with fluoroscopy (or bronchoscopy). Thoracic radiographs are indicated for suspected lower airway disease, with careful attention paid to classic radiographic patterns of the pulmonary parenchyma. Bronchial patterns develop as the peribronchiolar tissues

CHAPTER  8  Stabilization of the Patient with Respiratory Distress

TABLE 8-2  Drugs Used to Calm Dyspneic Dogs and Cats Drug

Initial Dose and Route

Notes

Butorphanol tartrate*

0.2-0.4 mg/kg IM or IV

Respiratory distress/ anxiety in cats

Acepromazine*

0.01-0.02 mg/kg IV

Respiratory distress/ anxiety in dogs

Methadone

Dogs: 0.1-0.5 mg/kg Additional sedation IV, or 0.5-2 mg/kg in dogs and cats SC or IM Cats: 0.05-0.1 mg/kg IV, or 0.2-0.6 mg/kg IM or SC

Propofol

2-4 mg/kg IV, to effect

Slowly titrated to gain airway control

Morphine

Dogs: 0.2-0.5 mg/kg IV, IM, or SC Cats: 0.1 mg/kg IV, IM, or SC (can increase to 0.2 mg/kg if necessary)

Relax splanchnic vasculature in cases of pulmonary edema. In addition to those listed above

*Can be used in combination (if there are no contraindications).

become inflamed, often consistent with lower airway disease (e.g., asthma, chronic bronchitis). Interstitial patterns develop with thickening of the fibrous structures of the lung, as seen with pulmonary neoplasia or fungal infections. Alveolar patterns, characterized radiographically by air bronchograms, are caused by fluid accumulation in the alveoli. These may be secondary to cardiogenic or noncardiogenic pulmonary edema, pneumonia, or hemorrhage. Radiographic distribution of the alveolar pattern can help further distinguish the cause of disease. A cranioventral opacity, most commonly observed in the right middle lung lobe, usually indicates aspiration pneumonia. A dorsocaudal distribution is seen with many causes of noncardiogenic edema (e.g., airway obstruction, electrocution, post-ictal, with near-drowning). A perihilar alveolar pattern, observed around the base of the heart, can be seen with cardiogenic edema. In addition, these cases often have signs of left atrial enlargement and pulmonary venous congestion. Any condition affecting the pleural space (e.g., fluid accumulation, pneumothorax, diaphragmatic hernia) should also be identified with a radiograph. Radiographic signs consistent with pleural space disease include visualization of widened pleural fissures, retraction of lung lobe margins, blunting of the costophrenic angle on the ventrodorsal view, and the silhouette sign with the heart and the diaphragm.

Ultrasonography The use of ultrasound in the emergency setting has significantly increased in recent years. There is a clear tradeoff between obtaining immediate results and the quality of the examination that can be performed based on both patient and operator (experience) factors. When

47

used in a focused manner, a “fast” thoracic ultrasound examination can be helpful. Importantly, appropriate equipment (including transducer frequencies) must be available, the examiner should have sufficient training in ultrasound imaging techniques, and the clinician must learn to interpret the obtained images correctly. In the patient with respiratory distress, ultrasound imaging is especially useful for identifying pleural effusion and pericardial effusions, assessing left atrial size (for left-sided congestive heart failure), and identifying a gas/fluid interface consistent with lung parenchymal disease. Complete blood counts may be useful for distinguishing inflammatory diseases from stress. Coagulation testing is indicated in patients with pleural space or parenchymal bleeding and assists in identification of acquired coagulopathies requiring clotting factor and vitamin K replacement therapy. Serum biochemical profiles aid in evaluating organ function, documenting concurrent diseases, and evaluating serum albumin concentrations. Arterial blood gas samples, although sometimes difficult to obtain in small and critical patients, are useful for assessing ventilation, oxygenation, and acid-base status. A high partial pressure of carbon dioxide indicates hypoventilation, whereas a low value confirms hyperventilation. Partial pressure of oxygen and oxygen saturation of arterial blood inform the clinician about efficacy of gas exchange and assist in determining the magnitude of the respiratory dysfunction. Recently several tests have been identified that may help distinguish cardiac from primary respiratory causes of respiratory distress. The cardiac troponin I (cTnI) and serum N-terminal pro-B-type natriuretic peptide (NT-­ proBNP) can be elevated in patients with cardiac disease and may help determine the primary disease process in these patients. Importantly, the specific cut-off values for the natriuretic peptides differ between test type (BNP versus NT-proBNP), between patient type (dog versus cat), and depending on whether disease is isolated or concurrent (heart disease only, respiratory disease only, or both). The sensitivity, specificity, and practical application of these tests are still under investigation but may hold some future promise in point-of-care testing.

Treatment Plan Once the cause of respiratory distress is localized to a region of the airway, lung, or pleural space, specific diagnostics and definitive therapy can be initiated. Light sedation and supplemental oxygen often are required to manage the case before more definitive therapy is directed. Providing an oxygen source via an induction chamber, oxygen cage, nasal cannula, face mask, or semiclosed Elizabethan collar can quickly raise the inspired oxygen concentration and improve clinical signs. In patients with high airway obstructions, supplemental oxygen can be delivered through a large needle placed directly into the trachea or via a temporary tracheotomy. Patients with pronounced expiratory dyspnea and expiratory wheezes likely have bronchial inflammation, narrowing, or collapse. Regardless of cause or species affected, the emergency plan includes supplemental oxygen, inhaled bronchodilator (see Chapter 161), and a

48

SECTION  I  Critical Care

fast-acting parenteral corticosteroid. Because bronchitis is often associated with infectious and parasitic causes, further diagnostics may be required for a longer-term treatment plan. The cause of lung parenchymal disease should be identified because it is likely to dictate treatment. Patients with pneumonia are usually systemically ill. Fever, dehydration, leukocytosis with an inflammatory left shift, and inflammatory airway cytology are all signs of pul­ monary infection. In addition to supplemental oxygen, these patients should receive intravenous fluids, antibiotics, and physical therapy to encourage loosening and clearance of the infectious material. A mitral murmur, lung crackles, and serous-to-pink-tinged acellular airway fluid may indicate pulmonary edema, requiring diuretic therapy (see Chapter 176). Blood in the airway is seen with trauma and acquired coagulopathies such as rodenticide intoxication and, if severe enough, may require transfusion of clotting factors and/or red blood cells (see Chapter 31). With pleural fluid accumulation, fluid cytology and radiographs are often necessary to distinguish the cause (see Chapter 164). Thoracocentesis is a valuable therapeutic and diagnostic tool when approaching pleural space disease. If pleural accumulation of air or fluid is rapid or if the fluid is viscous and inflammatory, a thoracostomy tube can facilitate drainage and allow repeated evacuation of the pleural space. Respiratory distress in dogs and cats can be chal­ lenging. Definitive diagnostic investigation may not be

CHAPTER 

possible at the time of presentation, but critical observation and focused physical examination help rank differential diagnoses of respiratory distress. The clinician should have a thorough understanding of the manifestations of multiple differentials of respiratory distress based on the pattern of breathing and be able to quickly identify appropriate treatments. A rational emergency diagnostic and treatment plan is based on understanding of respiratory function and alterations associated with specific diseases.

References and Suggested Reading Lee JA, Drobatz KJ: Respiratory distress and cyanosis in dogs. In King LG, editor: Textbook of respiratory disease in dogs and cats, St Louis, 2004, Saunders, pp 1-12. Mandell DC: Respiratory distress in cats. In King LG, editor: Textbook of respiratory disease in dogs and cats, St Louis, 2004, pp 12-17. Mellema MS: The neurophysiology of dyspnea, J Vet Emerg Crit Care 18(6):561-571, 2008. Oyama MA, et al: Assessment of serum N-terminal pro-B-type natriuretic peptide concentration for differentiation of congestive heart failure from primary respiratory tract disease as the cause of respiratory signs in dogs, J Am Vet Med Assoc 235(11):1319-1325, 2009. Payne EE, et al: Assessment of a point-of-care cardiac troponin I test to differentiate cardiac from noncardiac causes of respiratory distress in dogs, J Vet Emerg Crit Care 21(3):217-225, 2011. West JB: Pulmonary pathophysiology: the essentials, ed 8, Philadelphia, 2012, Lippincott Williams & Wilkins.

9 

Acute Respiratory Distress Syndrome EMILY K. THOMAS, Philadelphia, Pennsylvania LORI S. WADDELL, Philadelphia, Pennsylvania

A

cute respiratory distress syndrome (ARDS) is a severe inflammatory disorder of the lungs that can result in life-threatening respiratory failure in dogs and cats. It can be caused by a wide range of precipitating conditions, all of which lead to lung inflammation, alveolar capillary leakage, and protein-rich pulmonary edema. Acute lung injury (ALI) is a milder form of inflammatory injury to the lungs that also can progress to ARDS.

response syndrome (SIRS) or sepsis. Box 9-1 lists many of the risk factors proposed in dogs, but this list is not exhaustive. Sepsis of either pulmonary or nonpulmonary origin is the most common predisposing cause of ARDS identified in dogs. Risk factors have not been characterized in cats, but the few available reports suggest similar underlying etiologies. A single patient may have multiple precipitating causes.

Risk Factors

Pathophysiology

ARDS has many potential causes. It may result either from direct pulmonary insult or from a generalized inflammatory response such as systemic inflammatory

The pathogenesis of ARDS is similar regardless of the underlying etiology and is characterized by an overwhelming inflammatory process that leads to epithelial

CHAPTER  9  Acute Respiratory Distress Syndrome

BOX 9-1 

BOX 9-2 

Risk Factors for the Development of ARDS   in Dogs

Differential Diagnoses

Direct Lung Injury Common Causes Microbial pneumonia Aspiration pneumonia Pulmonary contusions Less Common Causes Smoke inhalation Near-drowning Lung lobe torsion Noncardiogenic pulmonary edema Indirect Lung Injury Common Causes Sepsis/SIRS Shock Severe trauma Less Common Causes Pancreatitis Systemic infection Multiple transfusions Drugs and toxins Organ torsion

damage in the lung. Macrophages, neutrophils, and proinflammatory cytokines such as tumor necrosis factor and interleukin-1β interact to cause alveolar and vascular epithelial injury. Three overlapping phases of inflammation are typically described. The exudative phase begins as a diffuse vascular leak syndrome, with infiltration of erythrocytes and inflammatory cells and effusion of protein-rich fluid into the alveoli; progressive pulmonary edema and hemorrhage result. Activation of inflammatory cells causes release of harmful mediators that contribute to ongoing lung injury. Synthesis of surfactant is impaired, with consequent alveolar collapse. Hyaline membranes (organized proteinaceous debris) form within the alveoli. In the proliferative phase that follows, a proliferation of type II pneumocytes and fibroblasts occurs in an attempt to repair damaged tissue. This leads to interstitial fibrosis. Lastly, the fibrotic phase is characterized by collagen deposition and the development of varying degrees of fibrosis before eventual resolution.

Historical Findings and Clinical Features The hallmark sign of ARDS is an acute history of severe respiratory distress. It is most commonly seen in intensive care unit patients with other underlying diseases but may affect any animal with a predisposing risk factor. The earliest signs, tachypnea and increased respiratory effort, rapidly progress to severe respiratory distress. Signs may develop within hours or up to 4 days after an inciting event. Clinical examination usually reveals severe respiratory distress with cyanosis. Dogs may expectorate a pink,

49

Cardiogenic pulmonary edema Volume overload Pulmonary thromboembolism Bacterial pneumonia Atelectasis Pulmonary hemorrhage Neoplasia

foamy fluid from the lungs. In the early stages harsh airway or loud bronchial sounds are heard on thoracic auscultation, but these rapidly progress to crackles. If the animal is intubated, sanguineous fluid may drain from the endotracheal tube. Tachycardia is common secondary to severe hypoxemia, with poor oxygen delivery to the tissues. Evidence of other underlying or systemic disease may be found.

Diagnosis In small animal veterinary medicine four criteria are required to diagnose ARDS (Wilkins et al, 2007). Respiratory distress should be acute in onset (< 72 hours), with one or more known risk factors present (see Box 9-1). Evidence of inefficient gas exchange is required, together with evidence of pulmonary capillary leak without increased pulmonary capillary pressure. Evidence of pulmonary inflammation is an optional fifth criterion. Other differential diagnoses should be considered if the above criteria are not met in a patient (Box 9-2).

Inefficient Gas Exchange Severe hypoxemia in arterial blood gas results provides evidence of inefficient gas exchange. Hypoxemia is further defined as a PaO2:FiO2 ratio of 200 or lower (ARDS) or 300 or lower (ALI) or as an increased alveolar-arterial gradient (normal value < 15 mm Hg while breathing room air). For accurate calculation, a known FiO2 is required (such as room air, oxygen cage, or mechanical ventilation). During mechanical ventilation, positive end-expiratory pressure (PEEP) or continuous positive airway pressure (CPAP) may reduce hypoxemia and affect results. The extent of hypoxemia is often sufficient to increase respiratory drive, resulting in hyperventilation and hypocarbia. However, if end-stage lung disease or respiratory muscle fatigue occurs, hypercarbia may be seen.

Pulmonary Capillary Leak Thoracic radiographs show characteristic diffuse, bilateral, pulmonary alveolar infiltrates (Figure 9-1), providing evidence of pulmonary capillary leak. Infiltrates affect more than one quadrant and may be asymmetrical or patchy. The ventral lung lobes may be the most severely affected. The heart and blood vessels should also be evaluated. Cardiomegaly, left atrial enlargement,

50

SECTION  I  Critical Care

A

B Figure 9-1  Left lateral (A) and dorsoventral (B) radiographs showing diffuse, pulmonary alveo-

lar infiltrates in an 11-year-old dog presenting with acute respiratory distress after anesthesia for a dental procedure. The cardiac silhouette is only partially visible but is normal in size, with normal pulmonary vasculature.

distended pulmonary vessels, or concurrent pleural effusion may suggest increased pulmonary capillary pressure secondary to congestive heart failure or fluid overload, rather than ARDS. If this is suspected, echocardiography is indicated to rule out cardiogenic pulmonary edema or volume overload. Pulmonary capillary leak with normal cardiac function may also be seen with noncardiogenic pulmonary edema related to seizures or acute upper airway obstruction. The pathogenesis is not fully understood, but mechanical disruption of the capillary endothelium from acute overload of the pulmonary circulation secondary to massive sympathetic stimulation and systemic vasoconstriction may contribute to the leak. Typically, this type of edema resolves over 24 to 48 hours with treatment, although in severe cases it can progress to ARDS. Radiographs commonly show asymmetric infiltrates with predominantly right-sided or caudodorsal quadrant involvement. A central venous catheter may be placed for both diagnostic and management purposes. Elevation of the central venous pressure (CVP), as well as visible jugular venous distention prior to catheter placement, may suggest congestive heart failure or fluid overload. Until recently, pulmonary arterial catheters were frequently used in humans to assess pulmonary capillary wedge pressure and left heart function (see Chapter 4). However, placement is invasive, and their use was not shown to improve outcome. Less invasive methods of assessment (such as echocardiography) are recommended in veterinary patients.

Additional Diagnostics Typical abnormalities in the complete blood count (CBC) include leukopenia due to sequestration of white blood

cells in the periphery and in the lungs and thrombocytopenia due to platelet sequestration or consumption. Changes in the serum biochemical profile (SBP) are often nonspecific, but hypoalbuminemia is common due to underlying disease and exudative protein loss into the pulmonary edema fluid. Prolonged coagulation times and elevated fibrin degradation products or D-dimers may indicate a consumptive coagulopathy. Cytologic evaluation and culture of bronchoalveolar lavage or transtracheal wash samples provide useful additional diagnostic information—if the animal is stable enough to perform these diagnostics. Neutrophilia of the lavage sample fulfills the optional fifth diagnostic criterion for evidence of pulmonary inflammation. Culture results will guide antibiotic therapy.

Therapeutics The first priority of treatment is to address the underlying cause of SIRS or primary lung injury, if possible, so that the source of ongoing injury is removed. Other than this, supportive care is the mainstay of treatment, and specific treatments for ARDS are still lacking despite ongoing research. However, improvements in supportive care have significantly reduced mortality in humans over the last decade.

Respiratory Support Animals with mild ALI may respond to oxygen supplementation alone (see Chapter 10) and may appear more comfortable following sedation with butorphanol (0.1 to 0.4 mg/kg IV, IM). However, ARDS patients usually require positive pressure ventilation (PPV) to achieve

CHAPTER  9  Acute Respiratory Distress Syndrome adequate gas exchange (see Chapter 11). PPV with PEEP recruits alveoli and increases functional residual capacity, allowing ventilation at lower FiO2 and preventing cyclical alveolar reopening and stretching with each breath. FiO2 should be 0.6 or lower to prevent oxygen toxicity. A strategy of protective lung ventilation should be employed, with tidal volumes as low as possible (ideally 6 to 8 ml/kg) in order to prevent overdistention of normal alveoli, shear stress, and progression of lung injury. Excessively high airway pressures (> 30 cm H2O) may cause further lung injury and should be avoided.

Fluid Therapy Fluid administration should be carefully evaluated to prevent fluid overload and worsening of pulmonary dysfunction. Measurement of CVP may aid in targeting fluid therapy. If volume overload is present, judicious administration of diuretics such as furosemide is indicated, with close monitoring of renal function. Colloidal support (fresh frozen plasma, synthetic colloids, or 25% human albumin solutions) is required for hypopro­ teinemic patients.

Pharmacotherapy Many treatments have shown promising results in experimental animal models, including corticosteroids, nitric oxide, exogenous surfactant, β2 agonists, and a variety of cyclooxygenase, thromboxane, and leukotriene inhibitors. However, none have been shown to have an effect on morbidity or mortality in human clinical trials. Therapies currently under investigation include mesenchymal stem cell therapy and inflammatory modulation using immunonutrition. Drugs used in veterinary patients with ARDS are limited to antibiotics (if appropriate for underlying disease) and supportive measures (diuretics, fluid therapy, anesthesia if PPV is required) as outlined above. A constant rate infusion of low-dose furosemide (0.1 mg/kg hour) has proved beneficial at decreasing lung water and peak airway pressure in dogs with experimentally induced

51

ARDS. Low-dose corticosteroids may be considered in patients with severe, early (< 72 hours) ARDS, but their use has not been substantiated by scientific data.

Patient Monitoring Patients require intensive care monitoring, with frequent arterial blood gas analysis, pulse oximetry, arterial blood pressure, urine output, temperature, electrocardiogram, thoracic radiographs, CBC, serum biochemical analyses, and coagulation monitoring. Patients are at high risk for aspiration pneumonia, and appropriate nursing care with careful use of analgesics and sedation should be provided.

Prognosis Humans with ARDS have an expected survival rate of 40% to 60% and often require mechanical ventilation for 4 to 6 weeks. Death may be caused by respiratory failure or by progressive multiple organ dysfunction and failure. Mortality in dogs and cats is even higher, and a grave prognosis must be given.

References and Suggested Reading DeClue AE, Cohn LA: Acute respiratory distress syndrome in dogs and cats: a review of clinical findings and pathophysiology, J Vet Emerg Crit Care 17(4):340-347, 2007. Dushianthan A et al: Acute respiratory distress syndrome and acute lung injury, Postgrad Med J 2011; Jun 4 (Epub ahead of print). Wilkins PA et al: Acute lung injury and acute respiratory distress syndromes in veterinary medicine: consensus definitions: The Dorothy Russell Havemeyer Working Group on ALI and ARDS in Veterinary Medicine, J Vet Emerg Crit Care 17(4):333-339, 2007. Parent C et al: Clinical and clinicopathologic findings in dogs with acute respiratory distress syndrome: 19 cases (19851993), J Am Vet Med Assoc 208(9):1419-1427, 1996. Parent C et al: Respiratory function and treatment in dogs with acute respiratory distress syndrome: 19 cases (1985-1993), J Am Vet Med Assoc 208(9):1428-1433, 1996.

CHAPTER 

10 

Oxygen Therapy VINCENT J. THAWLEY, Philadelphia, Pennsylvania KENNETH J. DROBATZ, Philadelphia, Pennsylvania

I

nadequate oxygen delivery to the tissues is commonly encountered in critically ill patients and results in a shift to anaerobic metabolism to support cellular func­ tions. Cellular energy production declines and lactic acid accumulates, which may exacerbate tissue injury and can lead to organ dysfunction or even death. Ensuring ade­ quate tissue oxygenation is a principal goal in the critical care setting. This chapter explores the major determi­ nants of tissue oxygen delivery as well as several methods that may be employed in an effort to improve blood oxygen content.

Indications for Oxygen Therapy Oxygen therapy is indicated in situations in which there is inadequate oxygen delivery to the tissues (hypoxia). Oxygen delivery depends on cardiac output, hemoglobin concentration, oxygen saturation of hemoglobin, and the amount of oxygen dissolved in plasma. It can be com­ promised by a number of pathophysiologic conditions including hypoxemia (poorly oxygenated arterial blood); decreased blood flow from cardiovascular shock, conges­ tive heart failure, or vascular obstruction; anemia; or decreased hemoglobin affinity for oxygen such as in carbon monoxide intoxication or methemoglobinemia. Clinical signs of hypoxemia include tachypnea, or­­ thopnea, and open-mouth breathing. Patients may appear anxious and stand with their head and neck extended and elbows abducted. Severely hypoxemic patients may be syncopal, obtunded, or comatose. Cyanosis is an in­­ sensitive marker for hypoxemia because it is only detected when the arterial partial pressure of oxygen is less than 50 mm Hg and there is greater than 5 g/dl of desaturated hemoglobin. Furthermore, cyanosis is not apparent in patients with severe anemia or mucous membranes that are pale due to hypoperfusion. There are five principal causes of hypoxemia. Low inspired partial pressure of oxygen, which may occur in intubated patients breathing an oxygen-poor gas mixture, patients rebreathing dead space gas, or patients living at a high altitude, can result in poorly oxygenated arterial blood. Hypoventilation occurs most frequently as a result of airway obstruction, neuromuscular disease, pleural space disease, or pain or in conditions that result in dys­ function of the chest wall or diaphragm. Impaired diffusion of oxygen across the alveolar-capillary membrane is an uncommon cause of hypoxemia. Diseases that result in pneumocyte proliferation or accumulation of cellular infiltrates or interstitial fibrin deposits may lead to thick­ ening of the alveolar membrane and diffusion barrier. 52

The most common cause of hypoxemia seen clinically is ventilation/perfusion (V/Q) mismatch, which occurs when pulmonary blood passes by poorly ventilated alveoli. V/Q mismatch is seen with pneumonia, pulmonary edema, hemorrhage, pulmonary thromboembolism, neoplasia, and acute respiratory distress syndrome (ARDS). Right-toleft vascular shunt represents an extreme case of V/Q mis­ match and may be seen in cases of lung lobe collapse or in some congenital cardiac defects. This is the only cause of hypoxemia that does not respond to oxygen supplementation. Measuring blood oxygenation can be accomplished via either pulse oximetry or arterial blood gas analysis. Pulse oximetry estimates the percent oxygen saturation of hemoglobin (SpO2), whereas arterial blood gas analysis measures the amount of dissolved oxygen in plasma (PaO2). The relationship between SpO2 and PaO2 is dem­ onstrated by the oxygen-hemoglobin dissociation curve. A shift in the curve to the right indicates improved oxygen delivery to the tissues, with a decrease in pH or an increase in temperature or in concentration of 2,3-diphosphoglycerate. An increase in pH or a decrease in temperature or in concentration of 2,3-diphosphoglyc­ erate shifts the curve to the left, indicating an increased binding affinity of hemoglobin for oxygen. A PaO2 less than 80  mm  Hg or SpO2 less than 93% indicates hypoxemia, and oxygen supplementation is warranted. When pulse oximetry and arterial blood gas analysis are unavailable, the decision to supplement oxygen should be based on physical examination find­ ings that suggest hypoxemia or decreased tissue oxygen delivery. However, not all patients with clinical signs referable to the respiratory system are hypoxemic. For example, tachypnea may be noted with anxiety, pain, increased temperature, or metabolic acidosis. If there is any doubt, supplemental oxygen should be provided.

Techniques for Oxygen Supplementation There are several methods available to provide supple­ mental oxygen, including flow-by, face mask, nasal or nasopharyngeal catheter, tracheal catheter, oxygen cage, and mechanical ventilation. The method selected depends on the severity of hypoxemia, the desired fraction of inspired oxygen (FiO2), the expected duration of therapy, equipment availability, patient compliance, and underly­ ing disease process(es). Sedation is often administered to patients with respiratory distress and in some situations may facilitate the delivery of supplemental oxygen.

CHAPTER  10  Oxygen Therapy

Flow-By Oxygen Flow-by oxygen, administered by holding the oxygen hose a few centimeters from the nose or mouth if the patient is panting, is a quick and easy method to provide short-term supplemental oxygen. Flow-by also may be useful in determining whether a patient is responsive to oxygen therapy before initiating long-term treatment. An FiO2 of 30% to 40% may be achieved by using oxygen flow rates of 2 to 5 L/min. Constant nursing attention is required because many patients turn away from the oxygen source. This method is also somewhat wasteful because a significant amount of oxygen may bypass the patient.

Face Mask Face masks are another option for short-term oxygen supplementation that can be set up quickly with minimal equipment. An FiO2 of 50% to 60% is possible with a well-fitted mask and a flow rate of 8 to 12  L/min. Poorly fitting masks should be avoided because they may limit the amount of oxygen delivered and create dead space that increases the work of breathing. Some patients may struggle during placement of a face mask, increasing tissue oxygen consumption and exacerbating hypoxemia; nasal catheterization or the use of an oxygen cage is suggested in these patients. Long-term use of a face mask is generally only possible in sedated or moribund patients.

Nasal Catheter Nasal catheters are useful for providing long-term oxygen supplementation and can be placed with ease in most patients. Advantages of nasal catheters include rapidity of placement and the ability to provide an FiO2 up to 90% while maintaining free access to the patient. Major dis­ advantages include the inability to accurately monitor delivered FiO2 and patient intolerance that may result in attempts to remove the catheter. To place a nasal catheter, first instill topical anesthetic (2% lidocaine or proparacaine) into the naris. A soft red rubber catheter (size 5 to 10 French) is premeasured from the naris to the medial canthus of the eye and marked at the level of the naris. Nasopharyngeal catheters can be placed by measuring from the naris to the ramus of the mandible. The tip of the catheter is lubricated and placed into the ventromedial aspect of the naris and then advanced quickly but gently to the premeasured length. Suture, staples, or tissue adhesive is used to secure the catheter to the face as close to the naris as possible and more proximally (ventral to the ear or on the forehead). Care should be exercised to avoid entrapment of the patient’s whiskers when securing the tube. Nasal prongs designed for humans may be used in place of a nasal catheter in patients that are not very mobile. Prongs are cut shorter as needed to fit snugly into the nares; they can be secured in place by tightening the tubing behind the head. Nasal prongs are easily dis­ lodged but may be useful in sedated, very ill, or brachy­ cephalic patients.

53

The oxygen flow rate selected depends on the size of the patient, but, in general, flow rates of 50 to 100 ml/ kg/min can provide an FiO2 of 30% to 50%. If a higher FiO2 is desired, placement of bilateral catheters is recom­ mended because flow rates exceeding 100 ml/kg/min may be uncomfortable for the patient and can injure the nasal mucosa. Humidification is suggested as oxygen bypasses the nasal passages and may dry and injure the respiratory mucosa. This can be accomplished by using a commercial in-line bubble humidifier or by bubbling the oxygen through an intravenous fluid bottle filled with sterile water. Complications of nasal oxygen administration include nasal mucosal jet lesions, sneezing, nasal discharge, epi­ staxis, and gastric dilation. If local irritation is observed, the catheter should be removed and replaced in the oppo­ site naris. A new catheter should be placed in the opposite naris every 48 hours to limit nasal mucosal injury.

Tracheal Catheter Tracheal catheters are useful in patients that will not tolerate a nasal catheter or for patients with anatomic abnormalities or pathology that precludes placement of a nasal catheter. Although mucosal injury is less likely to occur than with a nasal catheter, tracheal catheters are more technically challenging to place, are more inva­ sive, and often do not remain in place if the patient is mobile. Tracheal catheters can be placed by percutaneously inserting a large-gauge through-the-needle catheter into the trachea between two rings caudal to the larynx. The catheter is advanced to just above the carina at the level of the fifth rib. The needle is then withdrawn from the skin and secured in place. Alternatively, a red rubber catheter or argyle feeding tube may be used in place of a through-the-needle catheter. In this case, following appropriate local anesthesia and sedation, a small inci­ sion is made on the ventral cervical midline approxi­ mately four tracheal rings caudal to the larynx. A combination of sharp and blunt dissection is used to expose the trachea by laterally retracting the sternothy­ roid and sternohyoid muscles. A transverse incision is made through the annular ligament between two tracheal rings, and hemostatic forceps are used to guide the tube into the tracheal lumen. Humidified oxygen with flow rates similar to those for nasal catheters is used. Major complications in­­ clude tracheal jet injury, tracheitis, and kinking at the insertion site. Displacement of the catheter can lead to subcutaneous oxygen insufflation and subcutaneous emphysema, which may result in pneumomediastinum or pneumothorax.

Oxygen Cage Oxygen cages are sealed compartments that allow for accurate control of FiO2, ambient temperature, humidity, and carbon dioxide (CO2) elimination. Both commercial and custom-built cages are available but the ability to provide an FiO2 greater than 40% is limited except in the more expensive models. Most oxygen cages have a

54

SECTION  I  Critical Care

Plexiglas front to allow direct visualization of the patient at all times, as well as a conduit for monitoring leads and fluid lines that prevents oxygen from leaking out of the cage. Ambient temperature should be set at 22° C (70° F) with a relative humidity of 40% to 50%, although this may be adjusted as needed for hypothermic or hyperther­ mic patients. The major advantage of the oxygen cage is that it is a noninvasive method of supplementing oxygen in patients that may not tolerate more invasive measures. In addition, the relatively quiet environment may be beneficial for anxious dyspneic patients. Frequently mon­ itoring the patient’s temperature is essential because hyperthermia may develop, especially in large-breed dogs. For these patients, oxygen via nasal catheter is suggested. Disadvantages of oxygen cages include the equipment expense, oxygen waste, and isolation of the patient from the clinician. Within moments of the cage being opened, the FiO2 drops to room air level, which may cause clinical deterioration in the patient. Physical examination, pulse oximetry, and blood gas analysis with the door open do not accurately reflect the condition of the patient inside the cage.

Mechanical Ventilation Mechanical ventilation is recommended in patients with ventilatory failure or severe pulmonary pathology result­ ing in persistent hypoxemia despite supplemental oxygen (see Chapter 11). Other indications for mechanical ventilation include impending respiratory fatigue, intra­ cranial hypertension, and postresuscitation from cardio­ pulmonary arrest. Patients requiring high FiO2 for a prolonged period are at risk for pulmonary oxygen toxic­ ity and may benefit from mechanical ventilation because the use of positive end-expiratory pressure (PEEP) may allow for a reduction in FiO2.

Hyperbaric Oxygen Therapy Hyperbaric oxygen therapy (HBOT) involves exposing the patient to 100% O2 at supraatmospheric pressures, significantly increasing PaO2 and promoting oxygen dif­ fusion to the tissues. HBOT accelerates tissue healing, stimulates leukocyte and macrophage function, and has some antimicrobial effects. Although uncommonly used, applications of HBOT include skin flaps and grafts, poorly healing wounds, clostridial infections, and carbon monoxide toxicity. Complications that may arise with HBOT include pneumothorax, tympanic membrane rupture, oxygen-induced seizures, and pulmonary oxygen toxicity.

Complications Associated with Oxygen Therapy Oxygen therapy is commonly used in hospitalized patients; however, the potential for toxicity has been long recognized. Oxygen toxicity is thought to result from excessive production of reactive oxygen radicals that cause degradation of intracellular sulfhydryl groups and cellular membranes. Pulmonary endothelial permeability increases and protein-rich fluid accumulates in the interstitium and alveoli, leading to severe pulmonary dysfunction. Other complications include absorption atelectasis, peripheral arterial vasoconstriction, pulmonary vasodila­ tion, and decreased erythropoiesis. In chronically hyper­ capnic patients, central chemoreceptors become less sensitive to the effects of CO2 and hypoxia becomes the major impetus for breathing. Oxygen therapy in these patients may decrease the respiratory drive or worsen V/Q mismatch due to release of hypoxic pulmonary vasocon­ striction allowing blood flow to poorly ventilated alveoli.

Weaning From Oxygen Therapy Weaning should be attempted only after the underlying cause of hypoxia has been identified and addressed. There is no standard time over which weaning occurs; rather, weaning ideally takes place slowly while observing the patient’s response because abrupt discontinuation of oxygen therapy can lead to rapid deterioration. Oxygen therapy should be reinstituted if the patient shows signs of respiratory distress at any point during weaning. Moni­ toring pulse oximetry or arterial blood gases during weaning may help determine whether continued therapy is indicated.

References and Suggested Reading Court M: Respiratory support of the critically ill small animal patient. In Murtaugh RJ, Kaplan PM, editors: Veterinary emergency and critical care medicine, St Louis, 1992, Mosby, pp 575-580. Drobatz KJ, Hackner S, Powell S: Oxygen supplementation. In Bonagura J, Kirk R, editors: Kirk’s current veterinary therapy XII: small animal practice, Philadelphia, 1995, WB Saunders, pp 175-179. Dunphy ED et al: Comparison of unilateral versus bilateral nasal catheters for oxygen administration in dogs, J Vet Emerg Crit Care 12:245-251, 2002. Edwards ML: Hyperbaric oxygen therapy. Part 2: application in disease, J Vet Emerg Crit Care 20:289-297, 2010. Jenkinson S: Oxygen toxicity, New Horiz 1:504-511, 1993. Tseng LW, Drobatz KJ: Oxygen supplementation and humidifica­ tion. In King L, editor: Textbook of respiratory disease in dogs and cats, St Louis, 2004, Saunders, pp 205-213.

CHAPTER 

11 

Ventilator Therapy for the Critical Patient JULIEN GUILLAUMIN, Columbus, Ohio

I

n humans, modern mechanical ventilation (MV) took off during the Copenhagen poliomyelitis epidemic of 1952. Survival rates in the 1960s were 30% to 40% but dramatically improved to almost 90% in the early 1980s. MV in veterinary medicine is lagging behind its human counterpart, with less than 250 dogs and 100 cats reported in the clinical literature.

Indications The indications for MV in veterinary medicine include (1) ventilatory failure characterized by hypercarbia, with a cutoff of PaCO2 greater than 60 mm Hg or PvCO2 greater than 65 mm Hg; (2) hypoxemic failure, with objective cutoffs including a PaO2 lower than 60 mm Hg or pulse oximetry lower than 90% despite oxygen therapy (FiO2 ≥ 60%); and (3) increased work of breathing with a risk of respiratory arrest. This last criterion is a subjective assessment of a patient showing evidence of respiratory fatigue or substantial distress, even if the blood gas values are still acceptable. Under these circumstances, delayed intervention is unethical and medically inappropriate.

Prognosis There are only three large retrospective studies of MV in veterinary medicine (Table 11-1). Another set of four studies researched specific populations of canine patients (see Table 11-1). The prognosis for survival to discharge varies greatly depending on the primary disease process. Survival to discharge is reported to be up to 86% for animals with toxicoses, who are usually younger patients with reversible causes and no pulmonary parenchymal disease; 40% for those with pulmonary contusions; and 11% for post–cardiopulmonary resuscitation (CPR) patients (Hopper, 2007). The overall prognosis ranges from 21% to 71% in dogs and from 15% to 42% in cats (see Table 11-1).

Placing a Patient on the Mechanical Ventilator Selection of drugs for anesthetic induction and sedation depends on the clinician’s preference and the patient’s status (see Chapter 13). Some unconscious patients may not require drugs, but most will not tolerate MV without sedation. Various options are available. Most clinicians use a combination of benzodiazepine and an

opioid and then add propofol, barbiturates, ketamine, or dexmedetomidine as needed. For the benzodiazepines, midazolam is preferred over diazepam because diazepam binds to plastic syringes and infusion lines, can precipitate with other drugs, and is less available. Fentanyl is usually the opioid of choice, at “anesthetic doses” of 6 to 20 µg/kg/hr. Propofol is generally a safe anesthetic but its use generates some concerns, notably involving volume, cost, hyperlipidemia, and bacterial contamination because of the soy-based carrier. Long-term propofol use in cats is discouraged because it can cause Heinz body anemia. Pentobarbital was most widely used (65% to 80%) in veterinary medicine in the 1990s but has become obsolete. Although induction and plane of anesthesia are smooth on barbiturates, tremors and seizures can potentially occur at the time of weaning. Ketamine has some cardiovascular sparing effects and requires small volumes when administered as a constant-rate infusion. Dexmedetomidine has cardiovascular side effects including bradycardia, hypotension, and vasoconstriction but can be used at “microdoses” to enhance analgesia and sedation and to decrease the opioid and propofol requirement in some patients. Paralytics such as nondepolarizing neuromuscular blocking agents (NMBAs) are controversial in human medicine. NMBAs should only be used as a last resort and the clinician should first attempt to troubleshoot both the machine and the patient when patient-ventilator dyssynchrony (PVD) occurs.

Choosing the Correct Settings of the Mechanical Ventilator A mechanical ventilator moves gas (a mixture of oxygen and medical air) in and out of the lungs. All modern mechanical ventilators follow the equation of motion that links machine characteristics that can be manipulated and patient characteristics that depend on the primary disease and can change over time: Pressure = Volume/Compliance + Resistance × Flow The clinician enters variables into the machine to program the breath that will be delivered. With a pressurecontrolled breath, the machine delivers a breath up to a specific airway pressure. With a volume-controlled breath (technically flow-controlled), the machine delivers a certain volume in a given inspiratory time by controlling 55

56

SECTION  I  Critical Care

TABLE 11-1  Available Retrospective Studies or Case Series of Mechanical Ventilation in Small Animal Clinical Patients Median (Range) Duration of MV (Hours)

Survival to Discharge (%)

First Author–University–Reference

Timeframe

Population

King–U Penn–J Am Vet Med Assoc 204(7):10451052, 1994.

1990-1992

7 cats and 34 dogs with MV > 2 hours

28 (2-137)

38 (dogs); 42 (cats)

Campbell–U Penn–J Am Vet Med Assoc 217(10):1505-1509, 2000.

1994-1998

10 dogs with thoracic trauma

32 (8-77)

33

Beal–U Penn–J Am Vet Med Assoc 218(10):1598-1602, 2001.

1991-1999

14 dogs with cervical spinal disorders

Lee–U Penn–J Am Vet Med Assoc 226(6):924931, 2005.

1993-2002

Hopper–UC Davis–J Am Vet Med Assoc 230(1):64-75, 2007.

108 (10-312)

71

53 cats with any MV

11 (1-176)

15

1990-2001

124 dogs and 24 cats with MV > 24 hours

48 (24-356)

29 (dogs); 21 (cats)

Hoareau–U Penn–J Vet Emerg Crit Care 21(3):226-235, 2011.

1990-2008

15 dogs with brachycephalic syndrome

15 (2-240)

27

Rutter–Tufts Cummings U–J Vet Emerg Crit Care 21(5):531-541, 2011.

2003-2009

14 dogs with LMN disease

109 (5-261)

21

MV, Mechanical ventilation; LMN, lower motor neuron.

the flow of gas. Also, the clinician may choose to provide positive end-expiratory pressure (PEEP), in which the baseline pressure at the end of expiration remains supraatmospheric. This helps to prevent alveolar collapse and recruit alveolar units. The ventilator can generate different types of breath. In mandatory breaths, the ventilator determines either the delivery and/or the end of inspiration. Spontaneous breaths are initiated and terminated by the patient. Mandatory breath can be assisted, with the patient triggering the breath that is then delivered and terminated by the machine, or controlled, with the system triggering, delivering, and terminating the breath. This is called assist/control (A/C) or continuous mandatory ventilation (CMV). The ventilator can support a spontaneous breath by adding some positive pressure to “support” its tidal volume. With synchronized intermittent mandatory ventilation (SIMV), both spontaneous and mandatory breaths can be delivered in a synchronized manner, with the machine triggering, delivering, and cycling the breath if the patient does not. Newer modes, such as airway pressure release ventilation (APRV), are more frequently used for humans than for animals. When MV is initiated, the goal is to achieve the least aggressive settings to maintain adequate oxygenation (PaO2 80 to 100 mm Hg) and ventilation (PaCO2 35 to 45 mm Hg). The general guidelines for initial settings in animals are: • Mode A/C (or CMV) to provide maximum ventilatory support until the patient is stabilized. Some clinicians initially use “hybrid” modes such as SIMV. • Peak airway pressure of 15 to 25 cm H2O.

• Tidal volume of 10 ± 2 ml/kg, although in severe hypoxemic failure (“protective lung strategy”), tidal volumes are aimed for smaller than normal volumes (4 to 6 ml/kg). • Respiratory rate of 20 breaths per minute. • Inspiratory time of 1 sec, giving an inspiratory : expiratory ratio of 1 : 2. • PEEP 2 to 5 cm H2O, although higher levels of PEEP can recruit and prevent derecruitment of alveolar units (“open lung strategy”). Inspiratory pressure, respiratory rate, and PEEP can be manipulated to maintain acceptable oxygenation and ventilation. Peak inspiratory pressures up to 40 to 60 cm H2O and PEEP up to 20 cm H2O have been used to stabilize patients in severe respiratory failure.

Patient Care Long-term ventilation can be associated with several nursing care complications, including decubitus ulcers, peripheral edema, corneal ulceration, and oral ranula. These complications occur in at least 5% to 10% of MV veterinary patients. Well-padded tables, regular repositioning, and passive range of motion should be performed every 4 to 6 hours. Ocular ulcer prevention should be done by regular application of artificial tears. Oral care is an important part of the nursing of the MV patient. Canine patients on MV appear prone to ranula development and tongue swelling. Oral care with saline, diluted chlorhexidine solution, a commercial oral rinse, and/or protection with glycerin-soaked gauze is important. Providing early nutrition is essential for the ventilated patient. Ventilated patients can be fed enterally or parenterally. The combination of central parenteral nutrition

CHAPTER  11  Ventilator Therapy for the Critical Patient

57

BOX 11-1  Tracheostomy Tube Care • Clean stoma q12h (please ask primary clinician about tracheostomy tube dressing). 1. Gather supplies and wash hands. 2. If necessary, remove old dressing, being careful to keep tracheostomy tube in place. 3. Inspect the site around the tracheostomy stoma for signs of skin breakdown, infection, or irritation. 4. Using an antiseptic solution (e.g., chlorhexidine), clean   and prep the skin around the stoma as for a surgical procedure. 5. Using a cotton swab with a rolling motion, clean the skin area around the stoma and under the flange of the tube. Dried mucus and secretions can be removed by gently wiping with gauze soaked in saline. Wipe gently away from the opening. 6. Pat dry with a clean dry swab or pad. 7. If necessary, place clean tracheostomy dressing or a 4” × 4” gauze sponge folded in half under the flange. 8. Change tracheostomy ties as necessary if soiled. • Change and clean inner cannula (if applicable) q8h, or more frequently as needed if inner cannula becomes obstructed. 1. Gather supplies and wash hands. 2. Fill the removable basin with diluted 0.05%   chlorhexidine. 3. Glove, with nonsterile vinyl gloves, and gently remove old inner cannula. Discard gloves. 4. Glove, using sterile gloves. 5. Grab new inner cannula from the sterile pack or the removable basin. Rinse the inner cannula thoroughly with sterile water. 6. Dry the inner cannula using a sterile gauze sponge. 7. Insert new sterile disposable inner cannula into tube. 8. While still wearing sterile gloves, clean old inner cannula by gently removing encrustations and mucus using a sterile trach brush or sterile pipe cleaners. 9. Place the old, but now clean, inner cannula in the removable basin. • Nebulization q4-8h. • Change artificial nose every 5-7 days or if grossly soiled. • Suction PRN: Please ask primary clinician about saline instillation. • DO NOT routinely change tracheostomy tube. Follow protocol as needed. 1. Gather supplies and wash hands. 2. Glove with sterile gloves.

3. Remove the tracheostomy tube from the package and remove the inner cannula (if applicable) using aseptic technique. 4. Thread the outer cannula with neck tapes. 5. Test inflate the cuff and deflate it (if applicable). 6. Place the obturator into the outer cannula. 7. Lubricate the tip of the tube and the obturator with water-soluble lubricant to ease insertion. 8. When the new tube is fully ready for insertion, cut the tapes on the old tube. 9. Grasp the old tube by the neck flange and remove it in a downward motion. 10. When the old tube is out, immediately insert the new tube using gentle inward pressure and stay sutures. 11. IMMEDIATELY remove the obturator, inflate the cuff (if applicable). 12. Have an assistant wearing examination gloves secure the neck tapes with a square knot with enough space between the neck and the tie to allow one finger space. Patient Care with a Cuffed Tracheostomy Tube • If patient is spontaneously breathing, please DO NOT inflate the cuff. • If patient is ventilated, check cuff pressure q12-24h (goal is 15-20 mm Hg). Troubleshooting If tracheostomy tube falls out: • DON’T PANIC. • Assess patient’s breathing, as most of the patients will still breathe through normal airways or stoma. • You may use stay sutures to help keep the stoma open if necessary. • Ask for help. • Be ready to insert a new tube or proceed to an orotracheal intubation: sedation or anesthesia drugs, adequate material, oxygen source, and so forth. If acute dyspnea: • Provide oxygen +/− sedation. • Check patency of tracheostomy tube with chest auscultation and/or feeling from air moving out of the tube. • If patency of tracheostomy tube is lost, the options are: • Change inner cannula if applicable. • Suction tube. • Change tube.

Adapted from The Ohio State University—Intensive Care Unit, Standard Operating Procedures Book.

and enteral nutrition can provide the patient’s full caloric requirement and promote enterocyte health (see Chapter 7). Enteral nutrition may also decrease the risk of bacterial translocation. When enteral feeding is instituted, residual gastric contents should be monitored and a promotility agent added. Tracheal intubation should be done using a sterile endotracheal (ET) tube and aseptic technique. A lowpressure, high-volume, cuffed polyvinyl chloride ET tube is the most commonly used tube in veterinary medicine. Less rigid silicone ET tubes are also available. Rubber ET tubes are not recommended. The ET tube should be suctioned and changed whenever necessary.

With a tracheostomy, MV patients often can tolerate the machine with mild sedation, eliminating the need for anesthesia. Tracheostomy also avoids complications associated with the ET tube including ranula and macroglossia. The reported tracheostomy rate in veterinary medicine is 20% to 30%, a number similar to that for human patients, but is increased to 70% for patients in ventilatory failure. A high incidence of complications is reported in cats with tracheostomy, so appropriate warning and proper care are warranted (Box 11-1). MV patients have open airways with a continuous flow of dry gas, so the inspired air needs to be humidified to prevent desiccation of the respiratory mucosa using

58

SECTION  I  Critical Care

inline humidifier systems or “artificial noses,” such as a heat and moisture exchanger or a hygroscopic condenser humidifier. Ventilator patients are usually severely physiologically compromised and require intensive monitoring. Central catheters can be placed to monitor central venous pressure and for sampling. Arterial lines (femoral or dorsopedal) are the preferred method to measure blood pressure and can be used for blood sample collection. Urinary catheters are often placed to facilitate nursing care and quantify urine output. Other monitoring includes cardiac output, fluid balance (i.e., ins and outs, body weight), and ventilator waveform display (i.e., flowtime, pressure-time, volume-time, pressure-volume, and flow-volume). The ventilator waveforms help to identify PVD or changes in pulmonary compliance. Ventilated patients have an abnormal fluid homeostasis. In one study, healthy mixed-breed dogs that were ventilated for 24 hours receiving 5 ml/kg/hr of fluids had a decrease in urine output and an increase in urine specific gravity and showed edema with no significant changes in serum sodium concentration or cardiac index. Urine output improved following administration of lowdose furosemide. Polyuria and resolution of edema occurred following weaning from MV. This scenario is very common in clinical patients, with edema reported in up to 40% in veterinary studies. Several theories may account for the fluid-retaining state observed in MV patients. The syndrome of inappropriate antidiuretic hormone (SIADH) secretion is a well-reported consequence of MV in both humans and experimental canine studies and is also reported with use of opioids, especially fentanyl, in dogs. Use of positive pressure ventilation and (high) PEEP may also decrease venous return and cardiac output, which in turn can stimulate the release of ADH and aldosterone.

Oxygen toxicity describes the damage due to free radical and reactive oxygen species formation. Propagation of oxygen-derived free radical species can lead to DNA damage, lipid peroxidation, cell membrane disruption, and inactivation of sulfhydryl-containing proteins. In the lung, oxygen causes an inflammatory syndrome resembling acute respiratory distress syndrome (ARDS) with an exudative and proliferative phase (see Chapter 9). In the brain, oxygen toxicity is associated with blindness and/or seizures. Oxygen toxicity to the brain and lungs appears to be related to PaO2 rather than alveolar oxygen or FiO2. Wide individual and species sensitivity to oxygen are reported, but the current dogma is that oxygen toxicity can occur when FiO2 is 100% oxygen for more than 24 hours in humans, dogs, and cats. Clinically, FiO2 should be lowered to 60% or less as soon as possible. Ventilator-associated pneumonia (VAP) is a common complication of MV, and affects 10% to 50% of MV patients. Early onset VAP can be defined by the presence of two or more of the following: purulent respiratory secretions, increase or decrease in temperature, increase or decrease in white blood cell count, and worsening gas exchange within 48 hours of MV initiation. Risk factors for development of VAP include trauma, tracheostomy, duration of MV, multiple invasive lines, enteral feeding, and blood transfusion. The Centers for Disease Control and Prevention published guidelines for VAP prevention in human patients. Recommendations such as staff education, avoiding routine change of ventilator circuits, hand decontamination, use of gloves, and oral hygiene are guidelines that can be implemented in veterinary medicine. Oral and gastric decontamination with antibiotics, systemic antibiotic prophylaxis, or gastroprotectants is not recommended currently as it is unclear if it decreases the incidence of VAP in humans.

Complications of Mechanical Ventilation

Weaning a Patient From Mechanical Ventilation

Ventilator-induced lung injury (VILI) is a global term that includes barotrauma, volutrauma, atelectrauma, and biotrauma. Barotrauma is a misnamed process that involves formation of extraalveolar air in the form of pneumothorax or subcutaneous emphysema. Pneumothorax is reported in up to 15% of human patients and up to 30% of veterinary patients with MV. Gradients between the intraalveolar and extraalveolar pressures cause air to dissect along vascular sheaths and accumulate in the extraalveolar space. There is poor correlation between leak of air from the lungs and peak airway pressure. It has been postulated that “there is no pressure above which you will always cause a pneumothorax and there is no pressure below which you will never cause a pneumothorax.” Volutrauma is a complication of MV caused by stretchinduced trauma to the alveoli that increases epithelial and endothelial permeability. Atelectrauma results from cyclic opening and closing of alveoli that creates lung inflammation. In addition, the production of inflammatory mediators can cause direct local lung injury as well as worsening systemic inflammation in a process called biotrauma.

The objective for every MV patient is to be weaned off the ventilator. As the primary disease process is successfully treated or heals, the clinician should require the patient to breathe on its own with a decreased magnitude of ventilator support. Weaning should be attempted if there is evidence for improvement of the underlying cause for respiratory failure, there is adequate oxygenation (e.g., PaO2/FiO2 ratio above 200 to 300 on a PEEP less than 4 cm H2O), hemodynamic stability, and spontaneous breath taken by the patient. Weaning methods depend on the patient, the disease process, the clinician, and the ventilator itself. In general, sedation is decreased to achieve increased spontaneous breathing, to assess the ability of the patient to generate adequate tidal volume, and to maintain oxygenation without signs of ventilator fatigue with lowered FiO2 or PEEP. Ventilator settings are modified to decrease the amount of pressure support or mandatory breath. The patient is then disconnected from the machine but usually remains intubated and is provided with supplemental oxygen. Following extubation, the patient is placed on other forms of supplemental oxygen until there

CHAPTER  12  Analgesia of the Critical Patient is a complete resolution of its hypoxemia and the patient is able to sustain appropriate oxygenation on room air before being discharged from the hospital.

References and Suggested Reading Corona TM, Aumann M: Ventilator waveform interpretation in mechanically ventilated small animals, J Vet Emerg Crit Care 21(5):496-514, 2011. Ethier MR et al: Evaluation of the efficacy and safety for use of two sedation and analgesia protocols to facilitate assisted ventilation of healthy dogs, Am J Vet Res 69(10):1351-1359, 2008. Fisk BA, Moores LK: Sedation, analgesia, and neuromuscular blockage. In MacIntyre NR, Brandson RD, editors: Mechanical ventilation, ed 2, St Louis, 2009, Saunders Elsevier, pp 235-251.

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Haskins SC, King, LG: Positive pressure ventilation. In King LG, editor: Textbook of respiratory disease in dogs and cats, St Louis, 2004, Saunders Elsevier, pp 217-229. MacIntyre NR et al: Evidence-based guidelines for weaning and discontinuing ventilatory support: a collective task force facilitated by the American College of Chest Physicians; the American Association for Respiratory Care; and the American College of Critical Care Medicine, Chest 120(6 Suppl):375S95S, 2001. Stapleton RD, Steingert KP: Ventilator-induced lung injury. In MacIntyre NR, Brandson, RD, editors: Mechanical ventilation, ed 2, St Louis, 2009, Saunders Elsevier, pp 206-212. Wunsch H et al: Use of intravenous infusion sedation among mechanically ventilated patients in the United States, Crit Care Med 37(12):3031-3039, 2009.

12 

Analgesia of the Critical Patient NIGEL CAMPBELL, Raleigh, North Carolina

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linical pain is seen with trauma or surgery and often accompanies acute illness. This acute pain can contribute to the postinjury stress response and increase overall morbidity and mortality. If the initial pain response is not well controlled, adaptive responses occur in the pain pathways that lead to peripheral and central sensitization and hyperalgesia (“wind-up”). To get the best results, analgesia should be preemptive and multimodal whenever possible. To ensure that analgesia is adequate, frequent reassessment of patient comfort should be performed. This chapter reviews a number of drug therapies used for preventing and treating pain in dogs and cats. In addition, routes of administration and delivery of analgesic drugs are considered.

Opioids Opioids, the primary drugs for treating pain in the critical patient, also provide mild to moderate sedation, depending on the agent. The most commonly used opioids are the pure mu agonists (morphine, hydromorphone, oxymorphone, and fentanyl) and the partial mu agonist, buprenorphine. Butorphanol, a kappa agonist and a mu antagonist, provides less analgesia but more sedation. Fentanyl, a potent analgesic, has a very short half-life and therefore should be administered as a constant rate infusion (CRI) or a transdermal patch.

Methadone is a mu-receptor agonist that also inhibits N-methyl-D-aspartate (NMDA) receptors. It has similar duration and action to morphine but produces less sedation and vomiting. Intramuscular injection can be painful in cats. Tramadol is a weak mu-receptor agonist that also inhibits neuronal reuptake of norepinephrine and serotonin. There are reports of adequate analgesia being provided by oral tramadol (Lamont et al, 2008). Because of the risk of serotonin syndrome, tramadol should not be used in patients receiving monoamine oxidase inhibitors. Side effects can include sedation or dysphoria, especially in cats. Buprenorphine is increasingly used in clinical practice. In addition to parenteral administration, it can be administered via the oral transmucosal route (OTM). This route has been demonstrated to provide analgesia in the cat at 0.02  mg/kg (Robertson et  al, 2005). However, in the dog this dose has lower bioavailability and seems to provide little analgesia. A higher OTM dose (0.12  mg/ kg) has greater bioavailability, and in a study of dogs undergoing ovariohysterectomy (OVH) it appeared to be an alternative for postoperative pain management when given immediately before anesthetic induction (Ko et  al, 2011). However, drug cost and the volume that must be administered (in bigger dogs) may be concerns. Buprenorphine SR is an injectable, sustained-released (polymer)

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SECTION  I  Critical Care

formulation that is designed to release buprenorphine over a 72-hour period; in cats undergoing OVH this appeared to have an efficacy and adverse effect profile comparable to twice-daily OTM administration of buprenorphine (Catbagan et  al, 2011). There have been anecdotal reports of some dogs exhibiting dysphoria and anorexia when buprenorphine SR is used at higher doses.

Potential Adverse Effects of Opioids Critical patients often have altered drug metabolism. Therefore the respiratory depressant effects and dysphoria or excitement seen with higher doses of opioids in healthy patients may be observed with normal or even lower doses in critically ill animals. Opioids can be reversed readily with the use of naloxone; however, buprenorphine is harder to reverse due to its higher affinity for the mu receptor. Morphine can cause histamine release and lead to the development of hypotension and therefore is given intramuscularly (IM) or subcutaneously (SC) or is diluted for very slow intravenous (IV) administration. Bradycardia can occur with opioid use but is usually of little clinical significance and can be easily treated with atropine or glycopyrrolate. Mu agonists can cause nausea and vomiting even after a single dose and can contribute to a decrease in gut motility or ileus with more chronic exposure. Of the opioids, hydromorphone and methadone are the most likely to cause panting in dogs. This can lead to potential problems with gas exchange and difficulties when monitoring respiratory rate in dyspneic patients. Therefore these two opioids are best avoided in patients with respiratory compromise or hypoxemia. Additionally, perioperative use of hydromorphone has been associated with the development of postanesthetic hyperthermia, which can be severe (40 to 42° C [104 to 108° F]), in cats. If hyperthermia occurs, cooling measures should be used; if the patient’s temperature does not drop, reversal agents such as naloxone should be administered. Careful monitoring of body temperature and respiratory rate in patients receiving opioids, especially cats, is recommended.

Nonsteroidal Antiinflammatory Drugs Nonsteroidal antiinflammatory drugs (NSAIDs) work by inhibiting cyclooxygenase (COX) and preventing the production of prostaglandins (PGs), which decreases inflammation to provide analgesia. NSAIDs have a longer onset of action (45 to 60 minutes) compared with opioids and most provide analgesia for an extended period (12 to 24 hours). When used in combination with opioids, NSAIDs can have a synergistic effect and provide improved analgesia compared with use of either drug class alone. Side effects of NSAIDs include gastrointestinal ul­­ ceration, renal damage, and a decrease in platelet function. Accordingly, obvious contraindications to NSAIDs include gastrointestinal ulceration or bleeding, platelet dysfunction, renal dysfunction, and concurrent corticosteroid use. Furthermore, hypotension, intravascular

volume de­­pletion (from vomiting, diarrhea, hemorrhage, or other fluid losses), and congestive heart failure can also constitute relative or absolute contraindications because these disorders can compromise function of the kidneys and gastrointestinal tract. Thus NSAIDs are most safely used in normovolemic, hemodynamically stable patients. However, carprofen did not cause clinically relevant adverse effects in dogs anesthetized for fracture repair, even when it was administered before surgery or given to patients with trauma-induced alterations in renal function or hemostasis (Bergmann et al, 2005). Numerous NSAIDs are available in veterinary medicine. Those most commonly used in dogs include carprofen, deracoxib, firocoxib, and meloxicam. Only carprofen and meloxicam are available in an injectable form, so these tend to be used more in hospitalized patients that cannot tolerate oral administration of drugs. Commonly used NSAIDs in the cat are carprofen, ketoprofen, and meloxicam. NSAIDs must be used with caution in this species as cats have a low capacity for hepatic glucuronidation, which can lead to accumulation. Because of this, cat doses should never be extrapolated from those used in dogs.

α2-Adrenergic Agonists α2-Adrenergic agonists produce sedation and analgesia. Other effects include peripheral vasoconstriction with reflex bradycardia followed by centrally mediated vasodilation, respiratory depression, diuresis, and muscle relaxation. Due to the profound cardiovascular changes that occur with α2-adrenergic agonists (e.g., up to a 50% decrease in cardiac output), they should be limited to patients that are normovolemic and with stable cardiovascular status. Atropine or glycopyrrolate should not be administered concurrently with α2-adrenergic agonists because coadministration can lead to the development of hypertension and cardiac arrhythmias. Dexmedetomidine is now the most commonly used α2-adrenergic agonist in small animal medicine, having replaced medetomidine. Dexmedetomidine is the pharmacologically active enantiomer found in the racemic preparation of medetomidine. Dexmedetomidine can be given IV or IM or used as a CRI. α2-Adrenergic agonists can be easily reversed with atipamezole administered IM. The IV administration of atipamezole for reversal should be avoided because its use can lead to hyperexcitability or aggression.

Other Drugs N-Methyl-D-Aspartate Antagonists Ketamine is an NMDA antagonist that can be used as an adjunct to other analgesia methods to help prevent central sensitization and hyperalgesia. It is usually used as a CRI after a loading dose IV but can also be effective in the short term when given as a single dose. The dosages used are subanesthetic, so sedation generally does not occur.

CHAPTER  12  Analgesia of the Critical Patient Amantadine is an antiviral agent that is also an NMDA antagonist. It has been beneficial in the treatment of chronic pain from osteoarthritis when used orally in conjunction with NSAIDs (Lascelles et al, 2008), but further research is required to see if it has a role in the treatment of acute pain.

Gabapentin Gabapentin is an anticonvulsant drug that is helpful in the treatment of chronic neuropathic pain. It modulates voltage-gated calcium channels. Gabapentin is frequently recommended as part of chronic pain management in veterinary patients despite very few studies of its use. Perioperative administration of gabapentin in dogs undergoing forelimb amputation produced no significant difference in pain scores compared with administration of a placebo (Wagner et al, 2010). Further research is warranted to see if gabapentin is helpful in the management of acute pain.

Routes of Administration Drugs used to control pain are delivered by a variety of parenteral routes (including IM, IV, and SC) or through oral administration. Some drugs are most effectively administered by an IV CRI in the critical care setting. Additionally anesthetics can be administered locally, by epidural delivery, and via transdermal delivery systems.

Constant Rate Infusions CRIs offer the best means of achieving analgesia in the critical patient because they provide a consistent level of pain control that can be increased or decreased (within defined limits of dose) to suit the needs of the patient. Fentanyl is probably the most commonly used drug administered by CRI. Side effects of fentanyl can include nausea, bradycardia, and dysphoria as well as respiratory depression (at higher doses). A loading dose is given followed by the CRI. Ketamine can be used as a CRI to help prevent central sensitization and wind-up. Lidocaine CRIs have been shown to provide analgesia, but the exact mechanism has yet to be elucidated. A lidocaine CRI should NOT be used in cats because systemic toxicity is very likely due to a reduced ability to metabolize lidocaine. Neither ketamine nor lidocaine CRIs should be the sole method of analgesia; rather, they should be used in combination with a CRI of an opioid such as fentanyl or morphine.

Local Anesthesia Local anesthetic drugs work by blocking sodium channels to prevent nerve conduction and are one of the best ways to provide analgesia and prevent wind-up. The most commonly used drugs are lidocaine, which has a rapid onset of action (within 5 minutes) and lasts for 1 to 2 hours, and bupivacaine, which has a longer onset of effect (20 to 30 minutes) but a much longer duration of action (4 to 6 hours). Local infiltration, nerve blocks, splash blocks, and other local anesthetic protocols only last as long as

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the duration of the drug chosen. Additionally, some knowledge and training are required to effectively administer nerve blocks (Lemke and Dawson, 2000). To achieve a longer effect, wound or soaker catheters can be used. These are fenestrated catheters placed into a surgical or wound site before closure or near a nerve(s) that innervate the affected area. These catheters allow for a continuous nerve block or local wound infiltration. Soaker catheters have been shown to be an effective, viable means of providing local analgesia in postoperative veterinary patients (Hansen, 2008). Care must be taken when using local anesthetics, especially through a wound catheter, not to exceed the recommended safe dose, particularly in cats, a species especially sensitive to the toxic effects of local anesthetic drugs (Table 12-1). Signs of toxicity typically begin as nausea, progressing to hyperexcitability, tremors, seizures, and then cardiovascular collapse. Vomiting may be observed, especially in dogs.

Epidural Analgesia Epidural administration of drugs is an excellent way to provide analgesia to the caudal half of the body, including the abdomen. Preservative-free morphine (morphine PF) is used most commonly; having low lipid solubility, this drug remains in the epidural space longer than other opioids, with effects lasting 12 to 24 hours (Valverde, 2008). Buprenorphine has also been used effectively in the epidural space. Local anesthetic drugs can also be used in epidural analgesia but may lead to motor paralysis. Bupivacaine is usually administered, instead of lidocaine, because of its longer duration of action (2 to 4 hours). Side effects of epidurals can include vomiting, urinary retention, pruritus, and delayed regrowth of fur at the clipped site. The failure rate for epidurals is 20% to 30%. Epidural catheters allow more long-term analgesia but require strict asepsis and can be technically difficult to place. Radiographic verification is recommended after placement of epidural catheters. Contraindications for use of an epidural include hypotension, sepsis, coagulopathy, and skin infection at the site. Further information on epidurals and epidural catheters can be found in the references (Valverde, 2008).

Transdermal Analgesia Fentanyl patches can be used to provide long-term analgesia, but both onset of action and duration of effect can vary considerably. Uptake depends on many factors, including dermal blood flow, presence of fur, obesity, hypothermia, hypovolemia, and proximity to an external heat source. Because of this variation in uptake, animals must be closely monitored for either underdosing or overdosing. It takes 12 to 24 hours after application of the patch for steady-state plasma fentanyl concentrations to be achieved. For this reason, the patch needs to be placed the night before the infliction of surgical pain or alternate drugs must be administered to provide systemic analgesia until the fentanyl patch takes effect. The patch lasts approximately 72 hours in the dog and up to 5 days in the cat. These patches must be appropriately applied to

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TABLE 12-1  Dosages of Analgesic Drugs Drug

Dog

Cat

Buprenorphine

0.01-0.03 mg/kg IV, IM q6-8h; 0.12 mg/kg OTM

0.01-0.02 mg/kg IV, IM, SC, OTM q6-8h

Buprenorphine SR

0.12-0.27 mg/kg SC

0.12 mg/kg SC

Butorphanol

0.2-0.4 mg/kg IV, IM q1-4h

Opioids

0.2-0.8 mg/kg IV or SC q2-6h

Fentanyl

3-5 µg/kg IV (lasts 5-20 min)

Fentanyl CRI

2-3 µg/kg LD IV, then 2-6 µg/kg/hr (6-30 µg/kg/hr intra-op)

Fentanyl-Transdermal

2-4 µg/kg/hr

Hydromorphone

0.22 mg/kg IV, IM, SC q4-6h

0.1-0.2 mg/kg IV, IM, SC q4-6h

Hydromorphone CRI

0.05-0.1 mg/kg/hr

0.01-0.05 mg/kg/hr

Methadone

0.1-0.5 mg/kg IV q4h; 0.2-1.0 mg/kg IM q4h

0.1-0.5 mg/kg IV q4-6h; 0.2-0.6 mg/kg IM q4-6hr

Morphine

0.5-1.0 mg/kg IM, SC q4-6h; epidural: 0.1 mg/kg PF

0.1 mg/kg IM; epidural: 0.1 mg/kg PF

Morphine CRI

0.15-0.5 mg/kg LD SLOWLY IV, then 0.1-0.2 mg/kg/hr

0.2 mg/kg LD slowly IV, then 0.05-0.1 mg/kg/hr

Naloxone

0.01-0.04 mg/kg IV, IM

Oxymorphone

0.03-0.1 mg/kg IV, IM, SC q4h

0.01-0.05 mg/kg IV q4h; 0.01-0.1 IM, SC q4h

Tramadol

3-10 mg/kg PO q8-12h

3-5 mg/kg PO q12h

Carprofen

4.4 mg/kg SC once; 4.4 mg/kg q24h or 2.2 mg/kg   PO q12-24h PRN

2-4 mg/kg IV or SC once only

Deracoxib

1-2 mg/kg PO q24h Post-op pain: 3-4 mg/kg PO q24h for up to 7 days

Firocoxib

5 mg/kg PO q24h Post-op pain: 5 mg/kg PO q24h for up to 3 days

Ketoprofen

1-2 mg/kg IV, IM, or SC once; 1 mg/kg PO q24h up to   5 days

2 mg/kg SC q24h for up to 3 days; 1 mg/kg PO q24h for up to 5 days

Meloxicam

0.1-0.2 mg/kg IV or SC once; 0.1 mg/kg PO q24h PRN

0.2-0.3 mg/kg SC once only; 0.2 mg/kg SC followed by 0.05 mg/kg PO q24h for up to 4 days; 0.1 mg/kg PO on day 1, then 0.05 mg/ kg PO q24h

NSAIDs

α2-Agonists Atipamezole

0.05-0.2 mg/kg IM

Dexmedetomidine

1-5 µg/kg IV; 1-20 µg/kg IM

Dexmedetomidine CRI

0.5-2.5 µg/kg/hr

1-5 µg/kg IV; 1-10 µg/kg IM

Other Drugs Amantadine

3-5 mg/kg PO q24h

Bupivacaine

Up to 2 mg/kg for nerve blocks; 0.5 mg/kg for epidurals

Up to 1 mg/kg for nerve blocks; 0.5 mg/kg for epidurals

Bupivacaine (wound catheters)

Up to 2 mg/kg q6h

Up to 1 mg/kg q6-8h

Gabapentin

5-40 mg/kg PO q12h

5-20 mg/kg PO q12h

Ketamine Ketamine CRI

Analgesia without sedation: 0.1-1 mg/kg IV or IM 0.5 mg/kg IV LD, then 2 µg/kg/min (10 µg/kg/min intra-op)

Lidocaine

Up to 4 mg/kg for nerve blocks

Up to 2 mg/kg for nerve blocks

Lidocaine CRI

1-2 mg/kg LD IV then 30-50 µg/kg/min

NOT IN CATS

Lidocaine: Transdermal (10 × 14–cm patch)

1.4-2.3 kg (body weight) = ⅙ to ¼ patch; 2.7-4.5 kg = ½ patch; 5-9.1 kg = 1 patch; 9.5-18 kg = 2 patches; 18.6-27.3 kg = 2.5 to 3 patches; 27.7-45.5 kg = 3 to 4 patches

IV, Intravenous; IM, intramuscular; LD, loading dose; OTM, oral transmucosal route; PF, preservative-free; PO, orally; PRN, as needed; SC, subcutaneous.

CHAPTER  13  Anesthesia for the Critical Care Patient prevent ingestion, which might be fatal (and if therapy is continued in the home setting, parents must be advised about potential toxicity to children should a patch be ingested). Lidocaine is also available in a 5% patch and has been shown to provide local analgesia when placed after surgery. The patches can be cut to shape and are usually placed on either side of the incision. No systemic toxic effects have been seen in the dog or cat, but local skin irritation can occur (Weil et al, 2007).

References and Suggested Reading Bergmann HM, Nolte IJ, Kramer S: Effects of preoperative administration of carprofen on renal function and hemostasis in dogs undergoing surgery for fracture repair, Am J Vet Res 66:1356-1363, 2005. Catbagan DL et al: Comparison of the efficacy and adverse effects of sustained-release buprenorphine hydrochloride following subcutaneous administration and buprenorphine hydrochloride following oral transmucosal administration in cats undergoing ovariohysterectomy, Am J Vet Res 72:461-466, 2011. Ko JC et al: Efficacy of oral transmucosal and intravenous administration of buprenorphine before surgery for postoperative analgesia in dogs undergoing ovariohysterectomy, J Am Vet Med Assoc 238:318-328, 2011.

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Gaynor JS, Muir WM: Handbook of veterinary pain management, ed 2, St Louis, 2009, Mosby Elsevier. Hansen B: Analgesia for the critically ill dog or cat: an update, Vet Clin North Am Small Anim Pract 38:1353-1363, 2008. Lamont LA: Adjunctive analgesic therapy in veterinary medicine, Vet Clin North Am Small Anim Pract 38:1187-1203, 2008. Lascelles BD et al: Amantadine in a multimodal analgesic regimen for alleviation of refractory osteoarthritis pain in dogs, J Vet Intern Med 22:53-59, 2008. Lemke KA, Dawson SD: Local and regional anesthesia, Vet Clin North Am Small Anim Pract 30:839-857, 2000. Quandt J, Lee JA: Analgesia and constant rate infusions. In Silverstein DC, Hopper K, editors: Small animal critical care medicine, St Louis, 2009, Saunders Elsevier, pp 710-716. Robertson SA et al: PK-PD modeling of buprenorphine in cats: intravenous and oral transmucosal administration, J Vet Pharmacol Ther 28:453-460, 2005. Valverde A: Epidural analgesia and anesthesia in dogs and cats, Vet Clin North Am Small Anim Pract 38:1205-1230, 2008. Wagner AE et al: Clinical evaluation of perioperative administration of gabapentin as an adjunct for postoperative analgesia in dogs undergoing amputation of a forelimb, J Am Vet Med Assoc 236:751-756, 2010. Weil A, Ko J, Inoue T: The use of lidocaine patches, Compend Contin Educ Vet 29:208-210, 2007.

13 

Anesthesia for the Critical Care Patient DEREK FLAHERTY, Glasgow, Scotland

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ritically ill animals may require chemical restraint for a variety of procedures, ranging from minor interventions such as diagnostic imaging to major surgery. Although a clinician may be tempted to avoid anesthesia due to its inherent risks and instead perform complete procedures under sedation alone, deep sedation is likely to be a greater risk to the animal than “full” general anesthesia. Patients under deep sedation may be unable to maintain and protect their airway, may be breathing room air, and are rarely closely monitored during sedation. However, with general anesthesia the animal usually has an endotracheal tube in place, is receiving supplemental oxygen, and usually has one person dedicated to monitoring and maintaining physiologic function. This is not to say that sedative techniques should be avoided in critically ill animals, merely

that they should only be used in situations in which the procedure can be performed under “light” sedation (often combined with local anesthesia) using drugs that are minimally depressant to the cardiovascular (CV) and respiratory systems. If these caveats cannot be met, general anesthesia is usually preferable. In all critical care patients undergoing any form of chemical restraint, secure intravenous access always should be available, and oxygen should be supplemented at every opportunity. It is impossible to be prescriptive in terms of the anesthetic requirements of every critically ill animal, but, in general, this type of patient usually presents primarily with underlying dysfunction of the cardiovascular system, the respiratory system, or the central nervous system, although there is often multiorgan pathology.

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Anesthesia for Patients with Cardiovascular Dysfunction CV dysfunction may be related to volume depletion, vascular dysfunction, heart rhythm disturbances, advanced heart disease, or overt congestive heart failure. Appropriately categorizing CV risk and dysfunction is an important aspect of sedation and anesthesia of these patients. Special consideration should be directed to the preanesthetic period, induction of anesthesia, and maintenance.

Specific Patient Groups The main forms of CV dysfunction encountered in critical care patients relate to hypovolemia or to cardiac arrhythmias. Additionally, some older dogs are affected by advanced valvular heart disease or chronic heart failure. In cats cardiomyopathies (sometime occult) are relatively common. Hypovolemic Patients Hypovolemia may be present as a result of dehydration (e.g., protracted vomiting with intestinal obstruction) or blood loss. Virtually all sedative and anesthetic agents cause a degree of CV depression, so the use of these drugs in patients with depleted circulatory volume can result in a severe drop in arterial blood pressure (BP). Consequently, restoration of the circulating blood volume should be undertaken prior to any form of chemical restraint, although there may be an argument for “delayed resuscitation” in those animals with internal hemorrhage (see Chapter 1). Even following adequate volume resuscitation in hypovolemic patients, it is wise to provide chemical re­­ straint by choosing agents with the least CV-depressant effects and using the lowest doses possible, usually through coinduction and balanced anesthetic techniques (see sections on “Induction of Anesthesia” and “Maintenance of Anesthesia”). Patients with Cardiac Arrhythmias Cardiac arrhythmias are common in critical care patients. Although these may result from underlying cardiac disease, a number of extracardiac factors also may be responsible (e.g., hypoxemia, hypercapnia, electrolyte disorders). Regardless of etiology, the aim should be to restore normal cardiac rhythm before induction of anesthesia through treatment of underlying pathology, correction of exacerbating factors (e.g., hypokalemia), and judicious use (when necessary) of appropriate antiarrhythmic drugs (see Chapters 171 and 172). However, even with these measures, restoration of normal sinus rhythm may not always be possible, and consideration needs to be given to selection of an anesthetic technique that will not further exacerbate the arrhythmia. The main aims in critically ill patients with preexisting cardiac arrhythmias are to avoid agents that are proarrhythmic (e.g., α2-adrenergic agonists, thiopental, halothane) and use balanced anesthetic techniques to minimize the dose of any one agent. Hypoxemia, hypercapnia, and hypotension should be avoided in these animals because they may significantly exacerbate any

preexisting arrhythmia. Thus consideration should be paid to preoxygenation prior to induction of anesthesia, oxygen supplementation during the procedure (even if the procedure is performed solely under sedation), and possibly the use of intermittent positive pressure ventilation to avoid excessive hypercapnia, accepting that controlled ventilation may carry detrimental CV side effects (see the section on “Intermittent Positive Pressure Ventilation” later). Drugs that may be required to manage acute exacerbations of the arrhythmia (such as lidocaine) or extremes of heart rate (atropine or glycopyrrolate; esmolol or propranolol) should be readily available. Not only should these drugs be close at hand, but the appropriate volume to be administered calculated in advance. The electrocardiogram should be monitored before, during, and after the anesthetic periods.

Premedication/Sedation of Patients with CV Dysfunction A significant proportion of critical care cases with CV dysfunction may not require sedative premedication, particularly those that are severely hypovolemic. In general, patients with any degree of hypovolemia should not be given acepromazine because it causes vasodilation and will drop BP. The α2-adrenergic agonists (xylazine, medetomidine, dexmedetomidine) also should be avoided because they profoundly decrease cardiac output by affecting afterload and heart rate. In contrast, both opioids and benzodiazepines are relatively cardiostable and are extremely useful when dealing with high-risk CV cases. Although paradoxical excitement can occur when benzodiazepines alone are administered to healthy animals, this is much less likely when used in depressed, critically ill patients. Combining these drugs with an opioid also improves the degree of sedation and limits the likelihood of excitation. The two benzodiazepines commonly used in small animals are diazepam and midazolam. Diazepam is best administered intravenously because it is poorly absorbed and relatively painful when given intramuscularly; midazolam is preferable if the intramuscular route is to be used. Although the latter is significantly more expensive than diazepam, it can be mixed in the same syringe with opioid drugs; this cannot be done with diazepam because precipitation may occur. A variety of opioids (see Chapter 12) may be used in combination with the benzodiazepines, and the choice depends to a large extent on the procedure that the animal is undergoing. If there is preexisting moderate to severe pain, or if such pain is anticipated following the procedure, a full mu-agonist such as oxymorphone, hydromorphone, morphine, or methadone would be most appropriate because these can be titrated to the degree of pain. Partial agonists such as butorphanol or buprenorphine may be suitable alternatives but are less efficacious analgesics and should be limited to mild to moderate pain only. The full opioid agonists can also be antagonized (most commonly by naloxone) if the situation suddenly deteriorates, although this is uncommon if excessive doses are avoided. Table 13-1 lists suggested doses for each agent.

CHAPTER  13  Anesthesia for the Critical Care Patient

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TABLE 13-1  Opioids Commonly Used for Sedation/Premedication of Critically Ill Animals with CV Disease Suggested Dose and Administration Route

Approximate Duration

Morphine

0.1-1.0 mg/kg, SC, IM, or IV

4-6 hr (dog) 6-8 hr (cat)

Morphine may cause emesis and should be avoided when this is contraindicated (e.g., esophageal foreign body; raised intracranial pressure; penetrating eye injury). Morphine may cause histamine release, particularly when given IV; thus, if the IV route is used, the drug should be diluted and administered slowly over approximately 10 min. Doses at the lower end of the scale should be used in cats to avoid excitation.

Meperidine (pethidine)

3.5-5 mg/kg IM (dog) 5-10 mg/kg SC or IM (cat)

1-1.5 hr

Meperidine is contraindicated by the IV route because it may cause massive histamine release/cardiac arrest. Does not tend to achieve therapeutic analgesic levels in dogs when given SC, but may do so in cats if given at higher doses.

Methadone

0.1-1.0 mg/kg SC, IM, or IV

4-6 hr

Much less likely to cause vomiting than morphine. Antagonist at the NMDA receptor so may help block/reverse central sensitization.

Hydromorphone

0.05-0.1 mg/kg SC, IM, or IV

~4 hr

May cause vomiting, so contraindicated in similar situations to morphine (see above). May cause hyperthermia in cats.

Buprenorphine

0.01-0.02 mg/kg SC, IM, or IV

~6 hr

Partial opioid agonist. Duration of analgesia variable, with some studies suggesting up to 12 hr.

Butorphanol

0.2-0.8 mg/kg SC, IM, or IV

? 1-1.5 hr

Partial opioid agonist/agonist-antagonist. Analgesic efficacy extremely variable. Duration of action probably shorter than generally accepted.

Drug

Comments

IM, Intramuscularly; IV, intravenously; NMDA, n-Methyl-D-Aspartic Acid; SC, subcutaneously.

There is huge variability between individual patients in terms of dose requirements and analgesic response, and the doses/durations in Table 13-1 are intended only as a general guide.

Induction of Anesthesia Most of the commonly used induction agents (thiopental, propofol, alfaxalone) can cause hypotension even in healthy patients, and in critical animals this can be profound. For this reason, these agents are not recommended by themselves for anesthetic induction in patients with limited CV reserve. Although combinations of ketamine/ diazepam are considered relatively “cardiac-safe” in healthy animals (in that cardiac output and arterial BP are usually well maintained), the high preexisting (often maximal) sympathetic tone evident in most critically ill patients means that the animal may not be able to compensate for the direct negative inotropic effects of ketamine in the same manner as healthy animals; as a result, BP may fall to a similar extent to that of the previously discussed induction agents. Etomidate is a nonbarbiturate sedative-hypnotic drug often used as an intravenous induction drug in human patients with CV disease because it has minimal effects on cardiac output and arterial BP. Although not licensed for veterinary use, it has been extensively used in dogs and cats with significant preexisting arrhythmias, cardiac pathology, or ongoing hypovolemia. This drug must be

used with attention to potential adverse effects. Due to the high osmolarity of the solution, etomidate can cause pain on injection and thrombophlebitis. As a result, it is probably best administered into a free-flowing intravenous fluid line so it is suitably diluted before it enters the patient’s vein; this is probably more important in cats due to the small vein size. Etomidate can also cause myoclonus (twitching) at induction, as well as excitement and muscle movements during anesthetic recovery; this is much more common if the drug has not been preceded by a benzodiazepine or a potent opioid such as fentanyl. Additionally, etomidate causes suppression of cortisol production, so should only be administered as a single intravenous induction dose or acute hypoadrenocorticism may be observed. Some anesthesiologists recommend administering physiologic doses of glucocorticoids on the day that a patient receives etomidate. With all the aforementioned anesthetic induction agents, it is essential to minimize the dose used when administered to patients with unstable CV status. This can be achieved using a coinduction technique, which implies the use of one or more additional drugs alongside the main hypnotic agent. The coinduction drug(s) used should be capable of reducing the dose of hypnotic required to produce unconsciousness, while at the same time having minimal CV-depressant effects of their own. The most common coinduction agents used are the potent, short-acting opioids, such as fentanyl and alfentanil, and the benzodiazepines, diazepam and midazolam.

66

SECTION  I  Critical Care

For coinduction, one of these opioids or benzodiazepines (or a combination) is administered intravenously immediately before the chosen hypnotic agent, resulting in a reduced dose requirement for the latter and reduced CV depression. As an alternative, and particularly for those animals with severe CV compromise in which even a small dose of hypnotic drug may not be tolerated, a combination benzodiazepine/opioid induction protocol can be very useful. Because both groups of drugs are relatively cardiostable, they can be given in fairly high doses to achieve induction of anesthesia. The most common technique utilizes a combination of fentanyl and diazepam: a dose of 10 µg/kg fentanyl and a dose of 0.5 mg/kg diazepam are drawn up into separate syringes. After a 3- to 5-minute period of preoxygenation by facemask, half the fentanyl (5 µg/kg) is administered intravenously, followed by half of the diazepam (0.25 mg/kg). Adequate time must be allowed for the drugs to reach peak effect, since this technique results in slower induction than traditional intravenous induction techniques. In addition, the appearance of animals following benzodiazepine/opioid induction is different to that following “classical” anesthetic induction; these patients may occasionally remain in sternal recumbency and often appear quite awake, with centrally positioned glazed eyes. However, even in this state many still tolerate intubation of the trachea. If anesthesia is inadequate for endotracheal intubation, further increments of the two drugs are delivered until unconsciousness is achieved. On occasion, particularly if the animal was not significantly depressed prior to induction of anesthesia, inadequate hypnosis may not be achieved after the full doses of diazepam and fentanyl have been administered; unconsciousness can then be produced with an intravenous hypnotic such as propofol or alfaxalone, but only very small doses of these agents are required due to the anesthetic sparing effects of both fentanyl and diazepam. High doses of fentanyl can result in bradycardia; this can usually be avoided if the drug is given very slowly over several minutes, but it is wise to have an antimuscarinic (atropine or glycopyrrolate) drawn up and ready to administer, if necessary. Alternatively, some authorities recommend pretreatment with an antimuscarinic if a benzodiazepine/opioid induction technique is to be used, although this may in itself lead to some CV instability due to the likely transient tachycardia.

Maintenance of Anesthesia All the volatile anesthetic agents cause CV depression, either by direct effects on myocardial contractility (halothane) or by vasodilation (isoflurane, sevoflurane), and these effects are dose-dependent, so it is important to use as low a vaporizer setting as possible. Nitrous oxide, on the other hand, has minimal effects on CV function and allows a reduction in the concentration of volatile agent required to maintain anesthesia. Consequently, inclusion of nitrous oxide (if available) generally allows better preservation of cardiac output and arterial BP. Similarly, potent short-acting opioids given by intermittent intravenous bolus injection (fentanyl) or by constant rate infusion (fentanyl, alfentanil, remifentanil) are also

extremely useful in reducing the requirement for volatile anesthetics and promoting a relatively stable CV status during anesthesia; this is commonly referred to as a balanced anesthetic technique (although, more correctly, this term only applies if neuromuscular blocking drugs are also used). While exerting minimal direct effects on contractility and arterial BP, these short-acting opioids can reduce cardiac output by causing profound bradycardia and less frequently ventricular asystole. These adverse effects are more common when opioids are given by intravenous bolus injection, and especially if high doses are used. These complications, although seemingly more common with alfentanil and remifentanil, can occur with all three drugs and can be avoided in several ways: • Avoid giving intravenous boluses, and only use constant rate infusions (CRIs), bearing in mind that it takes time for a CRI to achieve stable therapeutic blood levels if not preceded by a bolus dose. • Preadminister atropine or glycopyrrolate immediately before these drugs (more important prior to alfentanil or remifentanil boluses than fentanyl, and probably unnecessary if only using them by CRI). • Most importantly, when using IV bolus techniques, slowly titrate the dose to the pulse rate during several minutes of administration. The downside to the relative cardiostability of the shortacting opioids relates to marked respiratory depression, so intermittent positive pressure ventilation is likely to be required (see the section on “Intermittent Positive Pressure Ventilation” later). Appropriate doses for the shortacting opioids during maintenance of anesthesia are given in Table 13-2. When these agents are not available, longer-acting agents, such as oxymorphone, morphine, or methadone, should be considered. Regional local anesthesia (e.g., epidural analgesia) should also be considered to minimize the requirement for anesthetic maintenance agents, as well as to maximize postoperative pain relief. These techniques are well described in the literature (see References and Suggested Reading) and generally require some training before they are mastered. Neuromuscular blocking drugs (“muscle relaxants”) may also be used in critically ill patients to minimize anesthetic requirements. Because these drugs have neither hypnotic nor analgesic activities, care should be paid at all times to maintenance of unconsciousness. These agents should not be used by those unfamiliar with them. Finally when dealing with patients with compromised CV systems, attention should be paid to support of oxygenation, since these patients are likely to suffer severe detrimental effects from even short periods of hypoxemia. This principle is applicable from preinduction through recovery because respiratory depressant effects of the anesthetic agents are likely to persist even after completion of the procedure.

Intermittent Positive Pressure Ventilation As described earlier, critically ill animals often receive potent short-acting opioid drugs as part of their

CHAPTER  13  Anesthesia for the Critical Care Patient

67

TABLE 13-2  Doses of Short-Acting Opioids Used During Maintenance of Anesthesia* Drug

IV Bolus Dose

IV CRI Dose

Potential Side Effects

Fentanyl

2-5 µg/kg (lasts ~ 20 min after single bolus dose)

0.1-0.7 µg/kg/min (dog) 0.1-0.5 µg/kg/min (cat)

Respiratory depression/apnea. Bradycardia.

Alfentanil

5-10 µg/kg (only lasts ~5 min after single bolus dose, so not commonly used in this manner during maintenance of anesthesia)

1-2 µg/kg/min

Respiratory depression/apnea. Bradycardia. Potential asystole if bolus dose not preceded by atropine or glycopyrrolate.

Remifentanil

Not recommended as a bolus

0.1-0.5 µg/kg/min

Respiratory depression/apnea. Bradycardia. Potential asystole if bolus dose not preceded by atropine or glycopyrrolate.

*Note: none of these are licensed for animal use.

anesthesia. This may result in significant respiratory depression with the consequent need for controlled ventilation (intermittent positive pressure ventilation [IPPV]), especially when higher opioid doses are used. IPPV also may be required during general anesthesia for other reasons such as preexisting respiratory impairment or during thoracotomy. In addition, the commonest acidbase disturbance encountered in ill animals is metabolic acidosis; the body’s normal response to this is a respiratory compensation with increased ventilation to lower carbon dioxide levels. However, because virtually all anesthetic agents depress ventilation, respiratory compensation may be inadequate or so depressed that a combined metabolic and respiratory acidosis develops. In these cases pH declines dramatically and severe acidemia may develop. Thus it may be prudent to consider IPPV when anesthetizing animals with preexisting metabolic acidosis and to hyperventilate them to maintain carbon dioxide at lower-than-normal levels to compensate for the metabolic acidosis. Among its adverse effects, IPPV tends to impair venous return, which reduces cardiac output and arterial BP. Many patients with moderate-to-severe metabolic acidosis are already hypotensive; thus institution of IPPV may actually worsen the degree of CV compromise. This creates a dilemma: allowing spontaneous ventilation in animals with metabolic acidosis may cause a further drop in pH with potential for worsening CV function, whereas institution of IPPV may help normalize pH but also depresses CV function. There is no “right answer” in this situation and judgment is required. If IPPV is used in any high-risk patient, inflation pressures should be kept as low as possible to minimize the depression of CV function.

Sodium Bicarbonate Intravenous sodium bicarbonate may be indicated in patients with moderate-to-severe metabolic acidosis. However, its use is somewhat controversial because administration is not without potential side effects. Although metabolic acidosis itself may undoubtedly lead to detrimental metabolic and negative inotropic

consequences, the adverse effects of sodium bicarbonate therapy may outweigh the benefits. Sodium bicarbonate combines with hydrogen ions in the body to produce carbonic acid, which rapidly dissociates into water and carbon dioxide. If ventilatory function is impaired, carbon dioxide can accumulate, leading to respiratory acidosis. Thus sodium bicarbonate therapy should only be considered when there is already adequate respiratory compensation. If carbon dioxide is higher than expected, the animal is unlikely to be able to eliminate the additional carbon dioxide produced by the administration of sodium bicarbonate. Even in animals with normal ventilation, the production of carbon dioxide following sodium bicarbonate administration can lead to a paradoxical cerebrospinal fluid (CSF) acidosis, since sodium bicarbonate cannot cross the blood-brain barrier (due to its ionization) but carbon dioxide can readily diffuse across. Animals receiving IPPV during sodium bicarbonate administration may require an increase in tidal volume or respiratory rate to eliminate the additional carbon dioxide being generated. Other possible side effects of sodium bicarbonate administration include an overshoot metabolic alkalosis, hypernatremia, hypokalemia, and hypocalcemia, as well as a leftward shift of the oxyhemoglobin dissociation curve, which limits oxygen delivery to tissues. Although alternative alkalinizing solutions are available (e.g., tromethamine [THAM]), they are less commonly used than sodium bicarbonate. Due to the potential adverse effects described previously, there are no generally accepted guidelines for sodium bicarbonate administration. The cause of the acidosis should be established first, the most common in the majority of veterinary patients being lactic acidosis associated with hypovolemia. Thus attempts at restoration of circulating volume should be undertaken as a first-line measure. Although this may not completely eliminate the acidosis, it is often sufficient to correct it to a milder level (pH >7.2) in which sodium bicarbonate may not be required. When it is determined that ventilation is adequate and metabolic acidosis severe, sodium bicarbonate is probably indicated. Dosage is based on blood-gas analysis and calculated as:

68

SECTION  I  Critical Care 0.3 × body weight ( kg ) × base deficit ( mmol/L ) = mmol of HCO3− requiired.

Sodium bicarbonate is available in a variety of concentrations, but the 8.4% solution is most convenient since 1 ml of this concentration contains 1 mmol (mEq) of HCO3−. Initially, approximately one half of the total volume calculated is infused over 20 to 30 minutes, and a repeat blood-gas analysis is then performed to avoid overcorrection. The aim of sodium bicarbonate therapy is not necessarily to restore the pH to within the normal range but to increase it to a level where it is less likely to be detrimental to the patient.

ICP

1

Anesthesia for Patients with Respiratory Dysfunction Critical care animals with respiratory impairment can be broadly subdivided into those suffering from pleural space disorders (e.g., pneumothorax), those with parenchymal disease such as pneumonia, and those with major airway obstruction. The most important point when dealing with these patients is to attempt to improve or stabilize respiratory function as much as possible prior to general anesthesia. In some cases, such as an obstructed airway due to laryngeal paralysis, anesthesia is required to correct the problem and allow intubation. In most cases of pneumothorax or pleural effusion thoracocentesis should be done first. Optimally this would proceed with oxygen supplementation and local anesthesia; however, some patients require sedation or anesthesia. Unless thoracocentesis can be performed under mild sedation and a local anesthetic block, it may be safer to administer general anesthesia because moderate-marked sedation may worsen respiratory function without the clinician having any control over ventilation. In terms of anesthesia, the general rule with the majority of respiratory disorders is to go from minimal interference to maximal support. This implies that in most cases premedication should either be withheld altogether or should be light. Thus drug choice is not particularly critical, but doses should be kept low. It is usually best to avoid potentially emetic drugs (e.g., xylazine, morphine, hydromorphone) in animals with respiratory compromise. Likewise, choice of induction agent is probably not important, but it should be given as a rapid bolus rather than titrated to effect, to achieve endotracheal intubation as quickly as possible. From this point, ventilation can be supported if necessary by IPPV. One additional point: preoxygenate all critically ill animals with respiratory impairment for 3 to 5 minutes prior to administration of the induction agent. A number of agents are suitable for anesthetic maintenance in these animals, although those providing a more rapid recovery (e.g., sevoflurane) may offer benefits. The tendency of nitrous oxide to expand gas-filled spaces would contraindicate its use during anesthetic maintenance in animals with closed pneumothorax; it should also be used with caution in other forms of respiratory disease unless adequacy of oxygenation can be confirmed by pulse oximetry or arterial blood-gas analysis. Regardless of the maintenance agent used, anesthetic-induced respiratory depression may persist for

3

2

ICV

Figure 13-1  Intracranial elastance curve.

some time in recovery, so supplemental oxygen should be provided during this period.

Anesthesia for Patients with Intracranial Pathology Administration of anesthesia for patients with intracranial pathology is not for the faint-hearted. A thorough understanding of the physiology underlying cerebral blood flow (CBF) and intracranial pressure (ICP) and the influence of sedative and anesthetic agents on these parameters is a prerequisite for successful anesthetic outcome. A few basic principles can be enumerated. The cranial vault is a rigid structure containing brain tissue, blood, and CSF. An increase in the volume of any one of these three components necessitates a reduction in volume of one of the others or an increase in ICP will ensue. As intracranial volume (ICV) increases, rises in ICP are initially prevented in normal patients by a process of isobaric spatial compensation. This entails initial redistribution of CSF from the cranial vault to the spinal compartment; once this reserve is exhausted, venous blood is redistributed away from the cranial vault. When these two mechanisms have been expended, however, continuing increases in ICV will result in ICP increasing sharply (Figure 13-1). If the animal is sitting at point 1 on the intracranial elastance curve (see Figure 13-1) and there is an increase in ICV for some reason (for instance, an increase in blood flow to the brain), there is likely to be movement of the graph to the right toward point 2. However, the compensatory effects previously described prevent an increase in ICP. If, on the other hand, the animal starts at point 2 on the graph, any small increase in ICV can lead to a dramatic increase in ICP. Unfortunately, it is not possible to determine at what point on the curve a patient lies, and one should therefore assume that any small increase in ICV will increase ICP. Precautions are taken to prevent this (see later). Cerebral function depends on adequate cerebral perfusion pressure (CPP), which is defined as the difference

CHAPTER  13  Anesthesia for the Critical Care Patient

69

CBF

PaCO2 MAP

PaO2

50 mm Hg

150 mm Hg

Figure 13-2  Effect of mean arterial blood pressure (MAP), PaO2, and PaCO2 on cerebral blood flow (CBF).

between mean arterial pressure (MAP) and ICP or central venous pressure (CVP), whichever is greater: CPP = MAP − ICP If ICP increases for any reason, cerebral perfusion can be maintained only if MAP rises. Marked elevations in MAP may occur in some patients, and these can trigger a baroreceptor response, resulting in a subsequent bradycardia. This is the so-called Cushing’s response, and should be suspected in any head trauma patient with bradycardia. When a Cushing’s response is suspected, arterial BP should be measured and there should be an attempt to lower ICP, usually by administering mannitol (0.25 to 1 g/kg intravenously over 20 minutes). Use of antimuscarinics to treat the bradycardia in these animals is contraindicated because this may lead to marked hypertension, which may in turn result in brain herniation. The brain normally compensates for variations in arterial BP through autoregulation; thus CBF is usually maintained at a constant level between MAPs of approximately 50 to 150  mm  Hg. Hypotension and hypertension lead to a decrease or increase in CBF, respectively (Figure 13-2). Alterations in PaCO2 have profound effects on CBF, with a directly proportionate relationship between PaCO2 levels of 20 to 80 mm Hg (see Figure 13-2). Thus, as CO2 levels increase, CBF also increases, and this may lead to elevations in ICP if compensatory mechanisms are already maximal (see Figure 13-1). This has important implications for control of ventilation during anesthesia in animals with intracranial disease. Within the normal physiologic range, changes in PaO2 have minimal effects on CBF (see Figure 13-2). However, hypoxemia (PaO2 < 60 mm Hg) dramatically increases CBF. General anesthesia can increase CBF and ICP through a variety of mechanisms. A number of the drugs commonly used for premedication, induction, and

main­tenance of anesthesia have effects on the cerebral vasculature. Sedative premedication may not be required in cases with intracranial pathology because consciousness may already be depressed. However, if required, opioids may provide mild sedation without significant effects on ICP. Morphine and hydromorphone should be avoided, however, due to the potential for vomiting, which can lead to an acute, dramatic elevation of ICP. In addition, acepromazine should also be avoided as it induces vasodilation, which increases CBF. If additional sedation is required after opioid administration, low doses (1 to 2 µg/kg) of medetomidine or dexmedetomidine appear to have minimal effects on ICP in experimental studies. Most induction agents are compatible with cranial pathology, with the exception of ketamine, which increases cerebral metabolic rate and CBF. To this author’s knowledge, no studies have assessed the effects on alfaxalone on CBF or ICP. Patients should be preoxygenated for 3 to 5 minutes by facemask prior to induction of anesthesia to avoid potential hypoxemia, with consequent increase in CBF. Similarly, endotracheal intubation induces a hypertensive response that can be avoided by ensuring that anesthesia is not excessively light prior to intubation and by administering either a short-acting potent opioid (fentanyl, alfentanil) or a bolus of lidocaine (dogs only), intravenously, just before attempted intubation. Both isoflurane and sevoflurane are suitable for maintenance of anesthesia in these patients, provided excessive depth is avoided, with several human studies suggesting that sevoflurane may result in improved outcome. Propofol CRI appears to be a suitable alternative maintenance technique in dogs. Since all anesthetics depress ventilation, the resultant increase in PaCO2 can lead to vasodilation, which in­­ creases CBF (see Figure 13-2), and potentially ICP. For this reason, IPPV should be undertaken, with the aim

70

SECTION  I  Critical Care

of maintaining PaCO2 at approximately 35 to 40 mm Hg in dogs and 30 to 35 mm Hg in cats. Finally, care should be taken with maintenance fluid provision in patients with intracranial pathology. Lactated Ringer’s solution (Hartmann’s solution) is slightly hypotonic and may promote cerebral edema; 0.9% saline is generally a better choice. Excessive administration rates also should be avoided.

References and Suggested Reading Kushner LI: Guidelines for anesthesia in critically ill feline patients. In Drobatz KJ, Costello MF, editors: Feline emergency

CHAPTER 

and critical care medicine, Iowa, 2010, Wiley-Blackwell, pp 39-52. Kushner LI: Pain management in critically ill feline patients guidelines. In Drobatz KJ, Costello MF, editors: Feline emergency and critical care medicine, Iowa, 2010, Wiley-Blackwell, pp 63-76. Leece E: Neurological disease. In Seymour C, Duke-Novakovski T, editors. BSAVA manual of canine and feline anaesthesia and analgesia, ed 2, Gloucester, 2007, British Small Animal Veterinary Association, pp 284-295. Lemke KA: Pain management II: local and regional anaesthetic techniques. In Seymour C, Duke-Novakovski T, editors: BSAVA manual of canine and feline anaesthesia and analgesia. ed 2, Gloucester, 2007, British Small Animal Veterinary Association, pp 104-114.

14 

Hyperthermia and HeatInduced Illness ELISA M. MAZZAFERRO, Stamford, Connecticut

H

yperthermia, defined as a severe elevation body temperature from 40.5° to 43° C (104.9° to 109.4° F), can occur with exposure to elevated ambient temperatures and high ambient humidity, after strenuous activity, or as a normal physiologic process in response to endogenous or exogenous pyrogens. A fever differs from hyperthermia in that with a fever, or pyrogenic hyperthermia, the thermoregulatory center set point in the hypothalamus is elevated in response to infection and inflammation. Nonpyrogenic hyperthermia is abnormal and is secondary to an inability to dissipate heat. Animals that exercise or are allowed to work or exert themselves under conditions of high environmental temperatures can develop hyperthermia in as little as 30 minutes unless adequate access to shade, water, and rest period is available.

Pathophysiology Core body temperature is controlled by a thermoregulatory center that is located in the hypothalamus. Heat balance occurs through the actions of heat-gaining and heat-dissipating mechanisms. Heat gain occurs through oxidative metabolic processes after eating, exercise or increased metabolic activity, and elevated environmental temperature. Heat-dissipating mechanisms mitigate heat gain and include changes in behavior such as

seeking a cooler location, peripheral vasodilation, and evaporative cooling in the form of respiratory heat exchange, radiation, and convection. When environmental temperature increases and approaches body temperature, evaporative heat loss becomes important to maintain normothermia. Domestic animals such as dogs and cats that largely lack sweat glands depend primarily on the dissipation of heat in the form of evaporative cooling from the respiratory system during panting. Panting is an adaptive mechanism to help dissipate heat and prevent hyperthermia. As body temperature increases, the thermoregulatory center in the hypothalamus is activated, senses a change in temperature, and sends a relay of signals to the panting center. The animal responds by panting, increasing both dead space ventilation and evaporative cooling mechanisms in an attempt to dissipate heat. Evaporative cooling occurs as air comes in contact with the mucous membranes of the upper airways. Evaporative cooling mechanisms are not efficient if high ambient humidity is present, and the body’s core temperature continues to rise. Early, an increase in dead space ventilation occurs, with little effect on carbon dioxide elimination. As hyperthermia progresses, however, metabolic alkalosis can occur. With prolonged hyperthermia, the body’s normal adaptive mechanisms no longer compensate, and cerebrospinal fluid hypocapnia and alkalosis, factors that normally

CHAPTER  14  Hyperthermia and Heat-Induced Illness decrease panting, are no longer effective, and panting continues. Convection is a second method of cooling by which heat is passively transferred from an overheated animal to a cooler surface. Peripheral vasodilation increases blood flow to the skin and periphery and helps to dissipate heat by convective mechanisms. Peripheral vasodilation causes a state of relative hypovolemia, and in order to maintain adequate blood pressure, splanchnic vessels constrict to maintain adequate circulating volume. Catecholamines are released, causing an increase in heart rate and cardiac output. Early in hyperthermia, there is an increase in cardiac output and decrease in peripheral vascular resistance. However, as hyperthermia progresses, blood pressure and cardiac output decrease when the body can no longer compensate. Perfusion to vital organs decreases and can result in widespread organ damage if left untreated. Widespread thermal injury occurs to neuronal tissue, cardiac myocytes, hepatocytes, renal parenchymal and tubular cells, and the gastrointestinal tract. The combined effects of decreased organ perfusion, enzyme dysfunction, and uncoupling of oxidative phosphorylation are a decrease in aerobic glycolysis and an increase in tissue oxygen debt, both of which contribute to increased lactate production and lactic acidosis. Lactic acidosis can occur within 3 to 4 hours of initial heat-induced injury. Direct thermal injury to renal tubular and parenchymal cells, decreased renal blood flow, and hypotension cause hypoxic damage to the tubular epithelium and cell death. As hyperthermia progresses, renal vessel thrombosis can occur with disseminated intravascular coagulation (DIC). Consistent findings in patients affected with severe hyperthermia are renal tubular casts and glycosuria on urinalysis in the presence of normoglycemia. Rhabdomyolysis can also be associated with severe myoglobinuria and pigment-associated damage to the renal tubular epithelium. The gastrointestinal tract is a key factor in multiorgan failure associated with hyperthermia. Decreased mesenteric and gastrointestinal perfusion and thermal injury to enterocytes often result in a disruption of the gastrointestinal mucosal barrier, with subsequent bacterial translocation. Bacteremia and elevation of circulating bacterial endotoxin can lead to sepsis, systemic inflammatory response syndrome (SIRS), and multiorgan failure. Patients with severe hyperthermia can present with hematemesis and severe hematochezia, and often slough the lining of their gastrointestinal tract. Thermal damage to the liver can result in decreased hepatic function, with elevations of hepatocellular enzyme activities and increased alanine transaminase (ALT), aspartate transaminase (AST), and total bilirubin. Necropsy findings in one retrospective study of 42 dogs with hyperthermia found centrilobular necrosis, widespread tissue congestion, hemorrhagic diathesis, and pulmonary infarction. Persistent hypoglycemia in affected patients may be associated with hepatocellular dysfunction and glycogen depletion. Decreased hepatic macrophage function and portal hypotension can also predispose the patient to sepsis, with associated bacteremia and SIRS.

71

Virchow’s triad (vascular endothelial injury, venous stasis, and a hypercoagulable state) develops during hyperthermia and heat-induced illness. Widespread endothelial damage with exposure of subendothelial collagen and tissue factor cause systemic platelet activation, consumption of clotting factors, and activation of the fibrinolytic pathway. Sluggish blood flow during periods of hypotension, decreased production of clotting factors, and loss of natural anticoagulants such as antithrombin from the gastrointestinal tract combine to predispose the patient to DIC. Massive global thrombosis associated with DIC can result in multiorgan dysfunction syndrome (MODS) and death. Finally, hyperthermia can cause direct damage to neurons, neuronal death, and cerebral edema. Thrombosis or intracranial hemorrhage can also occur with DIC. Damage to the hypothalamic thermoregulatory center, localized intraparenchymal bleeding, infarction, and cellular necrosis can all lead to seizures. Altered levels of consciousness are among the most common clinical signs of heat-induced illness. As hyperthermia progresses, severe central nervous system depression, seizures, coma, and death may occur. The potential for reversal of cerebral edema is related to the duration of the neurons to heat exposure. Severe abnormalities in mentation are associated with a negative outcome in animals with hyperthermia. In one retrospective study of dogs, the only presenting clinical sign that was negatively associated with outcome was if the animal was comatose on presentation. A less favorable outcome was also associated with the development of stupor, coma, or seizures within 45 minutes of presentation.

Risk Factors A number of factors can increase the risk of heat stroke, including high ambient humidity, upper airway obstruction, laryngeal paralysis, brachiocephalic airway syndrome, collapsing trachea, obesity, and a previous history of hyperthermia or heat-induced illness. A lack of shade and no allowance for a cooldown period after exercise can predispose an animal for the development of exertional heatstroke or exertional hyperthermia. Any animal that works or exercises in a hot humid climate without acclimation must be allowed time to rest in a cool, shady place with plenty of water every 30 minutes.

Differential Diagnoses Differential diagnoses in patients with rectal temperatures greater than 40.5° C (104.9° F) include a number of infectious and immune-mediated inflammatory diseases, such as those of the central nervous system (e.g., meningitis and encephalitis). Hypothalamic mass lesions affecting the thermoregulatory center are another cause, although rare. Other potential differential diagnoses include malignant hyperthermia (particularly in Labrador retrievers) and unwitnessed seizure activity. Toxins such as metaldehyde, strychnine, and neurogenic mycotoxins can also cause seizures and muscle tremors that can lead to hyperthermia. Opiates, especially hydromorphone, can result in profound hyperthermia, especially in cats.

72

SECTION  I  Critical Care

In an animal with no other signs of infection or systemic inflammation, heatstroke or hyperthermia must be considered on the list of differential diagnoses. This issue is important when considering treatment, as pyrogenic hyperthermia (fever) is a normal physiologic process in response to any number of endogenous or exogenous pyrogens. This occurs as the body attempts to kill the offending organism or mount an immunologic response. Nonpyrogenic hyperthermia results from an inability to adequately dissipate heat. Therefore antipyretic agents (such as nonsteroidal antiinflammatory drugs [NSAIDs]) are not only ineffective in reducing body temperature in animals with heat-induced illness, but are also contraindicated due to their potentially adverse side effects of reducing gastrointestinal and renal perfusion; they also contribute to gastrointestinal ulceration and renal failure.

Clinical Signs Patients that present with heat-induced illness or hyperthermia often have a history of excessive panting, collapse, vomiting, ataxia, hypersalivation, seizures, or diarrhea. Other clinical signs can include lethargy, muscle fasciculations or tremors, altered level of consciousness, seizure, hematuria, cyanosis, epistaxis, swollen tongue, head tremors, vocalization, stridor, and dilated pupils. Changes in mentation, oliguria, vomiting, hematemesis, diarrhea, respiratory distress, icterus, and petechial hemorrhages can occur almost immediately after heat-induced illness or within 3 to 5 days after the inciting event. All animals that have sustained heatstroke and hyperthermia should be watched carefully during this period.

Laboratory Changes Animals with hyperthermia should have serial complete blood counts (CBCs), biochemical analyses, coagulation tests (prothrombin test [PT], activated partial thromboplastin time [aPTT]), arterial blood gas, venous lactate, and urinalyses performed. Prerenal and renal azotemia may be present, with elevations in serum blood urea nitrogen (BUN) and creatinine secondary to renal tubular necrosis. Higher mortality has been reported when serum creatinine is greater than 1.5 mg/dl in dogs with heatinduced illness. Hepatocellular injury and hepatic thrombosis can cause elevation in serum ALT, AST, alkaline phosphatase, and total bilirubin. The presence of hypocholesterolemia, hypoalbuminemia, and hypoproteinemia has been associated with a less favorable outcome. Additionally, serum total bilirubin and creatinine were found to be higher in nonsurvivors than survivors. Elevations in creatine kinase (CK) and AST can occur secondary to rhabdomyolysis. Blood glucose may be decreased, but this is an inconsistent finding. A higher mortality rate has been observed in heatstroke patients whose blood glucose remained low despite aggressive supplementation or was less than 47 mg/dl. Packed cell volume and total solids may be increased secondary to hypovolemia and dehydration, with subsequent hemoconcentration. Elevations in peripheral nucleated red blood cells have been associated with increased morbidity and mortality in dogs with

heat-induced illness. Thrombocytopenia, prolonged PT and aPTT, and elevated fibrin degradation products (FDPs) may be observed in the presence of DIC. Thrombocytopenia is one of the most common clinicopathologic abnormalities observed in animals with heat-induced illness; however, in one study there was no significant difference in platelet counts of survivors versus nonsurvivors. Thrombocytopenia may not become apparent for several days after the initial insult, so serial CBCs should be performed over time in the most critical animals. The presence of coagulation abnormalities may or may not be associated with an increased risk of mortality. In one study, a calculated discomfort index, but not environmental temperature, was significantly associated with the development of DIC. Arterial blood gas analyses can be variable, with a respiratory alkalosis and metabolic acidosis and a mixed acid-base disturbance. The need for administration of sodium bicarbonate is a negative prognostic indicator. Urinalysis may reveal the presence of renal tubular casts or glucosuria, both indicators of renal tubular epithelial damage. Myoglobinuria secondary to rhabdomyolysis also can contribute to severe acute renal tubular necrosis.

Treatment Management of hyperthermia and heat-induced illness involves first treating the hyperthermia, along with providing cardiovascular support, and then treating any complications associated with the hyperthermia. These complications often occur simultaneously and may be evident in a critical patient at the time of presentation. Other problems may be recognized and require treatment during the course of hospitalization and recovery. Cornerstones of therapy include restoring effective cooling measures, restoring circulating intravascular blood vol­ ume, improving glomerular filtration and renal blood flow, stabilizing electrolyte balance, and providing broadspectrum antibiotics to minimize complications of bacterial translocation and sepsis. Rapid early recognition of hyperthermia and instituting early cooling measures are extremely important and can be performed by the first responders before the patient presents to the hospital. First, the animal should be moved to a cool area in the shade or indoors, away from direct sunlight. Next, the animal should be sprayed or covered with cool, but not cold, water. Cool packs can be placed in the axillary and inguinal regions. Air conditioning or cool fans also can help to dissipate heat and improve convective cooling mechanisms. The patient must be cooled to 39.4° C (103° F) within 30 to 60 minutes of initial presentation, but overcooling should be avoided. Immersion in ice baths or cold water is absolutely contraindicated because cold water immersion causes peripheral vasoconstriction and prevents vasodilation, one of the primary methods of cooling. Vasoconstriction results in further elevation of core body temperature and thus should be avoided at all costs. In one retrospective study, animals that were cooled prior to presentation by their owners had a more favorable prognosis and decreased risk of mortality than animals that were not cooled at the time of initial injury. A more recent study, however,

CHAPTER  14  Hyperthermia and Heat-Induced Illness found that cooling before time of presentation did not significantly affect outcome. The thermoregulatory center cannot function properly in animals with heat-induced illness, so overcooling can be associated with poor prognosis. Cooling the patient to lower than 39.4° C (103° F) causes a rapid drop in core temperature, and shivering can occur, which increases metabolic rate and further increases core body temperature. In one study, patients who were presented with hypothermia were more likely to die. Massaging the skin can increase peripheral circulation, improve peripheral blood flow, and improve heat dissipation. Other methods of cooling that have been described but that offer no real advantage or improvement to clinical outcome include administration of cool intravenous fluids, gastric lavage, cold-water enemas, and cool peritoneal lavage. Placing alcohol on the footpads has been described, but can further complicate overcooling, and is not recommended. Time is of the essence, and the first responder should get the animal to a veterinary facility as soon as possible. Animals that present to the veterinarian within 90 minutes of the inciting event have a more favorable prognosis than animals that are presented later. Intravenous fluids should be administered judiciously during the early stages of hyperthermia and heat-induced illness. Initially, fluid loss is not severe unless thirdspacing of fluid and loss from the gastrointestinal tract occur. Oversupplementation of crystalloids during this time can potentially increase the chance of or worsen cerebral edema and cause pulmonary fluid overload. Fluids should be tailored to each patient’s individual needs and can be administered based on central venous pressure, acid-base and electrolyte status, blood pressure, thoracic auscultation, and colloid oncotic pressure. A balanced electrolyte fluid such as Normosol-R, Plasma-Lyte A, or lactated Ringer’s solution can be given as determined by calculated dehydration deficits. If a free water deficit is present, as evidenced by hyperna­ tremia, the clinician should calculate the free water deficit and replace it slowly over a period of 24 hours to prevent further cerebral edema. Experimental evidence has also suggested that hydroxyethyl starch may be superior to saline alone for resuscitating animals with hyperthermia. Oxygen should be administered in animals with signs of upper airway obstruction. If laryngeal paralysis is present, sedative and anxiolytic agents such as acepromazine should be considered. In severe cases of upper airway obstruction and laryngeal edema, antiinflammatory doses of glucocorticoids can also be administered to decrease airway edema. General anesthesia and airway intubation should be considered in the most severely affected animals. Empiric glucocorticoids in patients without signs of airway obstruction are contraindicated because they can further impair renal perfusion and predispose to gastrointestinal ulceration. Broad-spectrum antibiotics such as a second-generation cephalosporin (Cefoxitin 30 mg/kg IV q8h), ampicillin (22 mg/kg IV q6-8h) with enrofloxacin (10 mg/kg IV q24h), and sometimes metronidazole (10 mg/kg IV q8h) should be administered to decrease bacteremia. Nephrotoxic antibiotics should not be administered because

73

compromised renal function is a serious concern in patients with hyperthermia. Antipyretic agents such as dipyrone, flunixin meglumine, carprofen, and etodolac are contraindicated for a number of reasons. First, the actions of such drugs are ineffective at decreasing temperature in an animal with a deranged hypothalamic thermoregulatory center. Their use may be justified in animals with pyrogenic hyperthermia but not in animals with heat-induced illness. Second, antiprostaglandins can potentially worsen hypothermia if present. Finally, in high doses antiprostaglandin drugs have been shown to decrease renal perfusion and can predispose the patient to gastrointestinal ulceration. Serious complications of hyperthermia include oliguria, ventricular arrhythmias, and seizures, and the need to treat any of these has been associated with a poorer outcome in some published studies. Urine output should be quantitated and calculated to observe if oliguric or anuric renal failure is present. After volume resuscitation, urine output should be 1 to 2 ml/kg/hr. If urine output is less, a constant rate infusion of dopamine at 3 to 5 µg/ kg/min can be started to increase renal perfusion and urine output. Ventricular arrhythmias should be monitored by electrocardiograph (ECG) and treated when necessary. The presence of ventricular rhythm disturbances and the need for antiarrhythmic therapy in the form of lidocaine (see Chapter 172) may be associated with a less favorable outcome in the hyperthermic patient. Finally, seizures should be controlled with diazepam (see Chapter 230).

Prognosis Severe hyperthermia can result in widespread organ failure and must be recognized and treated promptly. In most cases, prognosis is guarded to grave, depending on the presence of underlying diseases and complications. Mortality rates are directly associated with the duration and intensity of hyperthermia. In one study, mortality rate was 50%. Obesity, renal failure, and DIC all increase the risk of death associated with hyperthermia. Permanent renal, hepatic, and cerebral damage can occur, including permanent changes in the hypothalamic thermoregulatory center that can predispose the patient to further hyperthermic episodes. In most cases, the clinician must give a guarded prognosis. If death is going to occur, it usually happens within the first 24 hours of the incident. If an animal survives past 48 hours of hospitalization, the outcome is generally favorable. Animals who present with coma or hypothermia after a hyperthermic event generally have a very grave prognosis, even with extremely aggressive therapy.

References and Suggested Reading Aroch I et al: Peripheral nucleated red blood cells as a prognostic indicator in heatstroke in dogs, J Vet Intern Med 23:544-551, 2009. Bouchama A, Knochel JP: Heat stroke, N Engl J Med 346:1978, 2002. Bruchim Y et al: Heat stroke in dogs: a retrospective study of 54 cases (1999-2004) and analysis of risk factors for death, J Vet Intern Med 20:38, 2006.

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Bruchim Y et al: Pathological findings in dogs with fatal heatstroke, J Comp Pathol 140(2-3):97-104, 2009. Diehl KA et al: Alterations in hemostasis associated with hyperthermia in canine model, Am J Hematol 64:262, 2000. Drobatz KJ, Macintire DK: Heat-induced illness in dogs: 42 cases (1976-1993), J Am Vet Med Assoc 209(11):1894, 1996. Flournoy SW, Wohl JS, Macintire DK: Heatstroke in dogs: pathophysiology and predisposing factors, Comp Cont Educ Pract Vet 25:410-418, 2003. Flournoy SW, Wohl JS, Macintire DK: Heatstroke in dogs: clinical signs, treatment, prognosis and prevention, Comp Cont Educ Pract Vet 25:422-431, 2003. Haskins SC: Thermoregulation, hypothermia, hyperthermia. In Ettinger S, editor: Textbook of veterinary internal medicine, ed 4, Philadelphia, 1995, WB Saunders.

CHAPTER 

Holloway SA: Heatstroke in dogs, Comp Cont Educ Pract Vet 14(12):1598, 1992. Johnson SI, McMichael M, White G: Heatstroke in small animal medicine: a clinical practice review, J Vet Emerg Crit Care 16(2):112-119, 2006. Liu CC et al: Hydroxyethyl starch produces attenuation of circulatory shock and cerebral ischemia during heat stroke, Shock 22(3):288, 2004. Reiniker A, Mann FM: Understanding and treating heat stroke, Vet Med May:344-355, 2002.

15 

Thromboelastography KARL E. JANDREY, Davis, California BENJAMIN M. BRAINARD, Athens, Georgia

V

iscoelastic point-of-care coagulation instruments have become more popular owing to their unique ability to detect both hypocoagulability and hypercoagulability using a whole blood sample. Viscoelastic analyzers measure changes in the viscosity or elasticity of a blood sample as it turns from liquid to a fibrin clot during coagulation. The use of whole blood is ideal to re-create the physiology of coagulation ex vivo because it summates the contribution of each individual component (e.g., platelets, red blood cells, plasma factors) to hemostasis. The testing duration is generally short and the blood sample volumes required are relatively small. The most common viscoelastic coagulation machines used in veterinary medicine include the Thrombelastograph (TEG, Haemonetics [formerly Haemoscope]), Sonoclot, and rotational thrombelastometer (ROTEM). This chapter emphasizes some important technical aspects of thromboelastography, outlines principles of interpretation including some complicating factors, and highlights the potential value of this technology for monitoring coagulation disorders in veterinary patients.

Thromboelastography The principle behind thromboelastography is the measurement of the viscoelastic characteristics of clotting blood. Clot formation occurs in a rotating plastic cylindrical cuvette (the cup) with a stationary suspended piston (the pin) that is lowered into the center of the cuvette.

The cup rotates through an angle of 4°45’ with a 10-second cycle period. The pin is attached to a thin metal torsion wire. As clot formation progresses, the fibrin that is generated physically links the pin to the cup. As this connection strengthens, the rotation of the cup is transmitted to the pin and this torque is translated into the TEG tracing by the torsion wire. The graphic tracing is displayed in real time via the computer interface and proprietary software. The thromboelastograph generates a qualitative tracing, as well as quantitative values to describe the clot (Figure 15-1). The R-time is the time in minutes from when that blood is placed in the TEG until initial fibrin formation. Reaction time generally reflects coagulation factor levels but does not always correlate with prothrombin time (PT) and activated partial thromboplastin time (aPTT). The K-time measures in minutes the time it takes from initiation of clotting for a TEG tracing to reach a predetermined level (20 mm) of clot strength. The αangle measures in degrees the rate of fibrin buildup and cross-linking as a function of amplitude and time. Both K-time and α-angle are affected by the availability of fibrinogen, factor XIII, and to a lesser degree platelets. The maximum amplitude (MA, measured in mm), the widest part of the TEG tracing, is a direct result of fibrin production and platelet function and represents the final clot strength. Another measure of clot firmness is the elastic shear modulus (G, in dynes/second/cm2) and is calculated from the MA using the equation:

CHAPTER  15  Thromboelastography G = 5000 × MA/(100 − MA ) In addition to clot production, the TEG also demonstrates fibrinolysis; the percent decrease in the amplitude of the tracing 30 and 60 minutes following the MA is indicated as the lysis parameters (CL 30 and LY 30 and CL 60 and LY 60, respectively, measured in %). Lysis parameters are a measure of clot stability. Table 15-1 lists normal values for TEG parameters that have been reported in the literature.

TEG Operation There are no standard protocols for veterinary TEG; in general, samples are run as recalcified citrated samples

MA

LY 30

LY 60

α R

K

Figure 15-1  A generalized TEG tracing showing the most com-

monly reported values and how they relate to the tracing. R, R-time or reaction time, the time to the formation of the first fibrin strands; K, K-time, the time from the R-time until the tracing reaches 20 mm in width; Angle, α-angle, a measure of the rate of clot formation; MA, maximum amplitude, the widest part of the tracing, corresponding to the final clot strength; LY 30 and LY 60, the ratio of the amplitude at 30 and 60 minutes following the generation of MA to the MA; these parameters represent the speed of clot dissolution or fibrinolysis.

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(typically 3.2% sodium citrate at a 1 : 9 v/v ratio), at 37° C, and after a 30-minute rest period at room temperature. Vibration, shock, mixing, and rapid shifts in temperature during the rest period should be avoided. Although some laboratories use only recalcification with calcium chloride before starting the assay, this method depends on contact activation (intrinsic pathway) and may result in a prolonged assay time, especially in horses. This method is also associated with operator variability. The use of very dilute (1 : 50,000) or moderately dilute (1 : 3400) tissue factor (TF; Innovin, Siemens Healthcare) has been described in many species and decreases interoperator variability. Haemonetics provides prefilled vials containing a liquid kaolin solution, which strongly activates coagulation via the intrinsic pathway. Kaolin activation also decreases variability and has been described in small animal species. A recent publication that studied various activators (native, TF, and kaolin) for TEG analysis of cat blood showed that the activators are not interchangeable due to large coefficients of variation between activators. Because of variability between users and institutions, each institution should develop a specific protocol, decide on a specific reference interval, and identify a limited number of operators to maximize useful information from the assay. Protocols should specify guidelines for sample collection, a standard sample rest period following blood sampling, and a standard temperature for both the rest period and the TEG analysis. For research studies, a single operator is preferable, and duplicate testing should be considered if possible. If limiting the number of operators is not feasible, an activator such as TF or kaolin should be used.

TEG Interpretation In general, animals may be considered hypercoagulable if they have all or some of the following TEG characteristics: a faster time to the start of clot formation (a shorter R-time), a steeper α-angle (corresponding to more rapid clot formation), and a greater MA than the reference

TABLE 15-1  Survey of Reference Intervals or Experimental Ranges Generated for TEG in Dogs and Cats Using Various Activation Methods*

α-Angle (deg)

Maximum Amplitude (MA, mm)

n

Reference

1.2-4.6

39-74

44.5-61.7

120 (reference interval)

Pittman 2010

1.3-5.7

36.9-74.6

42.9-67.9

56 (reference interval)

Bauer 2009

2.3-7.7

27.5-58.7

39.0-59.0

18 (range)

Wiinberg 2005

Species, Activation Method

R-time (min)

K-time (min)

Dog, recalcification

2.1-11.0

Dog, kaolin

1.8-8.6

Dog, tissue factor (1 : 50000)

2.8-8.7

Cat, recalcification

3.3-19.8

1.9-6.6

32.5-64.6

38.3-60.7

15 (range)

Marschner 2010

Cat, kaolin

2.4-9.5

1.2-3.9

45.5-73.5

46.8-66.1

15 (range)

Marschner 2010

Cat, tissue factor (1 : 50,000)

3.2-12.5

1.9-5.8

34.1-64.3

40.3-62.8

15 (range)

Marschner 2010

*All samples rested at room temperature for 30 minutes prior to initiation of the test, with the exception of the canine kaolin–activated samples, which rested for 1 hour.

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SECTION  I  Critical Care

range. Some animals may display all these characteristics and some only an increased α-angle and MA. In human studies, the only parameter that has been correlated to an increased risk of thrombosis is an MA larger than the reference range. An association between TEG parameters and outcome measures has yet to be established in veterinary medicine. Animals with hypocoagulable states typically display a prolonged R-time if they have a decrease in coagulation factors. If animals are hypocoagulable due to thrombocytopenia, the R-time remains normal (because it is determined by plasma proteins), but the α-angle and MA will be significantly decreased. In coagulopathic patients with low fibrinogen due to conditions such as disseminated intravascular coagulopathies (DIC), the α-angle and MA will also be narrow compared with reference ranges.

Clinical Utility The use of the TEG in veterinary medicine has grown rapidly since the initial report in 2000, in which hypercoagulability was described in puppies with parvoviral enteritis. Hypercoagulability in this population was characterized by increased MA and was correlated to other laboratory measures such as decreased antithrombin and increased fibrinogen concentration. Four of nine puppies in this group had clinical evidence of catheter-associated phlebitis or venous thrombosis. One study used TF-activated TEG to describe both hypercoagulability and hypocoagulability in dogs with various types of metastatic neoplasia. TF-activated TEG has also been used to illustrate hypercoagulability and hypocoagulability in dogs with DIC. Dogs with a hypocoagulable TEG are more likely to have clinical bleeding. When TEG was compared against standard tests of coagulation in dogs admitted to an intensive care unit (ICU), positive associations were found between MA and α-angle and fibrinogen and platelet count, as well as between PT, aPTT, and R-time. Recent reports have addressed the usefulness or application of the TEG to the understanding of many disease states across species. These diseases include protein-losing nephropathies and enteropathies (where tendencies toward hypercoagulability were identified), hyperadrenocorticism (where affected dogs did not have TEG parameters different from a control group), and immune-mediated hemolytic anemia (where affected dogs also displayed hypercoagulability). Kaolin-activated TEG was used to evaluate coagulation in cats with hypertrophic cardiomyopathy (HCM) and indicated that, although individual cats may be hypercoagulable, there is significant overlap in values between healthy cats and those with HCM.

Important Aspects of TEG Interpretation The TEG tracing is significantly affected by hematocrit (Hct). As Hct drops, the tracing appears progressively hypercoagulable, with both a steeper angle and a larger MA. It is unclear if this is an in vitro phenomenon due to an altered ratio of plasma to cells or if it represents actual in vivo hypercoagulability. Platelet count is also important. Patients with thrombocytopenia less than 50 to

75 × 103 platelets/µL generate a hypocoagulable tracing. The TEG tracing (specifically MA) is also directly correlated to the patient’s fibrinogen concentration. Ongoing research in the veterinary TEG community is directed toward evaluating the effects of variable rest periods, test temperatures, and venipuncture techniques. With longer rest periods (greater than 60 minutes), the tracing appears progressively hypercoagulable. Resting the sample for 30 minutes at room temperature or at 37° C has no effect on the tracing (the TEG warms the blood to 37° C over 2.5 minutes, and the sample is greater than 30° C within 30 seconds). TEG reference intervals generated at 37° C and at 39° C appear similar. The quality of both venipuncture and the postsampling handling of blood is also important; as with any samples for coagulation testing, blood for the TEG should be obtained with minimal stasis or trauma. Overall, consistency of technique is the most important aspect of generating TEG tracings that are interpretable and comparable between patients.

Modifications to Thromboelastography Samples contaminated with unfractionated or lowmolecular-weight heparin or from patients treated with heparins may display significant TEG abnormalities. Unfractionated heparin concentrations as low as 0.1 U/ ml result in excessively prolonged R-times and may complicate data interpretation. For this reason, Haemonetics also manufactures TEG cups that contain a proprietary dose of heparinase. These cups are run in the same fashion as those without additives, but the heparinase inactivates any heparin present in the sample; theoretically this results in a tracing that shows the underlying coagulation status of the patient. This is an attractive technique not only for quality control of samples obtained via an indwelling catheter, but also because it may allow monitoring of the underlying coagulation state of animals that are receiving therapeutic doses of heparins. The only downside is that there is a specific dose of heparinase in each cup, and depending on the amount of heparin in the sample, complete inactivation may not occur. The heparinase cups may also be useful for generating a therapeutic monitoring protocol for patients receiving lowmolecular-weight heparin. The whole blood TEG tracing may also be modified by the addition of inhibitory substances. In humans, the in vitro addition of cytochalasin D and abciximab results in a significant decrease in MA and α-angle. In dogs, in vitro cytochalasin D is effective and results in a decreased MA and α-angle, but abciximab does not affect the tracing. TEG performed on citrated whole blood is not sensitive to platelet inhibition from commonly used drugs such as clopidogrel or aspirin; however, TEG PlateletMapping offers a way to work around this problem. Instead of a citrated sample, heparinized blood is obtained. The heparin prevents de novo thrombin formation and allows the TEG to be used as a modified platelet aggregometer. In order to create the tracing, Haemonetics provides an activator consisting of a mixture of reptilase (to convert fibrinogen to fibrin, in the absence of thrombin) and activated factor XIII (to cross-link the fibrin). The

CHAPTER  15  Thromboelastography addition of this activator (activator F) and a platelet agonist such as adenosine diphosphate (ADP) or arachidonic acid (AA) allows platelet activation and subsequent integration of platelets and fibrin into a clot that is demonstrable on the machine. Activator F used alone induces an MA resulting from fibrin(ogen) already present in the sample. AA or ADP combined with activator F generates an MA resulting from platelet activation and subsequent fibrin binding induced by the agonists. The percentage difference between the MA of these various measures is calculated to show the reduction in platelet function as a result of antiplatelet medications. This assay is sensitive to clopidogrel treatment in dogs and presumably would work for aspirin as well. To the authors’ knowledge, it has not been evaluated in cats, and the reptilase activator limits its use in horses. Inhibiting platelet function in the PlateletMapping assay, as a concept, may allow better differentiation in hypercoagulable animals if the coagulation changes arise from the platelet component or the plasma protein component, but further work is necessary to standardize this assay.

The TEG as a Tool for Therapeutic Monitoring As noted earlier, the TEG is very sensitive to heparin, and even subtherapeutic levels result in significantly prolonged assay times and may not generate a tracing. This may be partially avoided through the use of an activator such as TF, but even this may not be able to distinguish high concentrations of heparin. A recent in vitro study evaluating the use of heparinase cups and low-dose (1 : 50,000) TF activation identified different doses of dalteparin in canine whole blood, and the author (BMB) has used high-dose (1 : 3400) TF and normal cups to evaluate dogs receiving both unfractionated and low-molecularweight heparin. In both dogs with hemophilia and those with factor VII deficiency the TEG demonstrated hypocoagulability. The TEG can presumably be used to monitor dogs that

77

have other factor deficiencies as they are addressed therapeutically, although the value of a TEG analysis versus standard coagulation testing (e.g., PT, aPTT) in this context is debatable. In vitro studies in children have also demonstrated the sensitivity of the TEG in monitoring the reversal of tissue plasminogen activator (t-PA)–induced fibrinolysis by ε-aminocaproic acid (EACA); the TEG may be useful for this purpose in companion animals treated with EACA. A TEG analysis can give information about global hemostasis that is difficult to obtain using other currently available methodologies. Although the machine has a strong theoretic place in clinical veterinary medicine, standardization of protocols and clear correlations with other assessments of coagulation are necessary before the TEG becomes an instrument for everyday clinical evaluation of hemostasis in veterinary species.

References and Suggested Reading Bauer N, Eralp O, Moritz A: Establishment of reference intervals for kaolin-activated thromboelastography in dogs including an assessment of the effects of sex and anticoagulant use, J Vet Diagn Invest 21(5):641-648, 2009. Donahue SM, Otto CM: Thromboelastography: a tool for measuring hypercoagulability, hypocoagulability, and fibrinolysis, J Vet Emerg Crit Care 15(1):9-16, 2005. Ganter MT, Hofer CK: Coagulation monitoring: current techniques and clinical use of viscoelastic point-of-care coagulation devices, Anesth Analg 106(5):1366-1375, 2008. Kol A, Borjesson DL: Application of thrombelastography/ thromboelastometry to veterinary medicine, Vet Clin Pathol 39(4):405-416, 2010. Marschner CB et al: Thromboelastography results on citrated whole blood from clinically healthy cats depend on modes of activation, Acta Vet Scand 52:38, 2010. Pittman JR, Koenig A, Brainard BM: The effect of unfractionated heparin on thrombelastographic analysis in healthy dogs, J Vet Emerg Crit Care 20(2):216-223, 2010. Wiinberg B et al: Validation of human recombinant tissue factoractivated thromboelastography on citrated whole blood from clinically healthy dogs, Vet Clin Pathol 34(4):389-393, 2005.

CHAPTER 

16 

Critical Illness–Related Corticosteroid Insufficiency LAUREN SULLIVAN, Fort Collins, Colorado JAMIE M. BURKITT CREEDON, Cherry Hill, New Jersey

C

ortisol is a key hormone in the maintenance of homeostasis in both health and disease. It contributes to several important physiologic processes including immunologic, cardiovascular, and inflammatory modulation. The adre­­nal glands depend on an intact hypothalamic-pituitary-adrenal (HPA) axis for continuous and appropriate amounts of cortisol production. The adrenal glands must continually synthesize cortisol to meet cellular needs, with very little cortisol actually stored in the glands themselves. Impairment or dysfunction of the HPA axis is identified in approximately 40% of critically ill humans, depending on the underlying disease, and is most frequently observed in patients with severe sepsis, septic shock, trauma, or hemorrhagic shock. A similar incidence has been recently documented in critically ill dogs. Dysfunction of the HPA axis results in a relative, not necessarily absolute, decrease in cortisol production. This endocrine dysfunction was initially thought to result from insufficient cortisol production by the adrenal glands, and thus it was initially called relative adrenal insufficiency (RAI). Further elucidation of this disease has led clinicians to understand that dysfunction may occur anywhere along the HPA axis, and therefore critical illness– related corticosteroid insufficiency (CIRCI) is now the preferred term. The end result, insufficient production of cortisol to meet physiologic needs during severe illness, contributes significantly to morbidity and mortality within the critical care setting. An easily recognizable sign of critical illness–related HPA axis dysfunction is hypotension that is refractory to fluid resuscitation and vasopressor therapy.

Pathophysiology Although exact mechanisms require further investigation, CIRCI is a result of several aberrations evident during critical illness. Primary adrenal dysfunction may be due to hemorrhage or microvascular thrombi within the adrenal glands or due to drugs that suppress steroidogenesis. Secondary adrenal dysfunction occurs higher in the HPA axis, at the level of the hypothalamus or anterior pituitary gland. Inflammatory cytokines may cause suppression at the level of these structures, decreasing production of corticotropin-releasing hormone (CRH) or adrenocorticotropic hormone (ACTH). Finally, increased cortisol clearance, alterations in cortisol transport, or 78

decreased cortisol receptor affinity may also contribute to the development of CIRCI. A glucocorticoid deficiency is the final result of these mechanisms, but mineralocorticoid activity does not appear to be affected and usually remains intact. There may also be a genetic contribution to the development of CIRCI in dogs. P-glycoprotein plays a role in regulation of the HPA axis, and this axis may be suppressed in dogs with multidrug resistance protein 1 (MDR1) mutations. A study of healthy collies found that dogs with the MDR1 mutation had significantly lower basal plasma cortisol concentrations, as well as lower cortisol concentrations after ACTH stimulation. Some practitioners anecdotally report that herding breeds appear to have worse outcomes in response to stress; increased risk of HPA axis dysfunction and CIRCI may possibly explain this observation. Although this suggests that HPA axis testing is prudent in certain breeds of critically ill dogs, CIRCI may occur in any breed and warrants further investigation in any critically ill dog or cat that demonstrates clinical signs compatible with CIRCI.

Diagnosis CIRCI should be considered as a differential diagnosis in any critically ill animal that remains hypotensive despite adequate fluid resuscitation and vasopressor support. Other nonspecific signs may include fever, gastrointestinal upset, weakness, and depression, although it is difficult to clarify if these are signs of CIRCI or of the systemic inflammation that led to the CIRCI. The gold standard for definitively diagnosing CIRCI remains debatable in human and veterinary medicine. A basal cortisol should never be the sole diagnostic test used because these levels can often be normal or elevated. An ACTH stimulation test, along with appropriate clinical suspicion, is the current recommendation for identification of animals with CIRCI. In dogs, 0.5 µg/kg (low dose) to 250 µg/dog (standard dose) of cosyntropin can be administered IV, with serum cortisol concentration measured just prior to cosyntropin administration (“pre-ACTH”) and serum cortisol concentration measured 1 hour after cosyntropin administration (“post-ACTH”). A Δ-cortisol can then be determined by subtracting the pre-ACTH cortisol from the post-ACTH cortisol. A similar protocol can be used in cats by injecting 125 µg/cat IM, then calculating Δ-cortisol from

CHAPTER  16  Critical Illness–Related Corticosteroid Insufficiency measured pre-ACTH and 1-hour post-ACTH cortisol samples. According to a recent review article about CIRCI in small animals, CIRCI can be highly suspected in critically ill dogs if one of the following criteria is met: (1) normal or elevated basal cortisol, ACTH-stimulated cortisol is less than the normal reference range; (2) normal or elevated basal cortisol, ACTH-stimulated cortisol that is greater than baseline by less than 5%; (3) a Δ-cortisol of 3 µg/dl or less; or (4) improvement in cardiovascular status following glucocorticoid supplementation (e.g., improvement in arterial blood pressure, weaning from vasopressors). Criteria for diagnosing critically ill cats with CIRCI are still undetermined. There is still much controversy concerning the use of the ACTH stimulation test when diagnosing CIRCI in humans and animals; however, most clinical veterinary research has used this test to identify HPA axis dysfunction. There are several recognized limitations to the ACTH stimulation test when diagnosing CIRCI. This test only evaluates the ability of the adrenal glands to make cortisol, but does not evaluate the integrity of the entire HPA axis. It also does not evaluate the cortisol responsiveness of peripheral glucocorticoid receptors. Additionally, normal cortisol reference ranges for critically ill dogs and cats have not been established. Also, total cortisol measures both the fraction of cortisol that is protein bound and the fraction that is freely circulating. Only freely circulating cortisol is biologically active. Thus concentrations of free cortisol may be altered in critical illness even when the total cortisol is normal, a discrepancy the ACTH stimulation test does not address. Finally, recent studies in humans suggest that there may be little or no correlation between ACTH stimulation test results and hypotension’s responsiveness to low doses of hydrocortisone in septic shock. Because of these limitations to the ACTH stimulation test, the appropriate method(s) for diagnosing CIRCI in human and veterinary medicine will likely change after additional investigation.

Veterinary Evidence Several clinical studies that evaluated the presence of CIRCI in critically ill animals have been published. One prospective cohort study (Martin et al, 2011) observed 31 dogs with a variety of acute critical illnesses including sepsis, severe injuries, and gastric dilation-volvulus (GDV). Of these 31 dogs, 55% demonstrated at least one biochemical abnormality suggestive of HPA axis dysfunction (defined as an ACTH-stimulated cortisol less than the reference range, a plasma endogenous ACTH concentration less than the reference range, or no response to an ACTH stimulation test). In this study, dogs with a Δ-cortisol of 3 µg/dl or less were 5.7 times more likely to require vasopressor therapy. A second study (Burkitt et al, 2007) evaluated 33 septic dogs and identified CIRCI in 48% of the population. These authors also found that dogs with a Δ-cortisol of 3 µg/dl or less were at higher risk for developing systemic hypotension and were also 4.1 times more likely to die.

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In one case report (Durkan et al, 2007) a critically ill cat recovering from polytrauma developed CIRCI, defined as an inadequate response to ACTH stimulation and a Δ-cortisol of 3.2 µg/dl. One study of 19 septic cats (Costello et al, 2006) reported that the septic cats had a decreased cortisol response to ACTH compared with normal cats, but made no specific recommendation for diagnosis in the species. Ongoing work in septic cats to determine the appropriate identification of CIRCI will hopefully provide some future guidelines for this species.

Treatment and Prognosis Hydrocortisone (0.5 mg/kg IV QID, or 0.08 mg/kg/hr as a constant rate infusion) is considered the glucocorticoid of choice when treating CIRCI because it is structurally identical to endogenous cortisol in dogs and has a relatively short duration of HPA axis suppression. The dose of hydrocortisone used is considered low dose, with the intent of improving cardiovascular stability without predisposing to further complications (e.g., new infections, superinfections). Hydrocortisone is considered to be one fourth as potent as prednisone, allowing extrapolations to be made if hydrocortisone is unavailable for treatment. Clinical markers for successful hydrocortisone therapy include improvement in blood pressure or other cardiovascular parameters and successful weaning from vasopressor therapy. Hydrocortisone therapy can be weaned (approximately 25% per day) once the animal’s condition has stabilized and the underlying disease is resolving. An ACTH stimulation test should be repeated following discontinuation of exogenous glucocorticoids to ensure that CIRCI is no longer present. The endocrine dysfunction observed with CIRCI is typically transient and recoverable, meaning animals should not require glucocorticoid supplementation long term. Prognosis is largely based on the severity of the underlying disease, but the presence of CIRCI typically indicates significant illness that requires intensive care and owner commitment.

References and Suggested Reading Burkitt JM et al: Relative adrenal insufficiency in dogs with sepsis, J Vet Intern Med 21:226-231, 2007. Costello MF et al: Adrenal insufficiency in feline sepsis. In Proceedings: ACVECC Postgraduate Course 2006: Sepsis in veterinary medicine, p. 41. 2006. Durkan SD et al: Suspected relative adrenal insufficiency in a critically ill cat, J Vet Emerg Crit Care 17(2):197-201, 2007. Guma N, Brewer W: Relative adrenal insufficiency in the critical care setting, Compend Contin Educ Small Anim 30(12):E1-E9, 2008. Martin LG et al: Pituitary-adrenal function in dogs with acute critical illness, J Am Vet Med Assoc 233(1):87-95, 2008. Martin LG: Critical illness–related corticosteroid insufficiency in small animals, Vet Clin Small Anim 41:767-782, 2011. Peyton JL, Burkitt JM: Critical illness–related corticosteroid insufficiency in a dog with septic shock, J Vet Emerg Crit Care 19(3):262-268, 2009.

CHAPTER 

17 

Evaluation of Canine Orthopedic Trauma RANDALL B. FITCH, Ladera Ranch, California

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linical evaluation of the trauma patient for orthopedic injury is multifaceted. Although outward injuries such as fractures may be apparent, an awareness of more insidious threats is also of critical importance. Cardiovascular stability and the identification of associated injuries should be prominent considerations inasmuch as mortality rates for trauma patients are reported at 7% to 12.5% (from spontaneous death or euthanasia). Additionally, between 39% and 60% of small animals that present with fractures have recognizable thoracic trauma. This chapter emphasizes the diagnostic approach to the dog with orthopedic trauma (see Chapter 18). Recognition and stabilization of life-threatening conditions may delay a thorough orthopedic evaluation. Also, key components of a typical orthopedic evaluation such as gait assessment can be especially challenging and may require support with a sling or harness. Other barriers to a complete examination include bandages and splints that may have been placed due to lacerations, abrasions, or fractures. Therefore completion of a thorough orthopedic examination may need to be performed over time. Historical information helps clarify the cause of injury and expected associated injuries. For example, patients with gunshot wounds have a higher incidence of additional penetrating injuries to the abdomen or thorax, whereas patients who suffer vehicular trauma have a high incidence of pelvic trauma. These incidence and risk factors impact the diagnostic workup and treatment performed. Preexisting conditions should not be overlooked because they may become especially relevant following trauma and are often forgotten in the excitement of patient stabilization.

Orthopedic Examination Although a complete gait and mobility workup may not be feasible immediately following trauma, standing weight-bearing assessment remains an important tool for appraising a patient’s neurologic and orthopedic functions. The position of the limbs with the patient in a standing position allows the clinician to assess muscle strength, girth, and tone and search for any neurologic injury such as radial nerve injury or brachial plexus trauma. If functional changes are noted in the limb, further neurologic evaluation should be pursued including spinal reflexes and sensation. Additional assessment involves lifting each limb to determine the amount of weight placement, 80

proprioception, and weight balance between limbs. Further neurologic evaluation is indicated if weakness or conscious proprioceptive deficits are found. Limbs should be compared for differences in symmetry. The vertebral column should be examined for any derangement. Weight distribution, posture, weight bearing, and limb positioning should be assessed from multiple perspectives (from both sides, front, and back). Many orthopedic injuries have characteristic postural changes easily recognized in a standing position (as with coxofemoral luxation). A systematic approach or checklist is likely to improve efficiency and accuracy of diagnosis. The standing examination provides the most direct and specific assessment of weight bearing, symmetry, and function.

Palpation Starting with the cervical spine, one can manipulate and palpate the osseous and muscular structures to detect discomfort. The clinician should flex and extend the neck through full range of motion, including lateral, dorsal, and ventral flexion. The spine should be palpated throughout its extent. In addition to the spine, pelvis, forelimbs, and hind limbs should be assessed carefully and systematically to include palpation of bone, ligament, and muscles and evaluation of nervous system function.

Examination of the Forelimbs Palpation of the forelimbs should include palpation of each scapula for normality and symmetry. The spine of the scapula serves as an excellent barometer for assessing forelimb muscle atrophy, an indicator of preexisting forelimb lameness. It is useful to compare both muscular tone and development especially near osseous landmarks such as the spine, acromion process, and the greater tubercle of the humerus. The examiner should flex and extend all forelimb joints, including the shoulder, elbow, and carpus and each phalange. The latter also should be assessed carefully for swelling. Each forelimb joint should be evaluated for stability, displacement, or increased joint laxity. Shoulder luxations often demonstrate displacement, but subluxations are more subtle and require stress maneuvers to reveal instability. Elbow luxations are predominantly displaced laterally, with observable and palpable displacement of the radial head. Injuries to the carpus commonly produce hyperextension of the joint, which often requires stressed-view radiographs to document fully.

CHAPTER  17  Evaluation of Canine Orthopedic Trauma Limb fractures (of the humerus, radius, or ulna) often produce mechanical instability and displacement. Mechanical integrity of many of the long bones can be assessed through torsional stress. This is done by stabilizing the proximal aspect and rotating the distal aspect of the bone. The distal joint can be used as a lever when the limb is in flexion. For example, humeral integrity is evaluated by palpating the greater tubercle, which stabilizes the proximal humerus. By rotating the elbow to 90 degrees the antebrachium is used as a lever to apply controlled torsional stress to the humeral shaft. Rotation of the distal aspect of the humerus should produce proportional torsional rotation at the greater tubercle. Palpation of osseous structures is performed not only to detect displacement but also to identify discomfort (osteodynia) caused by bone contusion, “greenstick” fracture, or nontraumatic preexisting disorders such as neoplasia or panosteitis.

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with flexion of 45 degrees (the digit pads should rest against the forearm when flexed). Hyperextension injuries of the carpus result in excessive extension and pain. In some cases, the patient must be sedated to evaluate the degree of hyperextension or identify injuries to the collateral ligaments. Stressed-view radiographs are required in addition to standard views whenever stability is in question.

Examination of the Pelvis and Rear Limbs

Shoulder While assessing shoulder range of motion, the clinician should stabilize the scapula. To test shoulder integrity the acromion process is stabilized while the joint is placed in extension. Assessment for medial shoulder stability is complex due to contributions of the collateral ligaments and the additional support of regional muscles. Sedation is advantageous, with the patient in lateral recumbency. With the scapula stabilized and the shoulder in extension, valgus stress is applied on the limb by lifting the limb upward (in abduction) to determine medial stability. Normal glenohumeral abduction angles are less than 30 degrees and using the opposite shoulder for comparison is helpful. Assessment of lateral collateral stability is more difficult due to interference of the thorax and is done with varus stress applied. The shoulder range of motion, degrees of varus and valgus freedom, and rotation movement should be compared with the contralateral limb. Many shoulder joints pop or click without significance, but any translation of the humeral head in relationship to the acromion process is abnormal.

Following evaluation of the forelimbs, the orthopedic evaluation is systematically continued caudally across the thoracic, lumbar, and sacral spine until the pelvis is reached. Pelvic fractures and luxations are common presentations in trauma patients. Side-by-side comparison of pelvic symmetry is an effective aid for detecting pelvic injury. Side-by-side comparison of gluteal muscles and pelvic bony prominences (specifically the iliac crests, tuber ischi, and greater trochanters) can detect injuries to the pelvis. Integrity of the hemipelvis, sacroiliac, or coxofemoral joints can be assessed through palpation of these landmarks. Additional evaluation in lateral recumbency helps confirm injury by allowing more detailed orthopedic examination. Lateral recumbency also facilitates neurologic evaluation of the limb including evaluation of spinal reflexes (femoral and sciatic nerves), sensation, the perineum (anal tone and reflexes), the rectum, and the tail. Further evaluation of the pelvic limb begins with palpation of the femur and thigh muscles to determine if there is swelling, sensitivity to deep palpation, palpable instability, or crepitation. Many fractures of the femur or tibia can be discovered through specific palpation using proximal and distal osseous landmarks and applying torsional stress as previously described. Palpation of the distal limb is more easily performed with the patient in lateral recumbency. This provides better visual access to the medial surface of the lower limb for detection of lacerations, punctures, and abrasions. The rear limbs should be examined as previously discussed for the forelimb.

Radius, Ulna, and Elbow The radius and ulna are palpated from distal to proximal, and torsional stress is applied to assess stability. Injuries to the elbow are common. Flexion and extension of the elbow allow not only range of motion assessment, but also access to the anconeus, olecranon, and caudal joint structures. In full elbow flexion the carpus should almost touch the shoulder. With the elbow in extension and flexed at 90 degrees, integrity of the collateral ligaments is checked by applying medial and lateral force to the radius and ulna. Lateral condylar fractures are common. In these fractures, pain and displacement can be detected with digital pressure applied across the condyles.

Metatarsus The metatarsus is examined by placing stress in both mediolateral and dorsoplantar directions. Minor laxity is expected across the tarsometatarsal joints. Luxation, fractures, and swelling in the metatarsal region, including the calcaneus, are often detectable with palpation. With the metatarsal joint in flexion or extension, regional fractures, instability of the collateral ligaments and styloid process, and joint effusion may be evident. If joint flexion and extension are limited, periarticular osteophytes and joint degeneration may be present. Palpation of the calcaneal tendon at its point of insertion in the tibia may reveal pain, swelling, or displacement.

Carpus Carpal range of motion should be identified, as should any discomfort related to movement. Maximum extension of the carpus should be about 180 to 190 degrees,

Stifle Joints Stifle joints are common sites of injury, and therefore the clinician should concentrate on palpation of the stifles for abnormalities. Swelling, capsular fibrosis, and

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osteoarthritis are palpable during both standing and recumbent examinations and may obscure the normal anatomic features such as the patellar ligament. Preexisting stifle injuries are often exacerbated in trauma patients and may require further treatment. With the patient in lateral recumbency, injury to the cruciate and collateral ligaments may be identified as well as abnormalities of the quadriceps mechanism including the patella, the patellar tendon, and the tibial crest. Patellar stability can be assessed using torsional stress to displace the patella. This is done by extending the stifle, internally rotating the foot, and applying digital pressure to the patella medially. Externally rotating the foot, while simultaneously applying lateral stress, can be used to test for lateral patellar laxity. Valgus and varus force can be applied to the stifle to evaluate the integrity of the collateral ligaments. The medial collateral ligament is typically tighter compared with the lateral collateral ligament, which has mild rotational laxity. Evaluation for a cranial or caudal drawer sign is used to test the integrity of the cranial and caudal cruciate ligaments. Muscle tension, regional swelling, and coexisting injuries can make this evaluation more challenging and it may require reexamination. Drawer evaluation should be performed through a range of joint angles from flexion to extension to detect partial tears. Reduced drawer motion is often noted in patients with chronic cruciate ligament injuries due to the secondary periarticular fibrosis that restricts stifle motion. Drawer motion is not only an indicator of cranial cruciate ligament instability, but also evident with a torn caudal cruciate ligament (which is commonly traumatic). Fractures of the distal femur can also be confused with stifle joint injuries. Femur and Coxofemoral Joint Integrity of the femur is tested with torsional stress by first identifying the greater trochanter with the stifle flexed (90 degrees) and then rotating the distal femur using the lower limb like a lever. Normally the limb should move as one unit, with the corresponding rotation noted proximally and distally. Muscles and tendons overlying the femur also should be palpated. Injuries of the hip region are common and include coxofemoral (sub)luxations, femoral neck fractures, and acetabular fractures. Hip joint motion and comfort can be evaluated by flexing and extending the hip with a hand placed over the greater trochanter. During hip extension, the femur in a normal hip should extend caudally to a position almost parallel to the pelvis and without inducing pain. Degenerative joint disease is a common preexisting condition that limits range of motion and may induce pain and predispose to coxofemoral luxation. The integrity of the proximal femur and acetabulum can be evaluated by placing digital pressure on the greater trochanter and then placing the hip through a range of motion including torsional rotation of the femur. Crepitus is abnormal and may indicate proximal femoral neck or acetabular fractures. Capital physeal fractures produce palpable displacement of the proximal femur similar to a coxofemoral luxation. Acetabular fractures commonly produce medial displacement of the proximal femur that is detectable with digital

pressure placed on the greater trochanter. Further evaluation of the femoral neck may require “frog legged” radiographic views with the hind limbs abducted as well as standard lateral and extended ventrodorsal views of the pelvis. Coxofemoral luxation can result in displacement in any direction, with craniodorsal being most common. Patients with craniodorsal displaced hip luxation exhibit lameness and external rotation of the affected limb. The greater trochanter in these patients is caudomedially displaced with shortening of the affected limb length when compared with the contralateral limb on physical examination. In the normal hip, thumb placement between the greater trochanter and ischiatic tuberosity is displaced with external rotation of the limb. In the presence of a coxofemoral luxation, the thumb is not displaced with external rotation as the femoral head is not engaged into the acetabulum, allowing the femur to slide cranially. In patients with ventrally displaced coxofemoral luxation, the affected limb is comparatively longer when compared with the contralateral limb due to its ventral displacement. In addition, the limb is adducted and internally rotated. As indicated earlier, evaluation of the pelvis relies heavily on assessment of osseous landmarks including the iliac wings, ischiatic tuberosity, and greater trochanter. The pubic region is more assessable in lateral recumbency. Injuries to the pubis include contusions, gravity-dependent bruising, pubic fractures, prepubic tendon ruptures, and abdominal trauma.

Other Issues In patients with orthopedic trauma, additional evaluation should include assessment of neurologic status and vascular integrity. Vascular compromise is indicated by changes in limb color, temperature, and pulse quality. Thoracic trauma, abdominal trauma including body wall herniation (e.g., prepubic tendon injury associated with pelvic trauma), and head trauma also can be present in the patient with multiple trauma. For these reasons, a complete orthopedic evaluation may not be achievable until cardiovascular and respiratory stability are achieved.

Open Fractures Open fractures are special situations in which the wound requires immediate attention (clipping, bacterial culture, lavage, and dressing) and the fracture requires immobilization. They occur in association with a skin wound and are subdivided based on severity, contamination, and exposure of underlying bone. Shear injuries are severe open fractures in which the overlying soft tissues have been sheared away, typically due to abrasion from the road with minimal tissue available for closure. In shear injuries the joint and bone are typically exposed and require delayed closure and stabilization with bandaging over several weeks. Ultimately, the success rate even for these shear injuries is high, approaching 91% to 98% with appropriate treatment. However, initial case management is intensive and often requires daily bandage

CHAPTER  18  Emergency Management of Open Fractures changes. In many cases referral to a specialist is the best approach once the patient is stable. Definitive stabilization is commonly performed following many days to weeks of wound care. Daily wet-to-dry bandage changes combined with surgical débridement are used to achieve a clean, healthy wound before surgical stabilization with implants can occur (see Chapter 19). For more details on management see Chapter 18.

References and Suggested Reading Beardsley SL, Schrader SC: Treatment of dogs with wounds of the limbs caused by shearing forces: 98 cases (1975-1993), J Am Vet Med Assoc 207(8):1071-1075, 1995. Breshears L et al: Radiographic evaluation of ilial fracture fixation in the dog (69 cases), Vet Comp Orthop Traumat 15:64-72, 2004. Crowe DT: Assessment and management of the severely polytraumatized small animal patient, J Vet Emerg Crit Care 16(4):264-275, 2006.

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Kolata RJ, Kraut NH, Johnston DE: Patterns of trauma in urban dogs and cats: a study of 1000 cases, J Am Vet Med Assoc 164(5):499-502, 1974. Kuntz CA et al: Sacral fractures in dogs: a review of 32 cases, J Am Anim Hosp Assoc 31:142-148, 1995. Pavletic MM, Trout NJ: Bullet, bite and burn wounds in dogs and cats, Vet Clin North Am Small Anim Pract 36:873-893, 2006. Roush JK: Management of fractures in small animals, Vet Clin North Am Small Anim Pract 35:1137-1154, 2005. Shamir MH et al: Dog bite wounds in dogs and cats: a retrospective study of 196 cases, J Vet Med 49:107-112, 2002. Sigrist NE, Doherr MG, Spreng DE: Clinical findings and diagnostic value of post-traumatic thoracic radiographs in dogs and cats with blunt trauma, J Vet Emerg Crit Care 14(4):259268, 2004. Simpson SA, Syring R, Otto CM: Severe blunt trauma in dogs: 235 cases (1997-2003), J Vet Emerg Crit Care 19(6):588-602, 2009. Streeter EM et al: Evaluation of vehicular trauma in dogs: 239 cases (January-December 2001), J Am Vet Med Assoc 235(4):405408, 2009.

18 

Emergency Management of Open Fractures ROBERT J. MCCARTHY, North Grafton, Massachusetts

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pen fractures, defined as those in which fractured bone has been exposed to the external environment, represent between 5% and 10% of all fracture cases seen in small animal practice. Any open fracture must be considered contaminated and a source of potential infection. These fractures require immediate intervention and should be treated as surgical emergencies. Open fractures constitute a wide spectrum of injury severity and related consequences, and various classification systems have been developed based on factors such as wounding mechanism, hard and soft tissue damage, location, degree of contamination, and fracture configuration. Perhaps the most useful classification scheme was described by Gustilo, and is based primarily on the degree of soft tissue injury. In this system three different types of open fracture are possible (Table 18-1). Type I open fractures are associated with the lowest energy trauma, have a wound less than 1 cm long, and are generally clean. Type 2 open fractures have a wound greater than 1 cm long but no extensive soft tissue damage, flaps, or

avulsions. Type III open fractures have been divided into three subtypes based on worsening prognosis. Type IIIA fractures have adequate soft tissue coverage despite potentially extensive soft tissue laceration or flaps. In type IIIB fractures there is extensive soft tissue loss with periosteal stripping and bone exposure, often associated with massive contamination. Type IIIC fractures have concomitant arterial injury. Any fracture associated with highenergy trauma is classified as a type III injury, regardless of wound size. As with most classification systems, the Gustilo system has limitations. Many fractures do not fit perfectly into a single category. Furthermore, classification is only useful if it helps guide clinical management or determine prognosis. Although multiple studies have been published in human patients, this information is not readily available for dogs and cats. In reality there is a continuum of open fracture from simple to complex, with multiple variables determining recommended treatment protocol and prognosis.

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TABLE 18-1  Classification of Open Fractures Classification

Description

Type I

Wound < 1 cm in size and clean

Type II

Wound > 1 cm in size without extensive soft tissue damage, flaps, or avulsions

Type IIIA

Adequate soft tissue coverage of a fracture despite potentially extensive soft tissue laceration or flaps

Type IIIB

Extensive soft tissue injury loss with periosteal stripping and bone exposure Usually associated with massive contamination

Type IIIC

Open fracture associated with arterial injury

Any open fracture caused by high-energy trauma is classified as type III.

BOX 18-1  Treatment Protocol for Management of Patients with Open Fracture 1. Evaluate patient status and treat life-threatening injuries 2. Control hemorrhage 3. Place sterile dressing and bandage during patient stabilization 4. Assess vascular and neurologic status of limb 5. Obtain preliminary deep wound culture 6. Start antibiotic therapy 7. Manage pain 8. Obtain radiographs 9. Perform definitive surgical débridement and fracture fixation within 6-8 hours if possible

Initial Assessment and Emergency Management Treatment of an open fracture should be started at home. Owners are instructed to minimize all limb manipulation and to cover the wound and exposed bone with a sterile dressing if possible. A clean cloth or diaper is an appropriate alternative if bandage materials are not available. Owners should be warned that injured animals may bite, and they should consider placing a muzzle if necessary. Compression is usually sufficient to control hemorrhage during transport to the hospital. Initial veterinary management is directed toward evaluation and treatment of other potentially life-threatening injuries and pain management, unless the wound is inadequately covered or is hemorrhaging profusely (Box 18-1). In this situation a sterile dressing and pressure wrap should be applied. Ligation of actively bleeding vessels is occasionally required. Protruding bone should not be forced back into the wound at this time since this allows additional contamination of the fracture site. Evaluation of the stabilized patient begins with a thorough case history. Owners are questioned regarding the cause of the injury and the environment in which the

injury occurred. Whether the animal was “run into” or “run over” is significant because in the latter situation a substantial crushing component is more likely. The environment where the injury occurred may help determine potential wound contaminants and dictate the choice of future antibiotic therapy. Initial wound evaluation should be directed toward a careful assessment of the neurologic and vascular status of the limb because these findings may alter treatment options. Simple diagnostic tests include clipping a toenail short to check for active bleeding, evaluation of extremity pulses distal to the wound by palpation or by Doppler flow detection, limb temperature assessment, and patient recognition of extremity sensation. Although the degree of wound contamination and apparent soft and bony tissue trauma should be determined, limb manipulation must be minimized and wound probing avoided because these procedures increase contamination, cause vascular damage, and result in pain. Potential problems associated with small puncture wounds should not be underestimated because debris may be under the skin, deep in the wound and medullary cavity. Preliminary deep wound cultures should be obtained at the time of initial wound evaluation. In humans 50% to 70% of open fractures produce positive results when cultured at presentation, and in 66% of cases the bacteria cultured at presentation are the same as those later isolated from infected wounds. After the wound is assessed and cultured, radiographs are obtained and a more functional immobilization dressing is applied. The purpose of this bandage is to prevent additional contamination, preserve vasculature, and decrease pain. Most organisms that are recovered from the wound after the development of an orthopedic infection can be traced to the hospital; thus early protection of the wound is critical. Sterile dressings should be used in all cases and strict asepsis maintained. A splint is generally applied to support open fractures below the elbow or stifle, whereas a spica-type bandage is required to immobilize fractures more proximal on the limb. Fractures proximal to the elbow or stifle are frequently difficult to immobilize properly, and in many cases it may be preferable simply to cover the wound and confine the animal to a small cage. Antibiotics are always indicated for animals with open fractures because all wounds are contaminated and wounds that occurred longer than 6 to 8 hours before definitive surgical débridement and lavage are infected. In humans antibiotics administered within 3 hours of injury significantly decrease the rate of future wound infection. Risk of infection may be greater in animals with open fractures because of decreased host defense mechanisms caused by stress or because of vascular compromise. Choice of antibiotic is based on the cause of injury, nature of the wound, likely bacterial contaminants, and knowledge of commonly isolated bacteria from patients with osteomyelitis. Staphylococcus spp. cause between 50% and 60% of bone infections in dogs, and many of these infections are monomicrobial. In general, concerns about penetration of antibiotics into bone interstitial fluid are unfounded. First-generation cephalosporins such as cefazolin (Kefzol, 20 mg/kg q8h) are often the initial drugs of

CHAPTER  18  Emergency Management of Open Fractures choice because they are broad spectrum, can be given intravenously, are usually effective against β-lactamase– producing Staphylococcus spp., and are relatively inexpensive. If contamination with a gram-negative organism is expected, a fluoroquinolone antibiotic such as enrofloxacin (Baytril, 5 to 10 mg/kg SC q24h) or a penicillinderivative such as imipenem (Primaxin, 5 to 10 mg/kg IV q6-8h) may be added. Anaerobic infections are more common than previously thought, and clindamycin (Antirobe, 5 to 10 mg/kg PO q12h) or metronidazole (Flagyl, 25 to 40 mg/kg PO q12h) should be considered in addition to first-generation cephalosporins in animals with severely necrotic, avascular wounds. The initial choice of antibiotic is altered when culture and sensitivity test results become available. In type I and II open fractures that are not infected, antibiotic use can be discontinued immediately after fracture repair. In any type III open fracture or in type I or II open fractures that are infected, more prolonged use is indicated. In general, antibiotic therapy is continued for about 1 month in these cases. Antibiotics can be discontinued at that time if there is no clinical or radiographic evidence of infection. Recognition of pain is difficult in dogs and cats because even animals with severe pain may show no overt clinical signs. Open fractures are associated with extensive pain and anxiety in humans, and a similar situation is expected in animals. Pain should be treated with narcotic analgesics (see Chapter 12). Buprenorphine (Buprenex, 0.01 to 0.02 mg/kg IV or IM q6-8h), hydromorphone (Dilaudid, 0.05 to 0.2 mg/kg IV, IM, or SC q2-6h), methadone (Methadone hydrochloride, 0.1 to 0.3 mg/kg IV, IM, or SC q2-6h), and fentanyl (Sublimaze, 2 to 10 µg/kg/hr constant rate infusion [CRI] for dogs; 1 to 3 µg/kg/hr for cats CRI) all provide good analgesia, although fentanyl may be best for severe pain. A dermal fentanyl patch may be an adjunct for providing longer-term analgesia but should not be used in animals with poor peripheral perfusion because absorption will be unreliable. Fentanyl patches should also not contact heating pads because absorption may be increased to a level causing toxicity.

Surgical Débridement Patients with open fractures frequently require long hospitalization, multiple surgical procedures, and expensive medications; thus, before initiating definitive wound management and fracture repair, owners should be informed of the potential prognosis and cost. It is essential that the veterinarian communicate treatment options and prognosis in a manner that allows clients to understand the situation and then make rational, realistic decisions for themselves and their pets. An estimate in writing of the anticipated expense and treatment should be provided. Limb amputation may be a necessary alternative in some cases. Definitive surgical débridement of the open fracture wound should be performed as soon as safely possible, preferably within 6 to 8 hours after injury. This period is considered the golden period in which the wound is contaminated but bacteria have not had the opportunity to multiply and spread through adjacent tissues. If the patient is not yet stable enough for

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anesthesia, initial débridement can be attempted with a local anesthetic or a regional anesthesia technique such as an epidural. Neuroleptanalgesia also can be considered. Surgical preparation and removal of gross debris may be performed in the surgical preparation area, but definitive débridement is performed in the operating room. Most orthopedic infections originate from hospital organisms; thus strict aseptic technique is important. Sterile water-soluble gel can be placed in the wound to avoid contamination with hair while clipping. A waterimpermeable barrier is placed between the limb and the rest of the body and surgery table during débridement to prevent wicking of contaminated fluids from the environment into the operative field. The goal of surgical débridement is to convert a contaminated wound to a clean one. All foreign material and contaminated or dead tissue are removed, but undermining wound edges and extensive soft tissue dissection are avoided. Sharp dissection technique is preferred. Dependable features for predicting viability of muscle are ability to bleed, consistency, and contractility. Although commonly used, color is actually a relatively poor criterion because it depends greatly on the available light. If viability is questionable, it is better to leave tissue in place and remove it if necessary during a second procedure. As a guideline for débriding bone, if the bone has no softtissue attachment and is not critical for reconstruction of the fracture, it is excised. Bone that has no soft-tissue attachment but is critical for fracture reconstruction should be saved. Any bone that has good soft-tissue attachment is saved in the fracture site. Wounds are irrigated with liters of isotonic saline. Tap water has been used for wound irrigation but is not recommended because its hypotonicity may potentiate cellular damage. There is no evidence for incorporation of antibiotics, antiseptics, or reducing agents into lavage fluids in dogs and cats. In fact, each of these additives probably delays wound healing by inhibiting cellular proliferation. Various irrigation devices have been recommended, including professionally manufactured pulsating irrigation delivery systems, 35-ml syringes with 18-gauge needles, saline bottles with needle holes drilled in the cap, bulb syringes, and spray bottles. The target pressure for wound lavage is 6 to 8 psi, and this pressure is reproducibly accomplished by flushing with fluid from a 1-liter bag pressurized to 300 mm Hg with a cuff. Fluid is administered through a drip set attached to a 16- to 22-gauge needle. Too great a pressure with any method is generally indicated by the production of fluid bubbles in the local areolar tissue. Bullets retrieved from gunshot fracture wounds should be saved because of the potential for future litigation. A deep wound culture is obtained at the end rather than the beginning of surgery because this has been shown to correlate better with later infection.

Fracture Repair Fracture fixation is performed as soon as safely possible, preferably during the initial wound débridement. If immediate fixation is planned, the operative field, the equipment, and the surgeon’s gown and gloves should

86

SECTION  I  Critical Care

all be changed after the wound débridement. Rigid stabilization of the fracture increases patient comfort, improves blood supply to the tissues, facilitates wound healing, and promotes resistance to infection. A number of techniques can be used for fracture repair. In general, after surgical débridement type I open fractures can be treated in the same manner as a closed fracture. Higher-grade open fractures require special consideration when planning repair. External coaptation with splints and casts is rarely appropriate since wound care is difficult and stabilization is generally inadequate. Use of intramedullary pins is avoided if possible because they impede medullary circulation, may spread bacteria through the medullary cavity, and when used alone do not provide rigid stabilization. Bone screw and plate fixation can be used, but placement of a large metallic foreign body at the fracture site is a disadvantage. Implants potentiate bacterial proliferation because the surfaces become covered with glycolipid, which allows Staphylococcus spp. and other gram-positive organisms to adhere. The extensive open surgical approach required for bone plating also further compromises vascularity. Despite these limitations, rigid fixation with a bone plate and screws is generally acceptable and usually results in uncomplicated healing. External skeletal fixation is often the technique of choice because fixation pins can be placed away from damaged tissue and rigid stabilization is possible. External skeletal fixation is economical, is readily available, and does not require specialized equipment. The wound can be visualized and treated as needed. The Ilizarov ring external skeletal fixator may be particularly useful in these patients because very small fixation pins under tension are used. Autogenous cancellous bone grafts are indicated in many open fractures, since cortical defects are common and these fractures may heal slowly because of vascular and soft-tissue damage. Transplanted cancellous bone facilitates bone healing by means of osteoconductive, osteoinductive, and osteogenic properties. Cancellous bone grafts rarely become infected, and when they do they undergo harmless liquefactive necrosis. The graft

should be collected with a separate set of equipment and gloves to avoid contamination of the graft site. Alternately a combination of cancellous allograft and demineralized bone matrix providing osteoconductive and osteoinductive properties can be obtained commercially (Osteo-Allograft Mix). In severely avascular wounds bone grafting should be delayed 1 to 2 weeks to allow sufficient proliferation of granulation tissue to provide vascular support for the graft. If delayed grafting is performed, the incision should be through previously undamaged tissue if possible. Although cortical allografts have been used successfully in open fractures, they are not recommended because the risk of sequestration and resorption is high. Autogenous vascular bone grafts transplanted by microsurgery may prove beneficial in the future.

Wound Closure Wound closure can be performed if débridement results in a surgically clean wound with adequate vascularity that can be closed without tension. Dead space drainage should be accomplished with aseptically placed closed suction drains. In general, more severe type II and all type III open fractures should be handled as open wounds with delayed primary or secondary closure. If there is any doubt, it is always better to leave the wound open.

References and Suggested Reading Egger EL: Emergency treatment of musculoskeletal trauma. In Bright RM, editor: Surgical emergencies, New York, 1986, Churchill Livingstone, p 175. Grant GR, Olds RB: Treatment of open fractures. In Slatter D, editor: Textbook of small animal surgery, Philadelphia, 2003, Saunders, p 1793. Gustilo RB, Anderson JT: Prevention of infection in the treatment of 1,025 open fractures of long bones: retrospective and prospective analyses, J Bone Joint Surg 58:453-458, 1976. Piermattei DL, Flo GL, DeCamp CE: Open fractures. In Piermattei DL, Flo GL, DeCamp CE, editors: Small animal orthopedics and fracture repair, Philadelphia, 2006, Saunders, p 145. Seligson DS, Henry SL: Treatment of compound fractures, Am J Surg 161:696-701, 1991.

CHAPTER 

19 

Emergency Wound Management and VacuumAssisted Wound Closure STACY D. MEOLA, Wheat Ridge, Colorado JASON WHEELER, Charlottesville, Virginia

A

variety of wounds are seen during emergency practice. Many wounds in small animal practice are traumatic in origin, such as lacerations, bite wounds, open fractures, degloving injuries, and those resulting from automobile accidents and penetrating/ projectile objects. Additionally, envenomations, burns, and surgical dehiscence are commonly encountered. The mechanism of injury, the time from injury, and the level of wound contamination are all crucial management factors. Patient characteristics including age, obesity, nutritional status, serum albumin, and concurrent diseases such as hyperadrenocorticism, diabetes mellitus, and neoplasia also affect wound healing. The so-called golden period is the time from injury to development of infection with 105 organisms/gram of tissue. This time period, which on average lasts 6 hours, provides the best opportunities for wound management and closure. Wound healing begins immediately after injury and occurs in four phases. The first phase, the inflammatory phase, lasts up to 5 days and begins with hemostasis and the release of cytokines and inflammatory mediators to initiate migration of neutrophils toward the wound. The second phase is débridement of the wound by neutrophils and monocytes that mature to macrophages. Macrophages and neutrophils clean the wound bed of debris, bacteria, foreign material, and necrotic tissue. Débridement lasts for 3 to 5 days and sets up the wound bed for repair. The repair phase usually begins 3 to 5 days after the initial injury and lasts up to several weeks. During the repair phase angiogenesis, fibroplasia, and collagen synthesis set up the meshwork for epithelialization of the wound. The final phase, maturation of the wound, may last for years as connective tissue and collagen fibers remodel to increase wound strength.

Initial Assessment and Treatment Severe wounds are commonly seen in association with multiple traumatic injuries. The wounds are often im­­ pressive and can distract the clinician from more lifethreatening concurrent injuries. While the patient’s life-threatening injuries are addressed, the wound should be covered or bandaged for basic stabilization and to prevent further contamination by nosocomial organisms.

The wound can be evaluated, cleaned, and definitively managed at a later time.

Initial Patient Management The patient’s cardiovascular status should be fully stabilized with fluid therapy (see Chapters 1 and 2) and analgesic drugs such as pure mu opioid agonists administered (see Chapter 12) prior to addressing the wound. The wound should be covered with a sterile towel or sterile lubricating gel to prevent fur from contaminating the wound during clipping. The wound should be clipped with wide margins of 3 to 5 cm to allow for bandages or closure and to fully assess the wound’s margins. Once the wound has been adequately clipped of fur it should be flushed to reduce contamination and facilitate evaluation. A 1-L fluid bag placed into a pressure cuff inflated to 300 mm Hg, attached to a 16-gauge needle provides ideal pressure of 7 to 8 psi with which to flush the wound without causing further tissue damage and bacterial contamination (Gall and Monnet, 2010).

Wound Evaluation and Flushing Wounds should be fully evaluated before establishing a plan for repair. Extremities with wounds should be checked for distal pulses and sensation. Wounds with skin flaps should be evaluated for adequate blood supply, recalling that most arteries flow from rostral to caudal and proximal to distal. Accordingly, inverted V-shaped skin flaps with the narrow tip rostral or proximal may not heal properly. Crushing injuries, including bite wounds, may have an area of devitalized tissue beneath the wound surface and a compromised vascular supply that is inapparent initially. On average, tissue takes 24 to 72 hours to “declare itself.” Unfortunately, it is often very difficult to predict which tissues will become necrotic. Finally, wounds should be evaluated for joint or bone involvement or for penetration into cavities such as the thorax and abdomen. Prior to closure and after flushing, the wound should be cultured to ensure appropriate antibiotic coverage. Radiographs should be taken of any extremity wound or if communication with the pleural or peritoneal spaces is suspected. A contrast fistulagram study of the wound tract 87

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SECTION  I  Critical Care

can be performed using an ionic (diluted 1 : 1 with saline) or nonionic contrast agent to determine the extent of the wound or penetration into the thorax or abdomen.

Wound Closure There are four categories of wound closure: primary closure, delayed primary closure, secondary closure, and second-intention healing. Primary closure occurs within 24 hours of injury. Delayed primary closure occurs within 3 to 5 days of injury but before the development of granulation tissue. Secondary closure commences once granulation tissue is present, approximately 5 days after the injury. Second-intention healing occurs when the wound is left open to heal from the inside out; this takes much longer than primary or delayed primary closure.

Vacuum-Assisted Wound Closure Primary closure of a wound may not be possible for a number of reasons including loss of tissue, wound size, location of the injury, severe contamination, or concern for further devitalization of the wound edges. A variety of wound bandages are available for these situations. Commonly used débriding wound bandages include wetto-dry, dry-to-dry, sugar or honey, and vacuum-assisted wound closure (VAC) bandages. This last type of bandage is discussed in more detail in the next section.

Clinical Advantages of VAC Bandages VAC wound closure bandage therapy has been adapted successfully from the treatment of acute and chronic nonhealing wounds in humans. Early swine models (Morykwas et al, 1997) showed a 63% increase in granulation tissue with continuous suction and a 103% increase with intermittent suction over standard wet-to-dry bandages. In this study, bacterial clearance of the wounds occurred at day 4 with the VAC bandage, whereas greater than 106 organisms/gram were isolated at day 7 in controls. When VAC bandages were applied to humans with chronic nonhealing wounds, closure and a favorable outcome occurred in 171 of 175 patients (Agenta and Morykwas, 1997). VAC bandages are indicated in large contaminated wounds, burns, chronic open wounds, surgically dehisced wounds, and skin flaps and grafts, as well as to improve mesh graft survival. They can also be used in the treatment of septic peritonitis, but discussion of this is beyond the scope of this textbook (see Web Chapter 2). VAC bandages apply subatmospheric pressure to the tissue bed, decreasing interstitial fluid, tissue edema, and bacterial contamination. At the same time increases are observed in vascular supply, granulation tissue formation, epithelial cell migration, and cell mitosis. Recently the reduction of bacterial load with VAC therapy has been questioned; however, bacteria cultured from wounds in recent studies did not appear to hinder the formation of healthy granulation tissue. Despite higher aerobic bacterial load in wounds treated with VAC therapy, granulation tissue developed sooner (3 days) compared with wounds treated with standard dressings (Demaria et al, 2011). None of the wounds demonstrated signs of clinical

BOX 19-1  VAC Supplies 1. 2. 3. 4. 5. 6. 7. 8. 9. 10.

Open cell polyurethane foam (pore size 400-600 µm) Red rubber tubing Skin staples Suture Adhesive spray Stoma paste Occlusive dressing (such as Ioban) Suction tubing Suction canister Suction pump or wall suction

infection, which supports the theory that healthy granulation tissue does not develop in infected wounds and is a marker of wound health. Suction can be applied to the wound in a continuous or intermittent fashion. The advantage of continuous suction is that it requires less specialized equipment and is less painful. The advantage of intermittent suction is increased wound healing. Intermittent suctioning is cycled as 5 minutes on and 2 minutes off. The ideal suction pressure that increases blood flow to a wound is −125 mm Hg. To reduce seroma formation in surgically closed wounds, suction pressure is −50 mm Hg.

Application VAC bandage kits are commercially available (KCI Animal Health, San Antonio, TX); however, less expensive bandages can be made from routine supplies in a veterinary hospital (Box 19-1). Patients should be fully anesthetized for the initial placement of a VAC bandage. The wound should be clipped with wide margins and flushed. All grossly necrotic tissue should be débrided. Key steps in VAC bandage application include the following: 1. Sterile open cell foam is cut to conform to, then packed into, the wound (Figure 19-1, A); multiple pieces of foam can be used as long as they are touching or overlapping (Figure 19-1, B). 2. The egress tubing is fenestrated for additional openings and is tunneled into the foam or placed between two layers of foam; this tubing never should be placed on the wound itself. 3. The egress tube is sutured into place using a fingertrap suture pattern. 4. The foam is stapled to the edges of the wound to keep the foam in place. 5. A thin rim of stoma paste is applied approximately 2 cm from the entire circumference of the wound and the egress tube (Figure 19-1, C). 6. The foam and wound edges are sprayed with an adhesive. 7. The suction tubing is connected to the egress tubing and suction is applied before the application of the adhesive dressing to allow the foam to contract the

CHAPTER  19  Emergency Wound Management and Vacuum-Assisted Wound Closure

A

B

C

D

89

Figure 19-1  Application of a VAC bandage. A, The sterile open cell foam is packed into the

wound. B, Additional pieces of foam are added to fill the wound bed. C, The egress tubing is placed between the foam layers and secured. The foam is stapled to the wound edges and stoma paste is applied around the wound edges and the egress tube. D, The adhesive dressing is placed over the foam and suction is applied, giving the raisin appearance.

wound as the adhesive dressing adheres to the skin edges. 8. Sufficient suction has been applied when the foam is shriveled and looks like a “raisin” (Figure 19-1, D). If the wound is on an extremity, the VAC bandage can be covered lightly with a soft padded bandage to protect the adhesive dressing. A small window should be cut in the bandage to allow an area to view the VAC bandage to ensure suction is still applied. VAC bandages should be changed every 2 to 3 days. A VAC bandage left on for longer than 5 days can cause growth of granulation tissue into the foam, requiring surgical extraction of the foam from the wound. VAC bandages may be changed under general anesthesia or heavy sedation. It is common in the authors’ practice to attempt primary closure after 3 days of VAC therapy; however, this is largely case dependent.

Managing and Troubleshooting VAC Bandages VAC bandages require 24-hour hospitalization and monitoring by a trained staff. If suction is lost for long periods,

the wound becomes macerated and granulation tissue growth stops. The VAC bandage should be checked hourly for the raisin appearance. The suction tubing can be clamped with a large Carmalt forceps and disconnected to allow for walking the patient or administering other treatments that require disconnection from the suction apparatus. The most common sites of bandage leakage are at the egress tubing, at skin folds, in regions of high motion, and in tears to the adhesive film. Most leaks can be repaired by reapplying a second adhesive film on top of the first film and reapplying stoma paste around the egress tubing.

Cautions and Contraindications VAC bandages never should be placed on a distal extremity in a 360-degree fashion with the digits or the distal paw exposed. This type of VAC bandage placement will function as a tourniquet. If a wound is present on an extremity and is not small enough to place within a localized, noncircumferential VAC bandage, the distal extremity including the digits should be covered in foam and

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SECTION  I  Critical Care

incorporated into the bandage. The VAC bandage will not harm the intact or uninjured tissue distal to the wound. VAC bandages are contraindicated in a number of situations including: (1) dirty wounds that have not been débrided, (2) wounds that are actively bleeding or complicated by a coagulopathy, (3) wounds with untreated osteomyelitis, or (4) wounds contaminated with neoplastic cells. VAC bandages should not be placed over large blood vessels where the foam could erode through the vessel and lead to rapid exsanguination.

Complications Few complications occur when VAC bandages are applied correctly. Pain is the most commonly reported complication, but is decreased with the use of continuous suction. Analgesia in the form of nonsteroidal antiinflammatory drugs (NSAIDs) or opioids is administered as needed for concurrent injuries or for the VAC therapy itself. The most common complication observed by the authors is mild local dermatitis at the site of the stoma paste. If the paste is allowed to fall off with time, less irritation occurs. Adhesion of the foam to the wound bed can be decreased

by ensuring proper intervals between bandage changes. Mild bleeding is also possible. Two cases of toxic shock have been reported in humans; however, to the authors’ knowledge no cases have been reported in veterinary patients.

References and Suggested Reading Argenta LC, Morykwas MJ: Vacuum-assisted closure: a new method for wound control and treatment: clinical experience, Ann Plast Surg 38(6):563-577, 1997. Demaria M et al: Effects of negative pressure wound therapy on healing open wounds in dogs, Vet Surg 40(6):658-669, 2011. Gall TT, Monnet E: Evaluation of fluid pressures of common wound-flushing techniques, Am J Vet Res 71(11):1384-1386, 2010. Kirkby KA et al: Vacuum-assisted wound closure: application and mechanism of action, Compend Contin Educ Vet 31(12):E1-E7, 2009. Kirkby KA et al: Vacuum-assisted wound closure: clinical applications, Compend Contin Educ Vet 32(3):E1-E7, 2010. Morykwas MJ et al: Vacuum-assisted closure: a new method for wound control and treatment: animal studies and basic foundation, Ann Plast Surg 38(6):553-562, 1997.

WEB CHAPTER 

1 

Acid-Base Disorders HELIO AUTRAN DE MORAIS, Corvallis, Oregon STEPHEN P. DIBARTOLA, Columbus, Ohio

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cid-base disorders are often encountered in critical care and outpatient settings in association with several conditions. A clear understanding of metabolic-respiratory interactions and a systematic approach aimed at identifying the separate components of acidbase disorders not only serve as diagnostic tools, but also help in formulating therapeutic interventions. For example, abnormal acid-base balance may be harmful in part because of the patient’s response to the abnormality, as when a spontaneously breathing patient with metabolic acidosis attempts to compensate by increasing minute ventilation. Such a response may lead to respiratory muscle fatigue, with respiratory failure or diversion of blood flow from vital organs to the respiratory muscles, and eventually result in organ injury. Thus it is important to understand both the causes of acid-base disorders and the limitations of various treatment strategies. Blood pH and bicarbonate concentration can change secondary to alterations in carbon dioxide tension (PCO2), strong ion difference (SID), or total plasma concentration of nonvolatile weak buffers (Atot). Respiratory acid-base disorders occur whenever there is a primary change in PCO2, whereas metabolic acid-base disorders occur whenever SID or Atot are changing primarily. Changes in SID or Atot can be identified clinically by alterations in HCO3− concentration or base excess (BE). The SID is the difference between all strong cations and all strong anions. Strong ions are fully dissociated at physiologic pH and therefore exert no buffering effect. However, strong ions do exert an electrical effect because the sum of completely dissociated cations does not equal the sum of completely dissociated anions. Because strong ions do not participate in chemical reactions in plasma at physiologic pH, they act as a collective positive unit of charge, the SID. The quantitatively most important strong ions in plasma are Na+, K+, Ca2+, Mg2+, Cl−, lactate, β-hydroxybutyrate, acetoacetate, and SO2− 4 . The influence of strong ions on pH and HCO3− concentration can always be summarized in terms of the SID. Changes in SID of a magnitude capable of altering acid-base balance usually occur as a result of increasing concentrations of Na+, Cl−, SO24 − , or organic anions or decreasing concentrations of Na+ or Cl−. An increase in SID (by decreasing Cl− or increasing Na+) causes a strong ion (metabolic) alkalosis, whereas a decrease in SID (by decreasing Na+ or increasing Cl−, SO24 − , or organic anions) causes a strong ion (metabolic) acidosis. The main nonvolatile plasma buffers that constitute Atot act as weak acids at physiologic pH (e.g., phosphate, imidazole [histidine] groups on plasma proteins). An increase in the total concentration of phosphate leads to

Atot (metabolic) acidosis, whereas a decrease in albumin concentration causes Atot (metabolic) alkalosis.

Stepwise Approach A routine methodical approach to interpretation of blood gas data facilitates the clinician’s approach to the patient. The first step is a careful history to search for clues that may lead the clinician to suspect the presence of acid-base disorders, followed by a complete physical examination.

Obtain Simultaneous Blood Gas Measurement and Chemistry Profile Blood pH can vary due to changes in PCO2, SID, and weak and strong acid concentrations. Some strong ions (Na+, Cl–, and K+) and the most important weak acids (albumin and inorganic phosphates) are part of the chemistry pro­ file and will help in understanding why pH is changing.

Identify the Primary Disturbance The clinician should first consider the patient’s blood pH. The primary disturbance (respiratory or metabolic) can be identified by determining if PCO2 or HCO3− is changing in the same direction that pH changed. There are four classic primary acid-base disorders: respiratory alkalosis, respiratory acidosis, metabolic alkalosis, and metabolic acidosis. Metabolic acid-base disorders can be further divided based on changes in SID or Atot.

Calculate the Expected Compensation Any alteration in acid-base equilibrium sets into motion a compensatory response by either the lungs or the kidneys. The compensatory response attempts to return the ratio between PCO2 and HCO3− to normal and thereby minimize the pH change. A primary increase or decrease in one component is associated with a predictable compensatory change in the same direction in the other component (Web Table 1-1). Adaptive changes in plasma HCO3− in respiratory disorders occur in two phases: acute and chronic. In respiratory acidosis, the first phase represents titration of nonbicarbonate buffers, whereas in respiratory alkalosis, the first phase represents release of H+ from nonbicarbonate buffers within cells. This response is completed within 15 minutes. The second phase reflects renal adaptation and consists of increased net acid excretion and increased HCO3− reabsorption (decreased Cl− reabsorption) in respiratory acidosis and e1

e2

SECTION  I  Critical Care

WEB TABLE 1-1 

WEB BOX 1-1 

Compensatory Response in Simple Acid-Base Disturbances in Dogs and Cats CLINICAL GUIDE FOR COMPENSATION

Guidelines for Adequate Use of Compensatory Rules from Web Table 1-1

Disturbance

Dogs

Cats

Metabolic acidosis

↓ in PCO2 = 0.7 ×↓ in HCO3−

PCO2 does not change

Metabolic alkalosis

↑ in PCO2 = 0.7 ×↑ in HCO3−

↑ in PCO2 = 0.7 ×↑ in HCO3−

Time Sufficient time must elapse for compensation to reach  a steady state: Acute respiratory disorders: 15 minutes Chronic respiratory disorders: 7 days Long-standing respiratory acidosis: 30 days Metabolic disorders: 24 hours pH • Compensation does not return the pH to normal* • Overcompensation does not occur

Respiratory Acidosis Acute

↑ in HCO3− = 0.15 ×↑ in PCO2

↑ in HCO3− = 0.15 ×↑ in PCO2

Chronic

↑ in HCO3− = 0.35 ×↑ in PCO2

Unknown

Longstanding (>30 days)

↑ in HCO3− = 0.55 ×↑ in PCO2

Unknown

Respiratory Alkalosis Acute

↓ in HCO3− = 0.25 ×↓ in PCO2

↓ in HCO3− = 0.25 ×↓ in PCO2

Chronic

↓ in HCO3− = 0.55 ×↓ in PCO2

Similar to dogs

Modified from de Morais HSA, DiBartola SP: Ventilatory and metabolic compensation in dogs with acid-base disorders, J Vet Emerg Crit Care 1(2):39, 1991; and de Morais HSA, Leisewitz A: Mixed acid-base disorders. In DiBartola SP, editor: Fluid, electrolyte, and acid-base disorders, ed 3, Philadelphia, 2006, Elsevier, p 296.

decreased net acid excretion in respiratory alkalosis. Adaptive respiratory response to metabolic disorders begins immediately and is complete within hours. Some guidelines for use of compensatory rules from Web Table 1-1 are presented in Web Box 1-1. The definition of a simple acid-base disturbance includes both the primary process causing changes in PCO2 or HCO3− and the compensatory mechanisms af­­ fecting these measurements. Lack of appropriate com­ pensation is evidence of a mixed acid-base disorder. Compensation is said to be inappropriate if a patient’s PCO2 differs from expected PCO2 by more than 2 mm Hg in a primary metabolic process or if a patient’s HCO3− differs from the expected HCO3− by more than 2 mEq/L in a respiratory acid-base disorder.

Calculate Gaps and Gradients Calculating the various gaps and gradients can be useful in evaluation of acid-base disorders (Web Box 1-2). Strong Ion Gap and Anion Gap Increases in the anion gap (AG) and strong ion gap (SIG) are associated with increases in concentration of unmeasured anions, both strong (e.g., lactate, acetoacetate, β-hydroxybutyrate, strong anions of renal failure) and weak (e.g., phosphate). The AG also is used to

Values in the expected compensatory range • Do not prove that there is only one disturbance • Provide support for a simple acid-base disturbance, if consistent with the remaining clinical data From de Morais HSA, Leisewitz A: Mixed acid-base disorders. In DiBartola SP, editor: Fluid, electrolyte, and acid-base disorders, ed 3, Philadelphia, 2006, Elsevier, p 296. *Exceptions: Chronic respiratory alkalosis (>14 days), and potentially long-standing respiratory acidosis (>30 days).

differentiate between hyperchloremic (normal AG) and high-AG metabolic acidoses. The AG in normal dogs and cats is mostly a result of the net negative charge of proteins and thus is heavily influenced by protein concentration, especially albumin. At plasma pH of 7.4 in dogs, each decrease of 1 g/dl in albumin concentration is associated with a decrease of 4.1 mEq/L in the AG (Constable and Stämpfli, 2005). The SIG is not affected by changes in albumin concentration, and an increase in unmeasured strong anions is suspected whenever SIG is less than −5 mEq/L. The SIG has not been clinically tested in dogs and cats, but its derivation is sound, and it is superior to the AG for detecting increases in unmeasured strong anions in other species. Chloride Gap Chloride is the most important extracellular strong anion. Increases in chloride lead to metabolic acidosis by decreasing SID, whereas decreases in chloride cause metabolic alkalosis by increasing SID. Therefore plasma Cl− and HCO3− have a tendency to change in opposite directions in hypochloremic alkalosis and hyperchloremic acidosis. The contribution of Cl− to changes in BE and HCO3− can be estimated by calculating the chloride gap (see Web Box 2-2). Chloride gap values greater than 4 mEq/L are associated with hypochloremic alkalosis, whereas values less than −4 mEq/L are associated with hyperchloremic acidosis. Whenever sodium concentration is normal, the difference between the sodium and chloride concentrations ([Na+] − [Cl−]) can be used. Normally, [Na+] − [Cl−] is approximately 36 mEq/L in dogs and cats. Values greater than 40 mEq/L are an indication of hypochloremic alkalosis, whereas values less than 32 mEq/L are associated with hyperchloremic acidosis.

WEB CHAPTER  1  Acid-Base Disorders

e3

WEB BOX 1-2  Gaps and Gradients in Acid-Base Disorders Estimation of Unmeasured Anions During Metabolic Acidosis Anion Gap (AG) AG = (Na+ + K+) – ( HCO3− + Cl–)

Sodium-Chloride Difference Na – Cl = [Na+] – [Cl–] Only valid if [Na+] is normal

Strong Ion Gap (SIG) SIG = [albumin] × 4.9 – AG (for dogs) SIG = [albumin] × 4.58 – AG + 9 (for cats)

Interpretation Increased in • Hypochloremic alkalosis Normal in • Hypoalbuminemic alkalosis Decreased in • Hyperchloremic acidosis

Interpretation Increased in • Acidosis caused by addition of unmeasured anions (lactic acidosis, ketoacidosis, renal failure, poisonings) • Hyperphosphatemia (hyperphosphatemic acidosis) Normal in • Hyperchloremic acidosis Decreased in • Hypoalbuminemia (hypoalbuminemic alkalosis) • SIG is not affected by changes in albumin   concentration Estimation of Severity of Strong Ion Difference Alkalosis and Acidosis Caused by Chloride Changes Chloride Gap [Cl–]gap = 110 – [Cl–] × 146 / [Na+] (for dogs) [Cl–]gap = 120 – [Cl–] × 156 / [Na+] (for cats)

Alveolar-Arterial Oxygen Gradient Frequently, patients with respiratory acidosis or alkalosis also are hypoxemic. When determining management options, it is important to differentiate between hypoxia from primary lung disease (e.g., ventilation-perfusion mismatching) and alveolar hypoventilation by calculating the alveolar-arterial oxygen gradient, or (A – a) O2 gradient. Values less than 15 mm Hg generally are considered normal. If the (A − a) O2 gradient is increased, a component of the hypoxemia results from ventilationperfusion mismatching, although it may be increased in some patients with extrapulmonary disorders. Clinically, a normal gradient excludes pulmonary disease and suggests some form of central alveolar hypoventilation or an abnormality of the chest wall or inspiratory muscles. To increase the specificity of the test to diagnose ventilationperfusion mismatch, only patients with (A − a) O2 gradient values of more than 25 mm Hg should be considered abnormal (Johnson and de Morais, 2012). These patients are likely to have primary pulmonary disease, but extrapulmonary disorders cannot be completely ruled out.

Respiratory Acid-Base Disorders Disorders of PCO2 Respiratory acid-base disorders are those abnormalities in acid-base equilibrium initiated by a change in PCO2. The PCO2 is regulated by respiration: a primary increase in PCO2 acidifies body fluids and initiates the acid-base disturbance called respiratory acidosis, whereas a decrease in PCO2 alkalinizes body fluids and is known as respiratory alkalosis.

Identifying the Origin of Hypoxemia in Respiratory   Acid-Base Disorders Alveolar-Arterial Oxygen Gradient (A – a) O2 gradient = 150 – 1.25 PCO2 – PO2 Interpretation (In Hypoxemic Patients) Increased in • Pulmonary disease (e.g., ventilation-perfusion mismatch, right-to-left shunt) Normal in • Alveolar hypoventilation (e.g., central alveolar hypoventilation, abnormality in chest wall or   respiratory muscles)

Respiratory Alkalosis Respiratory alkalosis, or primary hypocapnia, is characterized by decreased PCO2, increased pH, and a compensatory decrease in HCO3− concentration in the blood. Respiratory alkalosis occurs whenever the magnitude of alveolar ventilation exceeds that required to eliminate the CO2 produced by metabolic processes in the tissues. Common causes of respiratory alkalosis include stimulation of peripheral chemoreceptors by hypoxemia, primary pulmonary disease, direct activation of the brainstem respiratory centers, overzealous mechanical ventilation, and situations that cause pain, anxiety, or fear (Web Box 1-3). It is difficult to attribute specific clinical signs to respiratory alkalosis in the dog and cat. The clinical signs usually are caused by the underlying disease process and not by the respiratory alkalosis itself. However, in humans, headache, light-headedness, confusion, paresthesias of the extremities, tightness of the chest, and numbness around the mouth have been reported in acute respiratory alkalosis. If the pH exceeds 7.6 in respiratory alkalosis, neurologic, cardiopulmonary, and metabolic consequences may arise. Such a pH only can be achieved in acute respiratory alkalosis before renal compensation ensues. Alkalemia results in arteriolar vasoconstriction that can decrease cerebral and myocardial perfusion. In addition, hyperventilation (PCO2 < 25 mm Hg) causes decreased cerebral blood flow, potentially resulting in clinical signs such as confusion and seizures. Treatment of respiratory alkalosis should be directed at relieving the underlying cause of the hypocapnia; no other treatment is effective. Respiratory alkalosis severe enough to cause clinical consequences for the animal is uncommon. Hypocapnia itself is not a major threat to the well-being

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SECTION  I  Critical Care

WEB BOX 1-3 

WEB BOX 1-4 

Principal Causes of Respiratory Alkalosis

Causes of Respiratory Acidosis

Hypoxemia (Stimulation of Peripheral Chemoreceptors by Decreased Oxygen Delivery) • Right-to-left shunting • Decreased FiO2 (e.g., high altitude) • Congestive heart failure • Severe anemia • Pulmonary diseases with ventilation-perfusion mismatch • Pneumonia • Pulmonary thromboembolism • Pulmonary fibrosis • Pulmonary edema • Acute respiratory distress syndrome

Large Airway Obstruction • Aspiration (e.g., foreign body, vomitus) • Mass (e.g., neoplasia, abscess) • Tracheal collapse • Asthma • Obstructed endotracheal tube • Brachycephalic syndrome • Laryngeal paralysis/laryngospasm

Pulmonary Disease (Stimulation of Stretch/Nociceptors Independent of Hypoxemia) • Pneumonia • Pulmonary thromboembolism • Interstitial lung disease • Pulmonary edema • Acute respiratory distress syndrome Centrally Mediated Hyperventilation • Liver disease • Hyperadrenocorticism • Gram-negative sepsis • Drugs • Corticosteroids • Central neurologic disease • Heatstroke Overzealous Mechanical Ventilation Situations Causing Pain, Fear, Anxiety Modified from Johnson RA, de Morais HSA: Respiratory acid-base disorders. In DiBartola SP, editor: Fluid, electrolyte, and acid-base disorders, ed 3, Philadelphia, 2006, Elsevier, p 283.

of the patient. Thus the underlying disease responsible for hypocapnia should receive primary therapeutic attention. Respiratory Acidosis Respiratory acidosis, or primary hypercapnia, results when carbon dioxide production exceeds elimination via the lungs. Respiratory acidosis almost always is a result of respiratory failure with resultant alveolar hypoventilation and is characterized by an increase in PCO2, decreased pH, and a compensatory increase in blood HCO3− concentration. Respiratory acidosis and hypercapnia can occur with any disease process involving the neural control of ventilation, mechanics of ventilation, or alveolar gas exchange resulting in hypoventilation, ventilation-perfusion mismatch, or both. Acute respiratory acidosis usually results from sudden and severe primary parenchymal (e.g., fulminant pulmonary edema), airway, pleural, chest wall, neurologic (e.g., spinal cord injury), or neuromuscular (e.g., botulism) disease. Chronic respiratory acidosis results in sustained hypercapnia and has many causes including alveolar hypoventilation, abnor-

Respiratory Center Depression • Drug-induced (e.g., narcotics, barbiturates, inhalant anesthesia) • Neurologic disease (e.g., brainstem or high cervical cord lesion) Increased CO2 Production with Impaired Alveolar Ventilation • Cardiopulmonary arrest • Heatstroke Neuromuscular Disease • Myasthenia gravis • Tetanus • Botulism • Polyradiculoneuritis • Tick paralysis • Drug-induced (e.g., neuromuscular blocking agents, organophosphates, aminoglycosides with anesthetics) Restrictive Extrapulmonary Disorders • Diaphragmatic hernia • Pleural space disease (e.g., pneumothorax, pleural effusion) • Chest wall trauma/flail chest Intrinsic Pulmonary and Small Airway Diseases • Acute respiratory distress syndrome • Chronic bronchitis and asthma • Severe pulmonary edema • Pulmonary thromboembolism • Pneumonia • Pulmonary fibrosis • Smoke inhalation Ineffective Mechanical Ventilation (e.g., Inadequate Minute Ventilation, Improper CO2 Removal) Modified from Johnson RA, de Morais HSA: Respiratory acid-base disorders. In DiBartola SP, editor: Fluid, electrolyte, and acid-base disorders, ed 3, Philadelphia, 2006, Elsevier, p 283.

mal respiratory drive, abnormalities of the chest wall and respiratory muscles, and increased dead space (Web Box 1-4). Most clinical signs in animals with respiratory acidosis reflect the underlying disease process responsible for hypercapnia rather than the hypercapnia itself, and subjective clinical evaluation of the patient alone is not reliable in making a diagnosis of respiratory acidosis. In fact, patients with chronic, compensated respiratory acidosis may have very mild clinical signs. Neurologic signs may develop, particularly in acute hypercapnia, and seem to

WEB CHAPTER  1  Acid-Base Disorders depend on the magnitude of hypercapnia, rapidity of change in CO2 and pH, and amount of concurrent hypoxemia. Acute hypercapnia causes cerebral vasodilation, subsequently increasing cerebral blood flow and intracranial pressure. Clinically, the effects of hypercapnia on the central nervous system (CNS) can result in signs ranging from anxiety, restlessness, and disorientation to somnolence and coma, especially when PCO2 approaches 70 to 100 mm Hg. The most effective treatment of respiratory acidosis consists of rapid diagnosis and elimination of the underlying cause of alveolar hypoventilation. For example, airway obstruction should be identified and relieved, and medications that depress ventilation should be discontinued if possible. A patient breathing room air at sea level will develop life-threatening hypoxia (PO2 < 55 to 60 mm Hg) before life-threatening hypercapnia. Thus supplemental oxygen and assisted ventilation are needed in treating acute respiratory acidosis. Although oxygen therapy may aid in the treatment of acute respiratory acidosis, oxygen may suppress the drive for breathing in patients with chronic hypercapnia. In chronic hypercapnia, the central chemoreceptors become progressively insensitive to the effects of CO2, and O2 becomes the primary stimulus for ventilation. As a result, oxygen ther­ apy may further suppress ventilation, worsening respi­ ratory acidosis. If oxygen is administered, PO2 should be kept between 60 and 65 mm Hg because the hypoxic drive to breathing remains adequate up to this level. When mechanical or assisted ventilation is begun, care must be taken to decrease PaCO2 slowly. A sudden decrease in PCO2 can result in cardiac arrhythmias, decreased cardiac output, and reduced cerebral blood flow. It can also lead to posthypercapnic metabolic alkalosis and rapid diffusion of CO2 from cerebrospinal fluid into blood, thus quickly increasing cerebrospinal pH.

e5

WEB BOX 1-5  Principal Causes of Nonvolatile Ion Buffer (Atot) Acid-Base Abnormalities Nonvolatile Ion Buffer Alkalosis (Decreased Atot) Hypoalbuminemia • Decreased production • Chronic liver disease • Acute-phase response to inflammation • Malnutrition/starvation • Extracorporeal loss • Protein-losing nephropathy • Protein-losing enteropathy • Sequestration • Inflammatory effusions • Vasculitis Nonvolatile Ion Buffer Acidosis (Increased Atot) Hyperalbuminemia • Water deprivation Hyperphosphatemia • Translocation • Tumor cell lysis • Tissue trauma or rhabdomyolysis • Increased intake • Phosphate-containing enemas • Intravenous phosphate • Decreased loss • Renal failure • Urethral obstruction • Uroabdomen From de Morais HSA, Constable PD: Strong ion approach to acid-base disorders. In DiBartola SP, editor: Fluid, electrolyte, and acid-base disorders, ed 3, Philadelphia, 2006, Elsevier, p 310.

Metabolic Acid-Base Disorders Disorders of Atot Albumin, globulins, and inorganic phosphate are nonvolatile weak acids and collectively are the major contributors to Atot. Changes in their concentrations directly change pH and HCO3− . Common causes of Atot acidosis and alkalosis are presented in Web Box 1-5. Nonvolatile Buffer Ion Alkalosis Hypoalbuminemic Alkalosis.  Hypoalbuminemic alka­ losis is common in the critical care setting. In vitro, a 1 g/ dl decrease in albumin concentration is associated with an increase in pH of 0.093 in cats and 0.047 in dogs (Constable and Stämpfli, 2005). Presence of hy­­ poalbuminemia complicates identification of increased unmeasured anions (e.g., lactate, ketoanions) because hypoproteinemia not only increases pH but also decreases AG. Thus the severity of the underlying disease leading to metabolic acidosis may be underestimated if the effects of hypoalbuminemia on pH, HCO3− , and AG are not considered. Treatment for hypoalbuminemic alkalosis should be directed at the underlying cause and the decreased colloid oncotic pressure.

Nonvolatile Buffer Ion Acidosis Hyperphosphatemic Acidosis.  Hyperphosphatemia, especially if severe, can cause a large increase in Atot, concentration leading to metabolic acidosis. The contribution of phosphate to Atot (and AG) can be estimated by multiplying the phosphate concentration in mg/dl by 0.58. Thus a phosphorus concentration of 5 mg/dl is equivalent to 2.88 mEq/L at a pH of 7.4. The most important cause of hyperphosphatemic acidosis is renal failure. Metabolic acidosis in patients with renal failure is multifactorial but mostly is caused by hyperphosphatemia and increases in unmeasured strong anions. Treatment for hyperphosphatemic acidosis should be directed at the underlying cause. Sodium bicarbonate administered intravenously shifts phosphate inside cells and may be used as adjunctive therapy in patients with severe hyperphosphatemic acidosis.

Disorders of SID Changes in SID usually are recognized by changes in HCO3− or BE from their reference values. The change in SID from normal is equivalent to the change in HCO3− or

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SECTION  I  Critical Care

WEB TABLE 1-2  Mechanisms for Strong Ion Difference Changes Disorder

Mechanism

Clinical Recognition

↓ In strong cations

↑ Free water (↓ sodium)

Dilutional acidosis

↑ In strong anions

↑ Chloride

Hyperchloremic acidosis

SID Acidosis

↑ Unmeasured strong anions

Organic acidosis

SID Alkalosis ↑ In strong cations

↓ Free water (↑ sodium)

Concentration alkalosis

↓ In strong anions

↓ Chloride

Hypochloremic alkalosis

From de Morais HSA, Constable PD: Strong ion approach to acid-base disorders. In DiBartola SP, editor: Fluid, electrolyte, and acid-base disorders, ed 3, Philadelphia, 2006, Elsevier, p 310.

WEB BOX 1-6  Principal Causes of Strong Ion Difference Alkalosis in Dogs and Cats Concentration Alkalosis (↓ in Free Water: Recognizable by ↑ Na+) • Pure water loss • Inadequate access to water (water deprivation) • Diabetes insipidus • Hypotonic fluid loss • Vomiting • Nonoliguric renal failure • Postobstructive diuresis Hypochloremic Alkalosis (↓ Cl– Corrected) • Excessive gain of sodium relative to chloride • Sodium bicarbonate administration • Excessive loss of chloride relative to sodium • Vomiting of stomach contents • Therapy with thiazides or loop diuretics From de Morais HSA, Constable PD: Strong ion approach to acid-base disorders. In DiBartola SP, editor: Fluid, electrolyte, and acid-base disorders, ed 3, Philadelphia, 2006, Elsevier, p 310.

BE from normal whenever the plasma concentrations of nonvolatile buffer ions (e.g., albumin, phosphate, globulin) are normal. A decrease in SID is associated with metabolic acidosis, whereas an increase in SID is associated with metabolic alkalosis. There are three general mechanisms by which SID can change (Web Table 1-2): (1) a change in the free water content of plasma, (2) a change in Cl−, and (3) an increase in the concentration of other strong anions. SID Alkalosis There are two general mechanisms by which SID can increase, leading to metabolic alkalosis: an increase in

Na+ or a decrease in Cl−. Strong cations other than sodium are tightly regulated, and changes of a magnitude that could affect SID clinically either are not compatible with life or do not occur. Conversely, chloride is the only strong anion present in sufficient concentration to cause an increase in SID when its concentration is decreased. Common causes of SID alkalosis are presented in Web Box 1-6. Concentration Alkalosis.  Concentration alkalosis de­­ velops whenever a deficit of water in plasma occurs and is recognized clinically by the presence of hypernatremia or hyperalbuminemia. Solely decreasing the content of water increases the plasma concentration of all strong cations and strong anions and thus increases SID. Therapy for concentration alkalosis should be directed at treating the underlying cause responsible for the change in Na+. If necessary, serum Na+ concentration and osmolality should be corrected. Hypochloremic Alkalosis.  When water content is normal, SID changes only as a result of changes in strong anions and can only increase with a decrease in Cl−. Hypochloremic alkalosis may be caused by an excessive loss of chloride relative to sodium or by administration of substances containing more sodium than chloride as compared with normal extracellular fluid composition (see Web Box 1-6). The goal of treatment of metabolic alkalosis is to replace the chloride deficit while providing sufficient potassium and sodium to replace existing deficits, thus correcting the SID. Renal Cl− conservation is enhanced in hypochloremic states, and renal Cl– reabsorption does not return to normal until plasma Cl− concentration is restored to normal or near normal. Dehydrated patients should be rehydrated accordingly. The SID can be corrected with a solution containing adequate amounts of chloride (e.g., 0.9% saline, lactated Ringer’s solution, KCl-supplemented fluids). In cases in which expansion of extracellular volume is desired, intravenous infusion of 0.9% saline is the treatment of choice. It can be difficult to treat metabolic alkalosis associated with chronic diuretic therapy (congestive heart failure) because sodium loads are poorly tolerated. Oral potassium chloride supplements can be prescribed if the gap is considerable and a lowering of diuretic dosage is not feasible. SID Acidosis Three general mechanisms can cause SID to decrease, resulting in SID acidosis: (1) a decrease in Na+, (2) an increase in Cl−, and (3) an increased concentration of other strong anions (e.g., L-lactate, β-hydroxybutyrate). Common causes of SID acidosis are presented in Web Box 1-7. Dilutional Acidosis.  Dilutional acidosis occurs whenever there is an excess of water in plasma and is recognized clinically by the presence of hyponatremia. Increasing the water content of plasma decreases the concentration of all strong cations and strong anions, and thus SID. Large increases in free water are necessary to cause an appreciable decrease in SID. It has been estimated that in dogs and cats, a decrease in serum Na+ concentration by 20 mEq/L is associated with a 5 mEq/L decrease in BE (de Morais and Leisewitz, 2012). Therapy

WEB CHAPTER  1  Acid-Base Disorders

WEB BOX 1-7 

WEB BOX 1-8 

Principal Causes of Strong Ion Difference Acidosis in Dogs and Cats

Common Causes of Metabolic Acidosis in Critically Ill Patients

Dilution Acidosis (↑ in Free Water: Recognizable by ↓ [Na+]) • With hypervolemia (gain of hypotonic fluid) • Severe liver disease • Congestive heart failure • Nephrotic syndrome • With normovolemia (gain of water) • Psychogenic polydipsia • Hypotonic fluid infusion • With hypovolemia (loss of hypertonic fluid) • Vomiting • Diarrhea • Hypoadrenocorticism • Third-space loss • Diuretic administration

Preexisting Disease Process Hyperphosphatemic acidosis Renal failure Hyperchloremic acidosis Renal tubular acidosis Renal failure Diarrhea High AG acidosis Diabetes mellitus Renal failure

Hyperchloremic Acidosis (↑ [Cl–] Corrected) • Excessive loss of sodium relative to chloride • Diarrhea • Excessive gain of chloride relative to sodium • Fluid therapy (e.g., 0.9% saline, 7.2% saline, KClsupplemented fluids) • Total parenteral nutrition • Chloride retention • Renal failure • Hypoadrenocorticism Organic Acidosis (↑ Unmeasured Strong Anions) • Uremic acidosis • Diabetic ketoacidosis • Lactic acidosis • Toxicities • Ethylene glycol • Salicylate From de Morais HSA, Constable PD: Strong ion approach to acid-base disorders. In DiBartola SP, editor: Fluid, electrolyte, and acid-base disorders, ed 3, Philadelphia, 2006, Elsevier, p 310.

for dilutional acidosis should be directed at the underlying cause of the change in Na+. If necessary, serum Na+ concentration and osmolality should be corrected. Hyperchloremic Acidosis.  Increases in [Cl−] can de­­ crease SID substantially, leading to so-called hyperchloremic acidosis. Hyperchloremic acidosis may be caused by chloride retention (e.g., early renal failure, renal tubular acidosis), excessive loss of sodium relative to chloride (e.g., diarrhea), or administration of substances con­ taining more chloride than sodium as compared with normal extracellular fluid composition (e.g., administration of KCl, 0.9% saline). Treatment of hyperchloremic acidosis should be directed at correction of the underlying disease process. Special attention should be given to plasma pH. Bicarbonate therapy can be instituted whenever plasma pH is less than 7.2. Organic Acidosis.  Accumulation of metabolically produced organic anions (e.g., L-lactate, acetoacetate, citrate, β-hydroxybutyrate) or addition of exogenous organic anions (e.g., salicylate, glycolate from ethylene glycol

e7

Labile Feature of an Evolving Process Hyperphosphatemic acidosis Phosphate-containing enemas Acute renal failure Hyperchloremic acidosis Diarrhea Postcorrection of chronic respiratory alkalosis High AG acidosis Diabetic ketoacidosis Uremic acidosis Lactic acidosis Toxicities (e.g., ethylene glycol, salicylates) Iatrogenic Hyperphosphatemic acidosis IV phosphate administration Hyperchloremic acidosis 0.9% Saline administration KCl administration Total parenteral nutrition High AG acidosis Propylene glycol as drug vehicle (e.g., nitroglycerin, diazepam) Gelatin administration (increases anion gap without causing acidosis) From de Morais HA, Bach JF, DiBartola SP: Metabolic acid-base disorders in the critical care unit, Vet Clin North Am 38(3):559-576, 2008.

poisoning, formate from methanol poisoning) will cause metabolic acidosis because these strong anions decrease SID. Accumulation of some inorganic strong anions (e.g., SO24 − in renal failure) will resemble organic acidosis because these substances decrease SID. The most frequently encountered causes of organic acidosis in dogs and cats are renal failure (uremic acidosis), diabetic ketoacidosis, lactic acidosis, and ethylene glycol toxicity. Management of organic acidosis should be directed at stabilization of the patient and treatment of the primary disorder. Patients with severe acidosis (pH < 7.1) and renal failure may benefit from small, titrated doses of NaHCO3. The efficacy of NaHCO3 therapy in renal failure partly is related to the shift of phosphate inside the cell, with consequent amelioration of the hyperphosphatemic acidosis. Sodium bicarbonate should be used cautiously because metabolism of accumulated organic anions will normalize SID and increase HCO3− . Treatment of lactic

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SECTION  I  Critical Care

WEB BOX 1-9  Common Causes of Metabolic Alkalosis in Critically Ill Patients Preexisting Disease Process Hypoalbuminemic alkalosis Liver failure Protein-losing enteropathy Protein-losing nephropathy Hypochloremic alkalosis Diuretic therapy Vomiting of stomach contents Labile Feature of an Evolving Process Hypoalbuminemic alkalosis Vasculitis Third space losses Hypochloremic alkalosis Vomiting of stomach contents Postcorrection of chronic respiratory acidosis Iatrogenic Hypochloremic alkalosis Bicarbonate administration Diuretic therapy Stomach draining From de Morais HA, Bach JF, DiBartola SP: Metabolic acid-base disorders in the critical care unit, Vet Clin North Am 38(3):559-576, 2008.

acidosis is controversial and sodium bicarbonate administration is not likely to help. Tissue hypoxia is considered the most likely underlying problem in lactic acidosis. Thus therapeutic measures should be taken to augment oxygen delivery to the tissues and to reestablish cardiac output. Sodium bicarbonate also is not indicated in ketoacidotic diabetic patients even if pH is less than 7.0 because NaHCO3 administration is associated with deleterious effects in human patients with ketoacidosis (Okuda et al, 1996; Viallon et al, 1999). Sodium bicarbonate is usually not necessary in such settings because the acidosis improves rapidly with appropriate management using fluid resuscitation, insulin, and correction of potassium deficits (Gauthier and Szerlip, 2002). Metabolic acidosis, especially lactic acidosis, uremic acidosis, and diabetic ketoacidosis, occurs commonly in critically ill patients. In one study, metabolic acidosis was the most common acid-base disorder in dogs and cats

(Cornelius and Rawlings, 1981). Conversely, metabolic alkalosis is not as common in dogs and cats in a critical care setting and is usually caused by hypoalbuminemia, vomiting of stomach contents, or overzealous furosemide administration. In human medicine, metabolic alkalosis accounted for more than half of all acid-base disorders in an intensive care setting and also is associated with high mortality rates. Because mortality is especially high when a pH in excess of 7.6 develops, intervention at a pH of 7.55 and greater has been recommended in human patients (Laski and Sabatini, 2006). In dogs, however, alkalemia is rare unless there is concomitant respiratory alkalosis (Robinson and Hardy, 1988). The main disease processes leading to metabolic acidosis in critically ill patients are expressed in Web Box 1-8, whereas those leading to metabolic alkalosis are shown in Web Box 1-9.

References and Suggested Reading Constable PD, Stämpfli HR: Experimental determination of net protein charge and Atot and Ka of nonvolatile buffers in canine plasma, J Vet Intern Med 19:507, 2005. Cornelius LM, Rawlings CA: Arterial blood gas and acid-base values in dogs with various diseases and signs of disease, J Am Vet Med Assoc 178(9):992-995, 1981. de Morais HSA, Constable PD: Strong ion approach to acid-base disorders. In DiBartola SP, editor: Fluid, electrolyte, and acid-base disorders, ed 4, Philadelphia, 2012, Elsevier, p 316. de Morais HSA, DiBartola SP: Ventilatory and metabolic compensation in dogs with acid-base disorders, J Vet Emerg Crit Care 1:39, 1991. de Morais HSA, Leisewitz A: Mixed acid-base disorders. In DiBartola SP, editor: Fluid, electrolyte, and acid-base disorders, ed 4, Philadelphia, 2012, Elsevier, p 302. DiBartola SP: Introduction to acid-base disorders. In DiBartola SP, editor: Fluid, electrolyte, and acid-base disorders, ed 4, Philadelphia, 2012, Elsevier, p 231. Gauthier PM, Szerlip HM: Metabolic acidosis in the intensive care unit, Crit Care Clin 18:298, 2002. Johnson RA, de Morais HSA: Respiratory acid-base disorders. In DiBartola SP, editor: Fluid, electrolyte, and acid-base disorders, ed 4, Philadelphia, 2012, Elsevier, p 287. Laski ME, Sabatini S: Metabolic alkalosis, bedside and bench, Semin Nephrol 26(6):404-421, 2006. Okuda Y et al: Counterproductive effects of sodium bicarbonate in diabetic ketoacidosis, J Clin Endocrinol Metab 81:314, 1996. Robinson EP, Hardy RM: Clinical signs, diagnosis, and treatment of alkalemia in dogs: 20 cases (1982-1984), J Am Vet Med Assoc 7(1):943-949, 1988. Viallon A et al: Does bicarbonate therapy improve the management of severe diabetic ketoacidosis? Crit Care Med 27:2690, 1999.

WEB CHAPTER 

2 

Drainage Techniques for the Septic Abdomen ADRIENNE BENTLEY, Philadelphia, Pennsylvania DAVID HOLT, Philadelphia, Pennsylvania

J

ohn L Yates wrote in 1905: “There is probably no detail in modern surgical pathology that deserves more thorough comprehension, but which is less definitively understood….than the nature of the reaction of the peritoneum to drainage.” Since Yates’s classic paper, there has been substantial investigation into the indica­ tions for and best methods of peritoneal drainage. However, universal guidelines for techniques of perito­ neal drainage and consistent indications for their appli­ cation have not emerged. Prophylactic drainage following routine, uncontaminated intraabdominal procedures has been largely abandoned in human surgery. In vet­ erinary medicine, postoperative abdominal drainage is now generally reserved for cases with generalized septic peritonitis. Septic peritonitis is a severe, life-threatening condition that poses many challenges for the small animal veteri­ narian. Obtaining an accurate and timely diagnosis; understanding peritoneal fluid and protein loss, hypovo­ lemia, sepsis, and the systemic inflammatory response syndrome; and effective resuscitation are vital to success­ ful treatment of peritonitis. Control of the source of peri­ toneal contamination remains the primary goal of exploratory laparotomy in cases of generalized septic peri­ tonitis. More recently, the benefits of copious intraopera­ tive peritoneal lavage and the need for postoperative peritoneal drainage have been questioned. Although a detailed discussion of peritoneal lavage is beyond the scope of this chapter, current recommendations include the judicious use of lavage to remove gross contamina­ tion and aspiration of the lavage fluid from the peritoneal cavity before closure (Platell, Papadimitriou, and Hall, 2000). This chapter focuses on the indications for and use of various drainage techniques in septic peritonitis. Postoperative drainage is indicated in septic peritonitis because a large volume of effusion has detrimental effects on peritoneal defense mechanisms and organ function. Web Table 2-1 shows a comparison of the most com­ monly used peritoneal drainage techniques, including closure of the peritoneal cavity without additional drain­ age, open peritoneal drainage, and closed-suction drain­ age. Patient factors to consider in selecting a method of peritoneal drainage include the success of source control and the severity of the peritonitis (Web Table 2-2). Cost and the availability of intensive nursing care may also influence the technique selected. Effective drainage of the peritoneal cavity in general­ ized septic peritonitis requires an understanding of

intraperitoneal fluid circulation, normal intraperitoneal pressures, and the response of the peritoneal cavity to insertion of a foreign body such as a drain. Fluid injected into the peritoneal cavity disperses throughout the cavity within 15 minutes to 2 hours, depending on the site of injection (Hosgood et al, 1989). The clinical implication is that although fibrin, the omentum, the viscera, and the mesentery may try to localize a focus of contamination, it is likely that contaminated fluid can spread rapidly throughout the peritoneal cavity. Within the peritoneal cavity, the gastrointestinal tract has a luminal pressure exceeding atmospheric pressure, whereas the pressure within the peritoneal space is subatmospheric. Even with experimental insufflation of air, the intraperitoneal pres­ sure never exceeds atmospheric pressure (Gold, 1956). Unless either the intraperitoneal pressure becomes higher than atmospheric pressure or air can enter the peritoneal cavity after surgery through a vent, drainage from the peritoneal cavity will not occur without the use of a vacuum system. Drains inserted into the peritoneal cavity are rapidly encased by the omentum and viscera (Yates, 1905). Thus in some studies it is not clear if drainage occurs from the peritoneal cavity or, more likely, from the encased area around the drain. In a previous experimental study in dogs, sump-Penrose drains were found to be encapsulated and isolated from the peritoneal cavity at necropsy after 48 hours (Hosgood et al, 1989). Despite this isolation, the drains continued to remove radiopaque contrast material from the peritoneal cavity. The use of closed-suction sili­ cone drains for septic peritonitis has been reported (Mueller, Ludwig, and Barton, 2001). Drains in the cases described continued to accumulate fluid for up to 8 days, seeming to indicate adequate function. However, it is not clear if closed-suction drains are encased to the same extent as sump-Penrose drains and are draining a local­ ized area or if they retain functional drainage of the peritoneal cavity despite being encased.

Indications for Postoperative Drainage The anticipation of significant postoperative fluid pro­ duction caused by inability to control the source of contamination, generalized peritonitis, or severe local peritonitis is an indication for postoperative drainage. The efficacy of the peritoneal defense mechanisms may be limited by a large volume of fluid, either ongoing effu­ sion or residual lavage. Phagocytosis of bacteria within e9

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SECTION  I  Critical Care

WEB TABLE 2-1  Comparison of Common Peritoneal   Drainage Techniques Closure without Additional Drainage

Open Peritoneal Drainage

ClosedSuction Drainage

Efficiency/ efficacy

Relies on host peritoneal mechanisms

Uncertain

Uncertain

Labor/ nursing care

Minimal

Extensive

Moderate

Cost

Minimal

Expensive

Moderate

Allows relaparotomy

Volume of effusion quantified

Other

examples of localized peritonitis in small animal surgery are found with prostatic and pancreatic abscesses. Local peritoneal drainage has been used to treat these condi­ tions and generally involved placement of one or more Penrose drains in the abscess cavity once débridement and local lavage were completed. These techniques have largely been replaced by omentalization. The abscess cavity is located by palpation, intraoperative ultrasound, or aspiration. It is opened, drained, and gently débrided with a moistened gauze sponge. After thorough local lavage with a warm, balanced electrolyte solution, the omentum is packed loosely into the cavity, and the abdominal incision is closed. The immunologic and angiogenic properties of the omentum promote local infection control and healing. The technique has been associated with long-term success in 19 of 20 dogs with prostatic abscesses (White and Williams, 1995) and 6 of 12 dogs with pancreatic abscesses (Johnson and Mann, 2006).

Generalized Peritonitis WEB TABLE 2-2  Suggested Criteria for Selecting a Method of Peritoneal Drainage Method

Criteria

Peritoneal closure   without additional drainage

Definitive control of the source of contamination Minimal peritonitis

Open peritoneal   drainage

Inability to control the source at first laparotomy Need for additional débridement at second laparotomy Suspected anaerobic infection such as colonic source Severe peritonitis Abdominal compartment syndrome

Closed-suction drainage

Definitive control of the source of contamination Moderate peritonitis

fluid depends on the presence of opsonins in the fluid, which can become depleted. Therefore the presence of fluid may allow rapid bacterial proliferation. A large volume of fluid may also limit the localization of the contamination and speed the systemic absorption of bac­ teria and endotoxins (Platell, Papadimitriou, and Hall, 2000). A large volume of effusion also increases intraab­ dominal pressure. In some cases, intraabdominal hyper­ tension is sufficient to cause cardiopulmonary dysfunction, anuria or oliguria, and intestinal ischemia (abdominal compartment syndrome) (Drellich, 2000; Conzemius et al, 1995).

Local Peritonitis In some cases peritonitis may not be generalized at the time of exploratory surgery. The two most common

Primary Abdominal Closure without Drainage The decision to close the peritoneal cavity without drain­ age is based on control of the source of contamination and adequate decontamination of the peritoneal cavity. The clinician then relies on the body’s peritoneal drain­ age and immune defense systems. Fluid absorption occurs primarily by passing through gaps (stomata) in the meso­ thelial cells into lymphatics and thereby the circulation. More microvilli are present on the mesothelial cells of the visceral peritoneum than the parietal peritoneum to promote movement of fluid toward the diaphragm for absorption. The number of mesothelial microvilli increases and lymphatics dilate in response to peritoneal inflammation. In addition to mesothelial cells, numerous immune cells are present in the peritoneal membrane and omentum, including macrophages, lymphocytes, and mast cells. The immune cells function in bacterial phago­ cytosis, antigen presentation, and antibody and cytokine production in cases of peritonitis. Finally, production of plasminogen activator inhibitor 1 by peritoneal mesothe­ lial cells promotes the organization of fibrous adhesions, which facilitate phagocytosis and localize contamination (Yao, Platell, and Hall, 2003). Lanz and colleagues (2001) reported 54% survival in a cohort of 28 cases of canine septic peritonitis managed with source control, intraoperative lavage, and closure of the peritoneal cavity without a means of additional post­ operative drainage. As discussed, this method of surgical management relies on peritoneal drainage and may be appropriate when the source of contamination can be controlled definitively and peritonitis is not severe.

Open Peritoneal Drainage Historically open peritoneal drainage has been reserved for the most severe cases of generalized septic peritonitis, which are anecdotally associated with a large volume of effusion after surgery. Assessment of the severity of

WEB CHAPTER  2  Drainage Techniques for the Septic Abdomen

WEB BOX 2-1  Factors Evaluated in Determining the Severity of Peritonitis • • • •

Volume of effusion Character of effusion: opacity, color, odor Presence of gross contamination: fecal matter, food, hair Serosal changes of abdominal organs: erythema, encasement with fibrous adhesions • Distribution of contamination and peritonitis: localized   or generalized

Web Figure 2-1  Open peritoneal drainage is established by leaving a gap between the edges of the linea alba.

peritonitis is largely subjective and based on individual experience but may include evaluation of factors shown in Web Box 2-1. Clear indications for open peritoneal drainage include the need for relaparotomy and anaero­ bic infection. Relaparotomy may be necessary in cases of ineffective source control or when additional débride­ ment is required. Although the type of infection may not be definitively known at the time of initial laparotomy, an anaerobic infection may be suspected when the colon is the source of contamination. Although intraabdominal pressure is not routinely measured in the clinical setting, open peritoneal drainage is indicated when intraabdomi­ nal hypertension results in clinical signs such as anuria or oliguria (Conzemius et al, 1995). Open peritoneal drainage is established through a long abdominal incision, extending from the xiphoid process to the pubis and including the most dependent portion of the abdomen. The falciform fat should be excised according to standard exploratory laparotomy technique, but omentectomy is not necessary. The linea alba is closed with nonabsorbable suture in a simple continuous pattern with a gap of 1 to 6 cm between the edges, depending on the patient’s size (Web Figure 2-1). The subcutaneous

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tissues and skin are not closed. A sterile bandage consist­ ing of laparotomy sponges and surgery towels under­ neath routine bandage material is applied and changed at least daily. If the bandage becomes wet and there is strike-through from peritoneal effusion or urine or if it becomes displaced, it should be replaced as soon as pos­ sible. A urinary catheter helps to maintain the integrity of the bandage, especially in male dogs. Although early reports (Woolfson and Dulisch, 1986; Greenfield and Walshaw, 1987) describe performing bandage changes outside of the operating room with the patient standing, current recommendations include changing the bandage in the sterile environment of the operating room with the patient sedated or anesthetized. During each bandage change, adhesions at the incision are digitally disrupted; the incision is checked for organ evisceration; and addi­ tional surgical procedures such as peritoneal lavage, débridement, and feeding tube placement are performed as needed. The decision to close the peritoneal cavity is based on reassessment of the same factors used in select­ ing open peritoneal drainage. Clinical studies report a mean duration of open peritoneal drainage of 4 to 5 days, with a range of less than 1 day to as long as 2 weeks (Woolfson and Dulisch, 1986; Greenfield and Walshaw, 1987; Winkler and Greenfield, 2000). Open peritoneal drainage is regarded as an efficient means of drainage, although evidence supporting this claim is limited. In an experimental study of five normal dogs, open peritoneal drainage resulted in rapid, equal, and relatively complete drainage of radiopaque contrast from the peritoneal cavity. Drainage occurred despite the fact that the laparotomy incisions were partially occluded by omentum in all five dogs at necropsy (48 hours after open drainage was established) (Hosgood et al, 1989). In another experimental study of six normal dogs, extreme variability in the volume of injected saline recovered through open peritoneal drainage precluded conclusions regarding drainage efficiency. Drainage occurred in these dogs despite omental adhesions along the entire length of the laparotomy incisions at necropsy (96 hours after open drainage was established) (Hosgood, Salisbury, and DeNicola, 1991). Similar to omental encasement of drains, the effect of omental adhesions to the laparotomy inci­ sion on the volume and distribution of fluid drained is unclear. Experimental studies evaluating the efficiency of open peritoneal drainage are limited by the lack of peri­ tonitis, small number of dogs, and small volume of peri­ toneal fluid (Hosgood et al, 1989; Hosgood, Salisbury, and DeNicola, 1991). The presence of peritonitis may help maintain the patency of laparotomy incisions and drains by resulting in a larger volume of effusion and omental adhesions to areas of the peritoneal cavity other than the incision or drain (Hosgood, Salisbury, and DeNicola, 1991). Finally, the minimum efficiency of peritoneal drainage necessary in clinical cases of peritonitis is unknown and likely case dependent. Hypoproteinemia and nosocomial infection are reported complications of open peritoneal drainage, the clinical significance of which is not well established. Clin­ ical reports have documented a relatively small number of patients with different bacterial culture results at the time of exploratory laparotomy and peritoneal closure.

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SECTION  I  Critical Care

Web Figure 2-2  Components of the Vacuum-Assisted Closure®

Web Figure 2-3  Components of a closed-suction drain in­­

Moreover, the presence of a different bacterium at the time of closure does not appear to impact survival (Winkler and Greenfield, 2000; Greenfield and Walshaw, 1987; Woolfson and Dulisch, 1986). Hypoproteinemia is a likely consequence of septic peritonitis, regardless of drainage technique. Total protein concentration was not different between animals managed by peritoneal closure and those managed by open drainage 48 hours after surgery. Although a similar number of animals in each group received hydroxyethyl starch, more animals in the open-drainage group received blood, plasma, and a jeju­ nostomy tube. Animals in the open-drainage group also stayed in the intensive care unit longer than animals in the closed-peritoneal group (Staatz, Monnet, and Seim, 2002).

by allowing the volume of effusion to be quantified and decreasing the frequency of labor-intensive bandage changes.

(VAC® Therapy) device include a foam sponge, fenestrated evacuation tubing, and an adherent layer. (Courtesy Kinetic Concepts, Inc.)

Vacuum-Assisted Closure Originally designed for use in a variety of chronic wounds, the Vacuum-Assisted Closure (VAC) device in human medicine has simplified the management of patients with open peritoneal drainage. The VAC device consists of a polyurethane ether foam sponge that is cut to fit the wound. An adherent layer is placed over the sponge, and fenestrated evacuation tubing is placed under the adher­ ent layer and connected to a vacuum pump through a drainage canister (Web Figure 2-2). Intermittent subatmo­ spheric pressure is applied to the wound through the VAC device (Venturi et al, 2005). Application of the VAC device to the open peritoneal cavity necessitates the addi­ tion of a fenestrated nonadherent layer (polyethylene) between the sponge and the peritoneal contents. The device is changed in the operating room as needed (Scott, Feanny, and Hirshberg, 2005). The VAC device promotes wound healing by increasing blood flow, decreasing tissue edema, and removing excess fluid. As a result, bacterial counts are also decreased in the wound (Venturi et al, 2005). The VAC device may provide advantages over tra­ ditional open peritoneal drainage in veterinary patients

clude a bulb reservoir connected to the fenestrated intraabdominal portion of the drain. (Jackson-Pratt drain courtesy Cardinal Health.)

Closed-Suction Drainage Closed-suction drainage is likely the most commonly used technique for the management of septic peritonitis in veterinary patients. Commercially available closedsuction drains, such as the Jackson-Pratt drain, consist of a fenestrated silicone drain connected to an external res­ ervoir by a nonfenestrated tube (Web Figure 2-3). The drain is typically positioned near the diaphragm and liver in the most dependent portion of the peritoneal cavity, although a more caudal position may be appropriate, depending on the source of the contamination. The non­ fenestrated portion of the drain is exited through a small paramedian incision in the body wall and secured with a nonabsorbable purse-string and finger-trap suture. Com­ pression of the bulb reservoir creates negative pressure within the peritoneal cavity. A bandage is typically applied to cover the exit site of the drain and to provide a means of attaching the bulb reservoir to the patient. The contents of the reservoir are easily emptied, typically every 6 hours. Mueller, Ludwig, and Barton (2001) reported 70% sur­ vival in a cohort of 30 dogs and 10 cats with septic peri­ tonitis managed with closed-suction drains. Drains were in place for a mean of 3.6 days with a range of 2 to 8 days. The volume of fluid produced was variable but decreased with time. The drains remained patent until removal as evidenced by ongoing fluid collection. However, it is unclear if the closed-suction drains removed fluid from the entire peritoneal cavity and what percent­ age of the total peritoneal fluid volume they drained. No significant complications were reported with use of the closed-suction drains. Only five patients had bacterial cultures of peritoneal fluid performed both at the time of surgery and at the time of drain removal. In the two

WEB CHAPTER  3  Gastric Dilation-Volvulus patients with a positive culture at drain removal, different bacteria were isolated compared with the intraoperative cultures, and both patients survived. Closed-suction drains are relatively inexpensive and easy to place and seem to be free of significant complica­ tions. Advantages of closed-suction drainage over open peritoneal drainage include the ability to quantify the volume of effusion and decreased cost and labor. Closedsuction drains have an advantage over physiologic peri­ toneal drainage in their apparent ability to drain a large volume of effusion rapidly. In addition, closed-suction drains provide readily available peritoneal fluid samples after surgery for cytologic and biochemical analysis. Their use is indicated in most cases of septic peritonitis when the need for postoperative drainage is anticipated but the severity of the peritonitis or volume of effusion does not warrant open peritoneal drainage.

References and Suggested Reading Conzemius MG et al: Clinical determination of preoperative and postoperative intra-abdominal pressures in dogs, Vet Surg 24:195, 1995. Drellich S: Intraabdominal pressure and abdominal compart­ ment syndrome, Compend Cont Educ Pract Vet 22:764, 2000. Gold E: The physics of the abdominal cavity and the problem of peritoneal drainage, Am J Surg 91:415, 1956. Greenfield CL, Walshaw R: Open peritoneal drainage for treat­ ment of contaminated peritoneal cavity and septic peritonitis in dogs and cats: 24 cases (1980-1986). J Am Vet Med Assoc 191:100, 1987. Hosgood G, Salisbury SK, DeNicola DB: Open peritoneal drainage versus sump-Penrose drainage: clinicopathological effects in normal dogs, J Am Anim Hosp Assoc 27:115, 1991.

WEB CHAPTER 

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Hosgood G et al: Intraperitoneal circulation and drainage in the dog, Vet Surg 18:261, 1989. Johnson MD, Mann FA: Treatment for pancreatic abscesses via omentalization with abdominal closure versus open peritoneal drainage in dogs: 15 cases (1994-2004), J Am Vet Med Assoc 228:397, 2006. Lanz OI et al: Surgical treatment of septic peritonitis without abdominal drainage in 28 dogs, J Am Anim Hosp Assoc 37:87, 2001. Mueller MG, Ludwig LL, Barton LJ: Use of closed-suction drains to treat generalized peritonitis in dogs and cats: 40 cases (19971999), J Am Vet Med Assoc 219:789, 2001. Platell C, Papadimitriou JM, Hall JC: The influence of lavage on peritonitis, J Am Coll Surg 191:672, 2000. Scott BG, Feanny MA, Hirshberg A: Early definitive closure of the open abdomen: a quiet revolution, Scand J Surg 94:9, 2005. Staatz AJ, Monnet E, Seim HB: Open peritoneal drainage versus primary closure for the treatment of septic peritonitis in dogs and cats: 42 cases (1993-1999), Vet Surg 31:174, 2002. Venturi ML et al: Mechanisms and clinical applications of the vacuum-assisted closure device, Am J Clin Dermatol 6:185, 2005. White RA, Williams JM: Intracapsular prostatic omentalization: a new technique for management of prostatic abscesses in dogs, Vet Surg 24:390, 1995. Winkler KP, Greenfield CL: Potential prognostic indicators in diffuse peritonitis treated with open peritoneal drainage in the canine patient, J Vet Emerg Crit Care 10:259, 2000. Woolfson JM, Dulisch ML: Open abdominal drainage in the treatment of generalized peritonitis in 25 dogs and cats, Vet Surg 15:27, 1986. Yao V, Platell C, Hall JC: Role of peritoneal mesothelial cells in peritonitis, Br J Surg 90:1187, 2003. Yates JL: An experimental study of the local effects of peritoneal drainage, Surg Gynecol Obstet 1:473, 1905.

3 

Gastric Dilation-Volvulus KAROL A. MATHEWS, Ontario, Canada

A

complex medical and surgical emergency, gastric dilation-volvulus (GDV) most commonly occurs in large and giant breeds of dog. However, it potentially can affect any size or breed of dog, as well as cats. In smaller breeds of dog the dachshund is overrepresented. Deep-chested conformation may increase the susceptibility to GDV. The prevalence of GDV increases with increasing age, with the greatest occurrence between 7 and 10 years of age. The frequency of occurrence has been reported at 2.4 to 7.6 per 1000 canine hospital admissions (Glickman et al, 1994). Although the cause of GDV has not been fully explained, potential contributing causes include delayed gastric emptying, pyloric obstruction,

aerophagia, and gastric engorgement that contribute to gastric dilation (GD). Volvulus possibly occurs secondarily to the dilation. To further complicate matters, gastric volvulus can occur without prior dilation, for example, with exercise after consumption of a large meal. Splenic torsion has also been causally implicated because malposition of the spleen frequently occurs with GDV; however, GDV also can occur in splenectomized dogs, possibly from increased space within the peritoneal cavity. Inhibition of gastric motility by pharmacologic agents, blunt abdominal trauma, spinal cord injuries, prolonged surgical procedures, or prolonged recumbency can also predispose dogs to GD. Cereal diets have been suggested as a

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SECTION  I  Critical Care

cause for GD; however, studies have not been able to confirm this finding. In predisposed dogs that consumed dry dog foods there was a 2.4-fold increased risk of GDV when an oil or fat was among the first four ingredients (Raghavan, Glickman, and Glickman, 2006). This chapter focuses on the initial and postoperative treatment of the animal with GDV. A detailed description of the pathophysiology of GD and GDV is covered elsewhere in the literature (Leib, 1987) and is only briefly outlined here as a basis for treatment rationale. The various techniques used for surgical correction of GDV can be obtained from standard surgical texts.

Prognosis Various studies of dogs with GDV and surgical intervention report overall mortality rates of 10% (Mackenzie et al, 2010), 16.7% (Beck et al, 2006), and 23% (Zacher et al, 2010). The prognosis for recovery may be associated with severity of systemic effects; however, prompt and optimal therapy can result in recovery in a high percentage of dogs that present with GDV. Development of GDV leads to both local and systemic consequences of varying degrees. Gastric ischemia results in gastritis that can progress to necrosis, with possible perforation and peritonitis. Compression of the caudal vena cava and portal vein results in decreased venous return to the heart, with subsequent reductions in cardiac output and systemic arterial blood pressure, and decreased perfusion of the myocardium and gastrointestinal tract. With gastrointestinal mucosal injury and subsequent translocation of bacteria and endotoxins, the patient is predisposed to bacteremia, sepsis, and septic shock. Avulsion of the short gastric and right gastroepiploic vessels may occur and cause intraabdominal hemorrhage. The splenic veins may become thrombosed. The outcomes of these events are hypotension, hypovolemia (from blood loss, plasma loss, and increased production and sequestration of gastric secretions), hypoxemia, acid-base and electrolyte abnormalities, sepsis, myocardial dysfunction, and disseminated intravascular coagulation (DIC). According to several published studies, certain physical examination and surgical findings, as well as labo­ ratory test results, offer guidance regarding mortality outcomes in dogs with GDV. Because plasma/blood lac­ tate measurements are a valuable indicator of systemic and gastric perfusion in the patient with GDV, this parameter has been used as a potential guide for identifying gastric necrosis. An earlier report indicated that a plasma/ blood lactate measurement greater than 6 mmol/L was associated with a 39% incidence of gastric necrosis. This translated to a 28% to 38% postoperative mortality when gastric resection was needed, and a 32% to 38% mortality when splenectomy was performed (De Papp et al, 1999). A more recent retrospective study determined an initial lactate concentration of more than 9 mmol/L as a cut-off value for survivors versus nonsurvivors with GDV (Zacher et al, 2010). In this study there was no significant difference between initial plasma lactate concentrations for survivors (mean ± standard deviation [SD] of 10.6 ± 2.3 mmol/L) and nonsurvivors (mean ± SD of 11.2 ± 2.3 mmol/L). However, after resuscitative

treatment and prior to surgery, the plasma lactate concentration was significantly lower (≤ 6.4 mmol/L), while the absolute and percentage changes in lactate concentration from baseline were significantly greater (changes of > 4.0 mmol/L and > 42.5%, respectively) in survivors compared with nonsurvivors. This study also reported that 26 of 64 dogs (41%) had gastric necrosis at the time of surgery; of these 26 dogs, 14 that underwent gastric resection were discharged from the hospital while 12 were euthanized or died during or immediately after surgery. Four dogs in this study were euthanized during the postoperative period because of deteriorating clinical status; three of these had no signs of gastric necrosis at the time of surgery (Zacher et al, 2010). Prognosis also may be associated with splenic injury. A history of GDV signs for more than 6 hours before presentation has been associated with increased risk of gastric necrosis and requirement for splenectomy (Beck et al, 2006). The requirement for splenectomy can result in mortality rates greater than for partial gastrectomy; however, the combination of partial gastrectomy and splenectomy produced the highest mortality in two studies (Mackenzie et al, 2010; Beck et al, 2006). The patient’s response to resuscitative therapy, as shown previously, appears to be of more value than initial lactate values in determining prognosis. The author has observed a lactate as high as 17 mmol/L in a patient with GDV, hemorrhage, and shock that within 3 hours of resuscitation returned to 3 mmol/L. This dog presented with a packed cell volume (PCV) of 35%, but with fluid resuscitation serious hemorrhage was revealed with a PCV of 15%. Whole blood was administered. Surgical exploration revealed avulsion of short gastric vessels and hemorrhage. The high lactate in this case was due to reduced oxygen delivery, not gastric necrosis. This case also highlights the importance of frequent monitoring of PCV during resuscitation. Thus, while lactate may be an indicator of prognosis in study populations, caution is required when interpreting this information to clients for a single patient. Importantly, most dogs recover from GDV with optimal preoperative, surgical, and postoperative management. A recent prospective study investigated whether myoglobin may be a useful prognostic indicator for mortality outcome in dogs with GDV (Adamik, 2009). The cut-off value for myoglobin was 168 ng/ml, with 89% of dogs with less than this value surviving to discharge, whereas only 50% with more than this value surviving. Although these results are interesting, more prospective data are needed to determine the overall prognostic value of this test.

Presentation Clinical signs vary with the extent of GD or GDV and may not parallel the degree of gastric or splenic injury. Owners aware of the clinical signs associated with GDV may seek veterinary assistance at the onset of GD, whereas dogs left alone for several hours may present moribund. Typically dogs with GD or GDV have varying degrees of cranial abdominal distention with hypersalivation and unproductive retching. These animals are restless,

WEB CHAPTER  3  Gastric Dilation-Volvulus dyspneic, or tachypneic and may or may not be depressed or moribund. In the early stages of GD, physical examination may reveal increased heart rate with strong pulses, normal or rapid capillary refill time, and normal mucous membrane color. In dogs with advanced GDV, weak, rapid pulses and pulse deficits can be present; mucous membranes may be pale pink to pale gray, with prolonged capillary refill time and the presence of petechiae; and the cranial abdomen may be tympanic with splenomegaly or free abdominal fluid.

Diagnosis The diagnosis of GDV is often obvious from the patient’s signalment and presenting clinical signs. Ra­­ diographic examination is necessary and useful if the diagnosis is equivocal or, if after decompression, surgical management may not be an option for the client (as differentiation of dilation alone from GDV will direct further management). The ability to pass an orogastric tube does not rule out the presence of volvulus. When necessary, abdominal radiographs with the dog in right lateral recumbency are usually diagnostic, unless a 360-degree torsion is present. Evaluation of this single radiographic view initially may minimize the stress to the patient associated with obtaining multiple planes. When volvulus is present, the pylorus is visualized on a right lateral survey radiograph as a gas-filled structure dorsal and cranial to the gastric fundus. A compartmentalization line is frequently observed between the pylorus and fundus. This line represents the pyloric antral wall folding back and contacting the fundic wall. The pylorus cannot be clearly identified in a left lateral projection. Pneumoperitoneum (free air within the abdomen) may indicate gastric rupture or air leakage after gastrocentesis. Electrocardiographic monitoring is essential in the patient with GDV because cardiac arrhythmias that require treatment (see section on Circulatory Resuscitation later) occur in many patients. Ventricular arrhythmias are the most common (Muir, 1982; Beck et al, 2006; Mackenzie et al, 2010). In addition, sinus tachycardia is almost always present in animals that present with GDV and is frequently associated with hypovolemia, pain, and anxiety. The minimal database recommended for assessment of the patient with GDV and for diagnosing complications associated with the GDV syndrome includes evaluation of systemic arterial blood pressure; packed cell volume (PCV), total plasma solids (TS), activated clotting time (ACT) or activated partial thromboplastin time (aPTT), platelet count, white blood cell count and differential; blood urea nitrogen, glucose and lactate concentrations; serum electrolytes; and venous blood gases or total serum carbon dioxide. This information is essential to manage the patient appropriately and to optimize outcome. Early on in GD, hypochloremic alkalosis secondary to gastric sequestration may be recognized. As a result of poor systemic perfusion (with or without hemorrhage), a primary lactic acidosis also occurs, resulting in two mixed acidbase disturbances that may produce a normal pH. However, the dog eventually becomes acidemic as the syndrome advances and perfusion is jeopardized further.

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A complete serum biochemical profile should be sub­ mitted to identify other organ dysfunction. Although coagulation status should be assessed, serum concentration of fibrin degradation products (FDPs), PT, aPTT, and platelet count were not found to be significantly associated with development of DIC in one study (Beck et al, 2006; Bateman et al, 1999a). However, the ACT and estimated platelet count from a blood smear provided the best accuracy for point-of-care tests in diagnosing DIC in general (Bateman et al, 1999b). Because the process of DIC is dynamic, it is recommended to perform serial evaluations of ACT* every 8 hours if the results are equivocal and the patient is not improving clinically. Point-ofcare testing is not very costly and greatly helps in both the diagnosis and treatment of suspected DIC (Cheng et al, 2011).

Initial Treatment Initial treatment should be considered in light of the presenting clinical signs and the consequences of the known pathophysiologic events. The primary objectives are to (1) prevent or reverse circulatory collapse (fluid +/– colloid resuscitation), (2) prevent or reduce the local and systemic events associated with GD or GDV by removing the inciting cause (gastric decompression and lavage), (3) treat associated complications (electrolyte and acid-base abnormalities, pain, cardiac arrhythmias, and sepsis), and (4) prepare the animal for surgical treatment. For the rare patient that presents with dilation alone without evidence of circulatory compromise, orogastric decompression is the initial treatment. For the typical patient with GD/GDV, circulatory compromise or collapse is present, and reversal of the shock state should be addressed before gastric decompression. In seriously compromised patients it may be necessary to partially decompress the stomach immediately to circumvent cardiorespiratory arrest. Gastrocentesis (see section on Gastric Decompression) is recommended in these situations to avoid the stress of orogastric intubation. In these patients complete decompression should be avoided until rapid fluid resuscitation is well under way. All patients with GDV require surgical intervention as soon as possible. Rarely, decompression may correct gastric malposition; however, surgical correction should be performed because medical management alone without surgical gastropexy results in a 75% recurrence rate.

Circulatory Resuscitation A 14- or 16-gauge 2- to 4-inch catheter is placed into the jugular or peripheral veins. A buffered (lactate or acetate) isotonic, balanced electrolyte solution is administered at an appropriate rate based on clinical presentation. An acidifying solution such as 0.9% saline solution is chosen if the patient is alkalemic. It is essential that rate and volume be administered based on the requirements of the individual patient. Fluid overload based on

*0.5 ml MAX-ACT tubes obtained from Helena Laboratories, Beaumont, Texas.

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SECTION  I  Critical Care

WEB TABLE 3-1  Parameters to Assess and Goals to Achieve with Fluid and Colloid Resuscitation Parameter

Goal

Mean arterial pressure

70-80 mm Hg

Systolic blood pressure

100-120 mm Hg

Central venous pressure

3-5 cm H2O

Mucous membrane color

Pink

Capillary refill time

1-2 sec

Heart rate

80-120 beats/min Variable with dog size and analgesic administration

Peripheral pulse (dorsal pedal) pressure

Moderate to normal strength

Mentation

Improved to normal for the situation

Urine output

1-2 ml/kg/hr

a preconceived rate can result in edema and be as deleterious as administration of inadequate volumes. A recommended rate for a balanced electrolyte solution is 1.5 to 2 ml/kg/min for dogs and 0.75 to 1 ml/kg/min for cats initially if the patient is hypotensive, if the patient is normotensive but with tachycardia, or when other evidence of hypovolemia is present. The clinician should continuously monitor the patient and make adjustments to the rate and volume of fluid administration on a moment-to-moment basis based on the individual patient’s needs and response to therapy (see Chapter 1). It is important to keep in mind that tachycardia may also be due to pain; therefore in this instance fluid overload must be avoided and appropriate analgesia administered. If large fluid volumes are anticipated for resuscitation, the crystalloid volume can be reduced by up to 40% if pentastarch (Pentaspan), hetastarch (Hespan), or VetStarch (Hospira) is administered at 10 to 20 ml/kg over 15 to 30 minutes (see Chapter 2). If shock is severe, 4 ml/kg of 5% or 7.5% hypertonic saline is administered over 5 to 10 minutes, followed by the aforementioned infusions of isotonic crystalloid or synthetic colloid solution until clinical signs of shock are reversed (Web Table 3-1). The TS and PCV should be measured every 30 minutes because acute hemorrhage may not be apparent at the time of initial presentation but is unmasked during fluid resuscitation. If the PCV decreases to less than 25% or the TS decreases to less than 4.5 g/dl, whole blood, packed red blood cell, or plasma transfusion should be considered. Blood or plasma can be administered at a rate of 20 ml/ kg over 1 to 2 hours, or more rapidly depending on the needs of the patient. If hypotension persists after calculated fluid volume has been administered, one should consider intravenous constant rate infusions (CRIs) of dopamine (Intropin) or dobutamine (Dobutrex) at 2 to 20 µg/kg/min. Adjustment in administration rates should be made as needed to achieve a satisfactory hemodynamic end point (see

Web Table 3-1). Norepinephrine (Levophed), 0.05 to 0.3 µg/kg/min IV, or higher doses to effect, can be administered if dopamine or dobutamine infusions fail to achieve the desired effect within a few minutes (see Chapter 3). The most common acid-base abnormality in animals with GDV is metabolic acidosis. This abnormality is frequently corrected by treating the underlying cause (shock) with aggressive resuscitative fluid therapy and gastric decompression. Bicarbonate ( HCO3− ) administration is not routinely necessary but may be indicated if serum ( HCO3− ) or total carbon dioxide is less than 12 mEq/L after fluid resuscitation. A suggested dose for HCO3− administration (in milliequivalents) can be calculated using the following formula: mEq HCO3− to administer = Body weight ( kg ) × (12 − patient [ HCO3− ]) × 0.3 The calculated dose can be administered intravenously over 30 to 60 minutes. Occasionally a patient may have a normal or increased blood pH, and empiric therapy with HCO3− shifts the oxyhemoglobin dissociation curve to the left, reducing the offloading of oxygen and thus oxygen delivery to the tissues. When lactic acidemia is present it should rapidly resolve with fluid therapy and correction of the GDV. Because lactate is a bicar­ bonate precursor, metabolism of lactate following restoration of perfusion also helps to correct the acidosis. In most instances reperfusion restores the acid-base status to normal without treatment with exogenous sodium bicarbonate. Ventricular arrhythmias including premature ventricular contractions (PVCs) and ventricular tachycardia (VT) frequently improve after circulatory resuscitation, gastric decompression, and administration of analgesic drugs. However, treatment is advised in the following situations: (1) if VT is sustained or paroxysmal at an instantaneous rate of 150 beats/min or more (120 beats/min under general anesthesia); (2) if VT is associated with a mean arterial pressure (MAP) less than 70 mm Hg; (3) when serious preexisting cardiac disease is present; (4) when an R-on-T phenomenon or closely coupled PVCs are evident; and (5) when polymorphic VT, including that of the torsades de pointes variety, is observed. One should not expect to totally abolish the arrhythmia and should not feel compelled to treat the ventricular rhythms that are not very fast, not causing hypotension, or not of a “malignant” morphology. Initial treatment for ventricular tachyarrhythmias is lidocaine (Xylocaine, Astra) administration at 2 mg/kg IV, followed by a CRI of lidocaine at 30 to 80 µg/kg/min if the arrhythmia is lidocaineresponsive. If the initial bolus is ineffective, one or two additional boluses can be administered within 5 to 10 minutes of the initial bolus. Failure of the rhythm to improve with lidocaine administration (reduction in rate to 120 to 140 beats/min and a reduction in VT or PVC complexity) requires reassessment of the electrocardiographic diagnosis and overall status of the patient (e.g., electrolyte, acid-base, sepsis, and pain), with consideration of alternative antiarrhythmic therapy. If there is uncertainty as to whether the arrhythmia is ventricular

WEB CHAPTER  3  Gastric Dilation-Volvulus or supraventricular in origin or if the ventricular arrhythmia is not responsive to lidocaine, procainamide (Pronestyl) is administered IV (6 to 10 mg/kg, rarely up to 20 mg/kg) by 2 mg/kg increments every 5 minutes (to avoid hypotension). If procainamide administration is effective, it is continued (6 to 10 mg/kg IM q6h or 25 to 40 µg/kg/min IV CRI). The administration of 20% magnesium sulfate solution (0.15 to 0.3 mEq/kg or 12.5 to 35 mg/kg) via 2- to 4-hour IV CRI three times in 24 hours may abolish or enhance the treatment response of patients with ventricular arrhythmias. For life-threatening arrhythmia, a magnesium sulfate dose (0.15 to 0.3 mEq/kg IV over 15 to 20 minutes) could be administered. Caution must be used with magnesium sulfate administration in patients with renal insufficiency (Dhupa, 1995). Sinus tachycardia frequently resolves with resuscitative treatment and analgesic support. If sinus tachycardia persists despite treatment or in the postoperative period, one should consider hypotension, hypovolemia, hypoxemia, anemia, hypercarbia, inadequate control of pain, gastric perforation, splenic infarction, or other major organ complications that would require immediate exploratory celiotomy. However, it is essential to ensure optimal resuscitation prior to surgery. A recent study identified that an increased time from presentation to surgery, while still performing surgery in a timely manner, was associated with a lower mortality rate. It was hypothesized that complete fluid resuscitation with stabilization before surgical intervention likely was the reason for reduced mortality (Mackenzie et al, 2010). Potassium-supplemented fluids, delivered through an intravenous line separate from the rapid infusion of crystalloids, should be administered at a dosage ranging from 30 to 80 mEq/L, delivered at a maintenance fluid rate when serum potassium concentrations are found ranging from 3.5 mEq/L to less than 2 mEq/L, respectively. If the animal is acidemic, the serum potassium concentration may decrease during treatment with buffering solutions as the acidosis resolves. This possibility should be anticipated, assessed, and addressed by an increase in the rate of potassium infusion as necessary. Potassium infusions can be delivered at a maximal rate of 0.5 to 1 mEq/kg/hr when serum potassium levels are less than 3 mEq/L, ventricular arrhythmias are present, and continuous electrocardiography and serial serum potassium monitoring are possible every 4 hours. Antibiotics with a spectrum of activity directed against gram-negative and anaerobic bacteria should be administered during fluid resuscitation (cefoxitin, 20 mg/kg IV q6h, or ampicillin, 20 mg/kg IV q6h). Translocation of gut bacteria into the systemic circulation is a common complication of GDV and gastrointestinal hypoperfusion. Administration of corticosteroids to patients with GDV is controversial. The author’s preference is to avoid this treatment due to its potential for exacerbating gastric hemorrhage. A possible exception to this recommendation is in the case of refractory shock that is unresponsive to pressor agents (a single dose of methylprednisolone [0.5 mg/kg]). If blood pressure improves, it may be necessary to repeat the dose if unresponsive hypotension recurs. Nonsteroidal antiinflammatory analgesics are not recommended in dogs with GDV.

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Gastric Decompression Gastric decompression is initiated after resuscitative fluid administration or during the administration of fluids if the dilation is severe (see later). If the dog requires sedation, fentanyl (2 to 5 µg/kg), hydromorphone (Dilaudid), or oxymorphone (Numorphan) (0.02 to 0.05 mg/kg IV) is administered to effect. It is essential to administer these analgesics very slowly, starting at the lowest dose to avoid nausea. Diazepam or midazolam (0.2 to 0.5 mg/kg IV) can be added concomitantly or following (but not before) the opioid, if needed to sedate noncompliant dogs prior to decompression. The pure mu agonists hydromorphone, oxymorphone, and fentanyl are preferred over partial agonists (buprenorphine) or agonist antagonists (butorphanol) because pure mu agonists have a rapid onset of action, reduce the inhalant anesthetic requirements, exert greater analgesic effects, and produce better sedation that facilitates tracheal intubation. To perform orogastric decompression, the dog is placed in sternal or lateral recumbency or in an upright sitting position. A large-bore tube is premeasured from the chin to the xiphoid, and the distance is marked with tape. The tube is lubricated with water-soluble jelly and passed carefully through an oral speculum (or 2-inch roll of tape) through the esophagus and into the stomach until the mark on the tube is at the level of the incisors. Rupture of compromised areas of the lower esophagus or stomach can occur if excessive force is used during orogastric intubation. If resistance to passage of the orogastric tube is experienced, the tube should be rotated gently while reattempting passage; alternatively, the position of the dog can be changed to facilitate passage. In some cases, passage of the tube may not be possible prior to anesthesia. Gastrocentesis should be performed immediately in patients with severe gastric distention and incipient cardiopulmonary arrest or in patients in which attempts at orogastric intubation have been unsuccessful and a delay in partial decompression with further repositioning will be detrimental to the patient. A 10 × 10–cm area is aseptically prepared caudal to the right costal arch. The area is percussed to identify the tympanic stomach and to avoid needle puncture of the spleen. An 18-gauge needle or over-the-needle catheter is placed through the abdominal wall into the lumen of the stomach to allow gas to escape. Further decompression is often not necessary if the patient is to undergo surgical correction immediately. However, if surgical correction may be delayed, orogastric decompression should be repeated after gastrocentesis to reduce the rapid accumulation of gas. Orogastric decompression is more easily performed at this time because release of pressure on the cardia usually facilitates passage of the tube. After orogastric decompression, the stomach is lavaged with warm tap water to remove residual food. This should be performed once the patient is under general anesthesia, with a cuffed endotracheal tube in place to prevent aspiration of gastric contents. The absence of blood or coffee ground material in the lavage fluid does not rule out gastric necrosis. If surgical correction cannot be performed imme­ diately, such as in a patient requiring long-distance

e18

SECTION  I  Critical Care

transport to a referral facility or when the unavailability of a surgeon precludes immediate surgical intervention, decompression may be maintained by placement of a weighted nasogastric tube with stylet (EN-tube), a pharyngostomy tube, or a temporary gastrostomy. Intermittent aspiration is required to maintain gastric decompression. Intermittent orogastric intubation is not recommended because this procedure is stressful and iatrogenic gastric rupture is a potential complication. In general, the recommendation is for definitive surgical correction for GDV within 1 to 2 hours after presentation. Early intervention, after an initial period of optimal circulatory resuscitation, has reduced postoperative fatality rates (Mackenzie et al, 2010). Prolonging the delay time carries increased risks for cardiac arrhythmias, splenic and gastric infarction, and gastric necrosis and perforation with subsequent peritonitis.

Surgical Treatment Oxygenation and a lidocaine bolus (2 mg/kg IV) followed by a lidocaine CRI of 50 to 120 µg/kg/min are recommended prior to general anesthesia. Lidocaine is recommended for both antiarrhythmic and systemic analgesic effects and to reduce the requirements for gas anesthesia (Valverde et al, 2004); the CRI dose depends on the presence of any ventricular arrhythmias. Anesthetic regimens appropriate for patients with GDV include hydromorphone (0.02 to 0.05 mg/kg), or fentanyl (5 to 10 µg/kg), with mask administration of isoflurane for the severely compromised patient and ketamine (2 to 5 mg/kg IV), combined with diazepam or midazolam (0.1 to 0.3 mg/ kg IV), and isoflurane for the stable, but moderately depressed patient. A fentanyl CRI (5 to 20 µg/kg/hr IV) should be considered to further reduce the inhalant concentration. Crystalloid, colloid, blood, or blood component administration; antiarrhythmic and electrolyte therapy; continuous electrocardiography; and serial blood pressure monitoring should continue throughout the intraoperative period. When the patient presents early with dilation alone, with no involvement of other organs and no significant metabolic abnormalities, a laparoscopic gastropexy may be an alternative to laparotomy (Rawlings et al, 2002). The permanent incisional gastropexy technique is fast and not technically challenging. It is now the preferred technique for definitive correction of GDV in the author’s hospital because of ease of performance and efficacy. This technique has replaced the previously used belt loop gastropexy. Regardless of the method used, it is recommended that areas of gastric necrosis or questionably viable stomach be removed during definitive surgical correction. Invagination into the gastric lumen of (potentially) nonviable tissue, as suggested in some texts, may predispose to DIC and is not recommended by the author. Similarly, if there are questionable areas of necrosis or thrombosis in the spleen or if the spleen does not return to a normal size after derotation, it should be removed. Unless a pyloric outflow obstruction can be clearly demonstrated, pyloroplasty is unnecessary, and the extended surgical time required to perform this procedure may

contribute to patient morbidity. If extended restriction (>24 hours) of oral food intake is anticipated, a jejunostomy tube should be placed for nutritional support.

Postoperative Management A partial list of potential complications in patients after surgical correction of GDV include cardiac arrhythmias; fluid volume overload; gastroparesis and ileus; vomiting or regurgitation; pancreatitis; DIC; gastric or abdominal incisional dehiscence; gastric ulceration; ischemic necrosis of the stomach, spleen, or gallbladder; peritonitis; incarceration of small bowel dorsal to the gastropexy site; or the development of acute renal failure. The intensity of postoperative care varies, depending on the severity of illness and surgical intervention. Additionally, cardiac arrhythmias in the postoperative period may result in death (Mackenzie et al, 2010). Optimal postoperative management includes (1) continuous electrocardiogram; (2) continuous or serial measurement of arterial blood pressure (goals are MAP >70 mm Hg and systolic pressure >110 mm Hg) and possibly of central venous pressure (goal is 3 to 5 cm H2O); (3) adequate analgesia (hydromorphone 0.05 to 0.2 mg/ kg q4h or to effect; fentanyl bolus 3 to 5 µg/kg, IV to effect, followed by 3 to 5 µg/kg/hr CRI); and (4) measurement of urinary output (0.5 to 1 ml/kg/hr). Persistent sinus tachycardia should be addressed as described previously. Additionally, where serum abnormalities were noted, the author recommends that biochemistries should be measured up to every 8 hours, with a goal of achieving normal values. Targets include serum K+ greater than 4.5 mmol/L, lactate below 2.5 mmol/L, venous pH 7.28 to 7.4, serum ( HCO3− ) 16 to 24 mmol/L (base excess ± 5), PCV 25% to 45%, and total protein 4.5 to 7.0 g/dl. Further recommendations include an ACT or aPTT, with platelet estimate and blood glucose concentration measured every 12 hours, and daily assessment of serum magnesium, creatinine, albumin concentrations, and complete blood count. Antithrombin levels ( 8 to 12 seconds) in cardiac rhythm that result in weakness, col­ lapse, or syncope may require emergent cardiac pacing. The simultaneous presence of malignant ventricular arrhythmias and complete AV block represents another situation in which pacing may either alleviate the tachyar­ rhythmia or permit safe use of antiarrhythmic drugs. Bradyarrhythmias that occur during anesthesia and those encountered with certain toxicities, especially overdose of calcium channel blockers, often respond well to tem­ porary cardiac pacing. e21

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SECTION  I  Critical Care

Dogs with sinus arrest may experience multiple synco­ pal episodes, but they are less likely to experience sudden death than dogs with third-degree AV block. In addition, dogs with sinus arrest are more likely to respond favor­ ably to pharmacologic management (anticholinergics or sympathomimetics), especially in the emergency or peri­ operative setting, which can often preclude or delay the use of cardiac pacing. In contrast, a permanent pacemaker is recommended for dogs with third-degree AV block and signs of syncope or low cardiac output. Attempts to medi­ cally treat this arrhythmia should be limited to the hos­ pital. Atropine rarely works, although one dose can be tried. Catecholamines are rarely effective in treating AV block, are proarrhythmic in patients with bradycardia, and most importantly delay potentially life-saving pacing therapy. Once the temporary pacing device has been placed and ventricular capture is established, the rate on the pulse generator is usually set between 70 and 90 pulses per minute for dogs. This rate is usually adequate to prevent syncope and meet hemodynamic demands at rest.

Bradyarrhythmia with Congestive Heart Failure In animals with simultaneous bradycardia and evidence of congestive cardiac failure, temporary pacing can be a successful adjunct to standard heart failure treatments. Although most patients with sinus node dysfunction or AV block do not present with CHF, dogs with profound bradycardia may develop pulmonary edema, pleural effu­ sion, or ascites. Some of these dogs have concurrent struc­ tural disease; for example, most dogs with sick sinus syndrome tend to have some degree of chronic degenera­ tive valve disease. Some benefit significantly from pacing along with medical therapy of CHF, and in those without structural heart disease such as dilated cardiomyopathy or severe mitral regurgitation, pacing may prevent rede­ velopment of CHF. An exception may be those dogs with atrial standstill due to atrial muscular dystrophy in which pacing may prevent syncope but cannot reverse the severe underlying myocardial disease. Because the long-term prognosis after permanent cardiac pacing for dogs with bradycardia and concurrent CHF may not be quite as good as for dogs with isolated bradycardia, assessment of overall cardiac status with echocardiography is important to determine the extent of concurrent structural cardiac disease prior to perma­ nent cardiac pacing. In the dog with bradycardia and concurrent CHF, temporary pacing can be performed for 1 to 4 days until signs of CHF have improved, the benefit of pacing is more clear, and the dog becomes a better candidate for general anesthesia. The external pulse gen­ erator is usually set at a rate between 120 and 140 pulses per minute until signs of CHF begin to resolve.

Cardiopulmonary Arrest During cardiopulmonary arrest (see Chapter 5) early iden­ tification of bradycardia and rapid initiation of a tempo­ rary pacing may supplement standard cardiopulmonary resuscitation (CPR) and may be beneficial for some

patients. Arrhythmias that may benefit from cardiac pacing include severe sinus bradycardia, advanced AV block, slow ventricular escape rhythms, and asystole. Cardiac pacing is usually not effective in animals with pulseless electrical activity (e.g., electromechanical dissociation) or for ventricular fibrillation. During CPR, pacing is usually attempted when atropine and repeated doses of epinephrine administration fail to increase ven­ tricular firing to a rate that is capable of providing ade­ quate perfusion for the patient. For pacing to be successful, ventricular capture must occur. Both ventricular capture and myocardial contrac­ tions from pacing are negatively affected by prolonged CPR as underlying myocardial ischemia, hypoxia, acidbase disturbances, and electrolyte abnormalities become more profound. In such cases, electrical capture may still occur at high current outputs, but the result may be pulseless electrical activity without effective ventricular contraction. Placement of the transvenous catheter during cardio­ pulmonary arrest is usually attempted without fluoros­ copy, and with the motion artifact that occurs on the ECG during CPR, the procedure can be exceedingly dif­ ficult. However, if open-chest CPR has been performed, the heart can often be paced directly by placing the pacing lead on the epicardial surface of the heart. The heart can be paced with this technique until the patient’s cardiac rhythm is stable or jugular vein access has been secured for transvenous placement of the lead. During CPR, TCP may be preferred if a defibrillator with transcu­ taneous pacing capability is available. The pacing rate may be dictated by other clinical parameters, but initially a pacing rate of 100 to 120 beats per minute or greater is recommended for cardiac pacing during CPR.

Temporary Transvenous Pacing Temporary TVP is minimally invasive and can be per­ formed within a short time by trained personnel. However, the approach requires significant knowledge of the car­ diovascular system and catheter manipulation, and TVP can be associated with small but significant risk. The success rate and incidence of complications are highly influenced by the experience of the clinician. Therefore emergency and critical care veterinarians should under­ stand the indications, equipment, techniques, and com­ plications associated with the procedure.

Transvenous Pacing Technique Insertion techniques can include the use of fluoroscopic imaging, intracavitary ECG monitoring, or blind advance­ ment in the jugular vein with surface ECG monitoring. Fluoroscopy is usually needed for placement of stiff, non­ floating catheters, while in many cases flow-directed cath­ eters can be advanced with some combination of ECG, echocardiographic, or fluoroscopic guidance. Balloon catheters may decrease procedure time and improve lead positioning. The ECG-guided technique is challenging, and prior experience with transvenous pacemaker implan­ tation using fluoroscopy is advantageous before attempt­ ing ECG guidance alone.

WEB CHAPTER  4  Pacing in the ICU Setting

A

e23

B Web Figure 4-1  A percutaneous sheath introducer is placed within the jugular vein via a modi-

fied Seldinger technique, and the pacing lead can be inserted through the non-bleedback port of the introducer as shown in A. The pacing lead is then connected to an external pulse generator to initiate cardiac pacing (B). The external pulse generator should be well secured to the patient to prevent lead dislodgment or migration as a result of movement.

Patient Preparation and Sedation A temporary pacemaker can usually be placed with the patient under light sedation and local anesthesia. Opiates, combined with a benzodiazepine, produce excellent mild sedation (i.e., oxymorphone, 0.05 to 0.1 mg/kg IV, or buprenorphine, 0.005 to 0.01 mg/kg IV in combination with diazepam, 0.1 to 0.2 mg/kg IV). General anesthesia may be needed in selected cases, but this is usually avoided due to concerns that induction of anesthesia could lead to severe bradycardia or asystole. Perioperative antibiotics should be administered to the patient if it is not on antibiotics at the time of the procedure. The right or left jugular vein, the femoral vein, or the saphenous veins can be used for placement of the pacing lead, depending on patient size and vascular access. In some dogs, a 4 or 5 French pacing wire may be success­ fully advanced up the lateral saphenous vein. Jugular vein access is easier, and the lead is less likely to migrate or dislodge. The right jugular vein is the more direct route to the right atrium and ventricle and avoids any issues related to a persistent left cranial vena cava, but the left jugular vein or femoral vein should be used for temporary lead wire placement if a future permanent transvenous pacemaker implantation is anticipated (as the right jugular vein is generally chosen for permanent pacing). The skin over the target vein is first clipped, quickly cleaned, and infiltrated with 2% lidocaine, after which the skin is aseptically prepared. The vessel can be accessed via a cut-down technique or by vascular puncture using a catheter sheath introducer system (5 to 8.5 French per­ cutaneous introducer) and a modified Seldinger approach (Web Figure 4-1, A). Once vascular access is secured, the pacing lead is passed into the vessel and toward the heart. Some operators prefer to insert the pacing catheter into

a telescoping plastic sleeve that can later be advanced to cover the catheter and interlocked with the vascular access sheath; this allows for repositioning with less risk of contamination. Continuous electrocardiographic monitoring is performed during lead insertion to identify correct pacing lead placement, ventricular capture, or ventricular ectopy that might require repositioning of the catheter. Difficulties in lead advancement can be encoun­ tered with variations in vascular anatomy (e.g., persistent left cranial vena cava). Placement Using Fluoroscopy Under fluoroscopic guidance, the pacing catheter is advanced into the right atrium and directed ventrally across the tricuspid valve into the right ventricle. If a flow-directed balloon pacing lead is used, then the balloon should be inflated in the right atrium to assist with passage of the catheter into the right ventricle. Passage of the pacing lead across the tricuspid valve is facilitated when the catheter is manipulated, preformed, or stiffened with a guidewire (if possible) to form an approximate 45-degree bend at the tip of the catheter. Subsequently, the pacing catheter is advanced until the tip of the catheter rests at the apex of the right ventricle. The terminals of the exter­ nal pacing device can then be connected to the lead to initiate cardiac pacing (Web Figure 4-1, B). In virtually all cases this is a bipolar pacing system and requires two connections. The external pulse generator is set in the “demand” (or VVI) mode so that spontaneous ventricular activity can be sensed and impulses are not delivered during the electrically vulnerable period of ventricular repolarization. Depending on the temporary pacing device used, the sensitivity may need to be modified gradually toward “asynchronous” (VOO) to achieve

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SECTION  I  Critical Care

Pacing spike

Web Figure 4-2  Electrocardiogram from a dog during temporary transvenous pacing. Note the high-frequency pacing spike, or pacing artifact, followed by distinct QRS and T waves.

capture and to prevent T-wave sensing. Ventricular capture should be confirmed by identifying a high-frequency pacing spike at the front of each ventricular-paced QRS-T complex on ECG (Web Figure 4-2). The pacing rate is set as previously described. The paced rhythm and heart rate, detectable via the ECG, should result in accompanying palpable arterial pulses at the same rate. Placement without Fluoroscopy ECG guidance may be used when fluoroscopy is unavail­ able, although this is much more difficult to perform effectively. The blind insertion technique is more likely to be attempted for emergency pacing for asystole (e.g., during CPR) or symptomatic third-degree AV block when fluoroscopy is not available. Placement of the catheter from the femoral vein without fluoroscopy is difficult and is not recommended for inexperienced operators. First, vascular access is secured as described earlier. Then, the approximate distance to the right atrium from the site of the vessel incision or sheath introducer is measured, and this distance is identified on the pacing catheter. A flowdirected balloon-tipped, bipolar catheter may be helpful so that the balloon can be inflated in the right atrium to facilitate catheter passage across the tricuspid valve. The balloon should be deflated once in the ventricle to avoid displacement into the pulmonary artery. Continuous ECG monitoring is observed as the catheter is advanced through the vessel toward the heart. For asystolic animals, the pacing catheter is connected to an external pulse generator in an asynchronous pacing mode with the lower rate limit set above the patient’s intrinsic rate at a comparatively high output. The surface ECG monitor allows for detection of capture, and once the electrode is against the right ventricular endocardium, a paced rhythm is noted. During the course of blind passage of the catheter one might note atrial pacing (P waves) on the surface ECG, or pacing of the diaphragm, and this might help alert the operator to the approximate location of the pacing lead and allow subsequent manipulation to direct the catheter into the right ventricle (Web Figure 4-3). The lead may coil within the right atrium, and repeated withdrawal and insertion of the lead with a twisting motion may facilitate passage of the lead across the tricuspid valve and into the right ventricle. If the patient has an intrinsic rhythm, the temporary pulse generator can be set in the “sense” mode with the current output set low (~2 milliamps). A unipolar ECG lead can be attached to the pacing lead, and the

location of the pacing catheter can be deduced from the characteristics of the unipolar electrogram. Again, this type of monitoring requires special training and experience. High right atrial pacing is usually indicated by an inverted P wave, midatrial pacing by a biphasic P wave, and lower right atrial pacing by a positive P wave. Once the catheter crosses the tricuspid valve, P wave amplitude decreases and QRS deflections are observed. Once the right ventricular intrinsic activity is sensed, the mode should be changed to the “pace” mode with the current increased while the catheter is positioned until capture is observed. Current should be sufficient to pace the heart and provide a 2 to 3 times safety margin for capture should the lead tip migrate. Marked ST-segment elevation on the unipolar ECG recording is an indicator of endocardial contact. A negative P wave is noted if the electrode passes into the pulmonary artery as the catheter tip is above the level of the atrium. Postoperative Monitoring A thoracic radiograph should be obtained after insertion of a TVP lead for verification of lead position. The tip of the lead should be positioned in the right ventricular apex. Once placement is determined to be successful and ventricular capture is confirmed, the rate of the pulse generator is adjusted to meet the patient’s needs as previ­ ously described. The current is set between 2 and 5 mA, or approximately twice the current needed to maintain consistent ventricular capture. The lead is secured to the patient’s neck (or rear leg) by placing waterproof tape on the catheter lead at the skin exit site and suturing the tape to the animal’s skin; alternatively, if a sterile sleeve system is used, a stress-loop is placed and a suture placed to secure the catheter. Finally, the insertion site is wrapped with a light bandage to protect it from external contami­ nation. The excess pacing catheter is included in the wrap of the neck (or rear leg), and the pulse generator is placed in a backpack or wrapped in a bandage around the dog’s thorax. Postoperatively, sedation and patient immobilization should be maintained to minimize the chance of lead displacement. Broad-spectrum antibiotic administration is elected by some clinicians. The bandage should be changed and the insertion site checked for signs of inflam­ mation or infection every 48 hours until the pacing lead is removed. Continuous ECG monitoring allows close observation of successful pacing and early identification of failure to capture or failure to sense intrinsic cardiac activity.

Complications Complications occurring during TVP can result in abrupt deterioration or even death of the patient. The most common issue is failure to pace the ventricle. This can result from migration of the lead away from the ventricu­ lar wall or out of the ventricle, fracture of the pacing lead, battery or pulse generator failure, or complications of lead insertion such as perforation of the vena cava or right atrium. When failure to capture is encountered, the following troubleshooting steps can be used to identify the source of the problem:

WEB CHAPTER  4  Pacing in the ICU Setting

e25

A

B

C

D Web Figure 4-3  ECG tracings during pacemaker placement without the aid of fluoroscopy

(e.g., blind insertion technique). A, The patient is in third-degree AV block prior to the procedure, with a slow ventricular escape rate. B, As the pacing lead is advanced toward the right ventricle, pacing spikes (arrowheads) can be noted to cause successful atrial capture with a P wave to follow the pacing artifact. C, As the pacing lead is advanced further, there is loss of capture; however, when looking at the dog one can identify pacing of the diaphragm. D, Following withdrawal and repositioning of the pacing lead in a ventral direction, capture of the right ventricle with successful right ventricular pacing is identified—the pacing output has been reduced and the pacing spike is very small.

1. Ensure that the pacing rate is set higher than the patient’s intrinsic heart rate. 2. Check that the battery is functioning normally. 3. Ensure good electrical contact between the connections of the pacing lead to the terminals of the pulse generator. The exposed portions of the lead should be evaluated for areas of fatigue or fractures. A cervical and thoracic radiograph may be necessary to detect breaks or to determine if the lead needs to be repositioned. 4. Slowly increase the current output from the pulse generator while observing the ECG to determine whether successful capture results. Successful capture

results if the lead tip has migrated away from the ventricular wall, leading to loss of ventricular capture. Repositioning the patient within the cage, or changing the animal’s neck position, may also temporarily solve this problem. 5. Adjust the pulse generator to an asynchronous mode, which will override the sensing and inhibition functions of the pulse generator. Although this can rarely lead to serious arrhythmia if a pulse is delivered in the vulnerable period of the T wave, this approach can be used to identify the location of the pacing lead and disorders in the sensing function of the pulse generator.

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SECTION  I  Critical Care

Additional complications that can occur in association with temporary TVP include cardiac dysrhythmias, anes­ thetic complications, vascular or cardiac perforation with the lead tip, intravascular thrombosis around the pacing catheter, and infection. Implantation of a permanent pacemaker is usually recommended by the third day of temporary pacing in order to reduce the risk of a catheterrelated infection. In human patients, the prevalence of temporary pacemaker–related complications can range as high as 20%, and they are more common in patients that require pacing for more than 48 hours. The incidence of serious thrombotic and embolic complications in humans ranges from 0.6% to 3.5%, although minor thrombotic events may be clinically silent. With appro­ priate precautions and meticulous technique, the poten­ tial complications associated with temporary pacing can be minimized. It is currently under debate whether the apex of the right ventricle is the most ideal location for lead place­ ment during permanent cardiac pacing. However, for temporary pacing, the location of the lead placement has less of a long-term deleterious effect on the heart function presented by electromechanical dyssynchrony, and the right ventricular apex is likely preferred for lead stability.

Transcutaneous External Pacing TCP can be achieved rapidly with very limited training and without moving a patient to fluoroscopy. It is likely the preferred pacing technique in animals that are uncon­ scious, in animals that are already under anesthesia, and in animals with severe systemic disease that cannot be easily transported from the intensive care unit (ICU) envi­ ronment. In addition, CPR can be safely performed with TCP because of the electrically insulating and flexible nature of the electrode pads. It has also been shown that TCP and TVP produce near equivalent hemodynamics. During TCP, electrical current is passed from an external pulse generator to self-adhesive electrode pads attached to the thoracic area. However, TCP also causes electrical stimulation of other muscles and creates significant muscle contraction and pain, necessitating general anes­ thesia for the duration of temporary transcutaneous pacing. Dogs may cry out if TCP is initiated without suf­ ficient anesthesia and analgesia. In general, TCP requires about 30 to100 times more current compared with TVP, and this technique is not tolerated in 10% of human patients because of the stinging and burning sensation experienced. Pediatric and adult pacing pads are avail­ able, and the use of longer pulse duration and larger electrodes has allowed human patients to tolerate higher applied current.

Transcutaneous Pacing Technique The materials required to provide TCP include airway and anesthetic equipment, ECG electrodes for rhythm moni­ toring, and the external pacing unit with two electrodes. Lifepak, Medtronic, and Zoll Medical provide proprietary pads, but other companies also offer pacing pads that can be used with adaptors. Pediatric pacing electrode pads

should be used for animals less than 10 to 15 kg. If the animal is conscious but hemodynamically unstable, it is important to first establish intravenous access and ensure that airway management can be provided once the patient is anesthetized. Then, an area over the chest at the right and left precordia with a size at least as large as the pacing pads is clipped. In a non-urgent situation, a small amount of alcohol is applied to the clipped area, and the skin is cleansed of hair and debris and then com­ pletely dried before the pacing pads are attached because this improves pad adherence to the skin. Subsequently, the pads are placed on the ventral aspect of the right and left thorax respectively, positioned where the apex beat is felt to be the strongest, sandwiching the heart between the two pads (Web Figure 4-4). The two pads should not be in contact with each other at the ventral aspect of the thorax. Lee et al (2010) found that in dogs the lowest capture threshold and the least severe muscle twitching were observed when the electrode pads are placed between the fifth and seventh costochondral joint on both sides. Application of a small amount of ECG cream to the very center of the pacing pad facilitates ventricular capture. In addition, the thorax should be wrapped with bandaging material in order to ensure good contact with the pads and the skin. The ECG lead of the pacing unit should be attached to the animal at this time for the pacing system to monitor the inherent cardiac rhythm properly, including sensing of native electrical activity. Although most units also record the ECG from the thoracic electrode patches, rhythm monitoring during external pacing is best done from standard limb leads to reduce the confusion of local muscle twitch artifact. It is therefore important to place the ECG electrodes away from the pacing pads, distal on the limbs, to obtain a clear ECG signal on the pacing unit monitor. The target heart rate is selected to maintain cardiac output and improve the blood pressure, with the selected rate based on the aforementioned recommendations for each clinical setting plus the clinical response to success­ ful pacing (e.g., pulse quality, membrane color and refill time, blood pressure). For bradycardia, start the pacing output at 0 mA, and increase the output by 10 mA until capture is achieved. For asystole start at the maximum current setting and decrease the output to a value above where capture is lost. To achieve external pacing capture in dogs, a relatively high current output is required. A current of less than 70 mA often does not usually result in successful ventricular capture, and in most cases capture is achieved between 70 and 110 mA. The ECG generated by TCP should only be interpreted on the pacing unit monitor. A built-in filter and blanking protection will change the high-output pacing stimulus to a smaller spike, preventing distortion of the ECG wave­ form. In contrast, regular ECG systems may display a huge pacing spike with no clearly identifiable peaks, while chest thumping produced by TCP contributes to artifacts. Capture can be assessed by finding pacer spikes followed by both a wide QRS complex and a distinct T wave with opposite polarity to the QRS complex (Web Figure 4-5). Because the ECG can be difficult to interpret and because both electrical and mechanical capture must

WEB CHAPTER  4  Pacing in the ICU Setting

A

e27

B

C Web Figure 4-4  A, Appropriate transcutaneous pacing pads should be selected for the size of

the patient, and the area of application should be shaved and cleaned. B, Electrical contact of the pads can be improved by the application of a very small amount of electrode gel in the very center of the pad. C, Once the pads are in place, on the right and left side of the thorax where the strongest apex beat is noted, the ECG leads are connected, anesthesia is induced, and transthoracic pacing can commence.

be achieved to ensure cardiac output, in all cases the effectiveness of ventricular capture must be confirmed by checking for a concurrent arterial pulse or using some other method. Arterial pressure can be monitored with a direct arterial line, a Doppler sphygmomanometer system, or an oxygen saturation monitor displaying a pulse wave­ form. Skeletal muscle contractions occur with pacemaker current output as low as 10 mA and are not an indicator of electrical or mechanical capture. These become more intense as the current output is increased. If surgery for permanent pacemaker therapy or intraab­ dominal procedure is required following TCP placement, it may be necessary to paralyze the animal during part of the surgery. The muscle stimulation of TCP can create so much body motion that surgical exposure and manip­ ulation of the jugular vein for permanent pacemaker placement or other surgery become difficult. These movements, along with the requirement for general anes­ thesia for humane TCP, represent two of the major draw­ backs to this method. To reduce muscle contractions,

neuromuscular blockade is effective but requires manual or mechanical ventilation because of diaphragm paraly­ sis. It has been the authors’ approach, during permanent pacemaker implantation in stable dogs, to only pace the heart using TCP if the escape rhythm drops below a rate of 30 beats per minute or if at a somewhat higher escape rate there is evidence of compromised perfusion or hypo­ tension. In most dogs without concurrent CHF, an escape rhythm of 30 beats per minute results in adequate perfu­ sion under anesthesia and the surgical approach is facili­ tated without the use of a paralytic agent or mechanical ventilation. If a permanent pacemaker is placed during TCP, it should be noted that the TCP pacing stimulus is sensed as a far-field signal by the permanent pacemaker in VVI or demand-mode even at currents as low as 1 mA. In this case, the permanent pacemaker is inhibited to pace, even after the output of the transcutaneous pacer is reduced below capture threshold, and blood pressure monitoring will reveal loss of pacing instantly. To avoid this

e28

SECTION  I  Critical Care

A

B Web Figure 4-5  Electrocardiograms obtained from a dog with sinus arrest that is undergoing

transthoracic cardiac pacing. A, The ECG obtained at baseline with the sensing mode of the transthoracic pacemaker turned on, but the pacing output set at 0 mA. The first five QRS complexes are ventricular in origin, followed by a pause in the rhythm, and then two junctional escape complexes are noted. The small triangles (inverted arrowheads) on each QRS complex indicate that the QRS has been sensed by the transthoracic pacing defibrillator. B, The pacing output has been increased to achieve ventricular capture and high-frequency pacing spikes (upward arrows) are followed by distinct QRS and T complexes indicating successful transthoracic pacing. In all cases, another method to confirm mechanical contraction should be performed (e.g., check for arterial pulse). In B, the first three QRS complexes are of supraventricular origin, and the fourth, eighth, and twelfth QRS-T waveforms are pacing beats initiated during pauses in sinus node firing (e.g., sinus arrest).

complication, the heart rate of the TCP should be set lower than that of the permanent pacemaker.

Complications Complications of TCP include failure to capture, superfi­ cial skin burns, muscle pain, and myocardial injury. Causes of failure to capture may be a result of electrode pad malposition, pneumothorax, pericardial or pleural effusion, or obesity. Pathologic examinations of myo­ cardial structure after TCP in canine models revealed areas of microinfarcts and an increase in cardiac bio­ marker levels (cTnI and CK-MB) for pacing longer than an hour.

Temporary Cardiac Pacing in Cats Bradycardia in cats rarely requires pacing because of the higher intrinsic ventricular escape rate. However, when severe bradycardia results in severe or frequent syncope, cardiac pacing is indicated. In most cats, TVP is preferred over TCP. Permanent TVP in cats can be associated with development of chylous effusion, especially when the lead is passed from the jugular vein and through the cranial vena cava, perhaps related to thrombosis and cranial cava syndrome. TCP is rarely performed in cats because laparotomy is required for the placement of the permanent epicardial pacing lead, and once the thorax is surgically opened the transthoracic pacing no longer works; however, a quick switch to a temporary epicardial lead, inserted between the pericardium and the

epicardium, allows control of the rhythm until the per­ manent pacing lead can be placed in the apex of the left ventricle. TVP via the jugular or femoral vein, using the same approach previously described, allows for control of the cardiac rhythm both before and during surgery. In general, cats are paced at a rate of 100 to 150 beats per minute. Much greater catheterization expertise is required for these procedures in cats.

References and Suggested Reading Bocka JJ: External transcutaneous pacemakers, Ann Emerg Med 18:1280-1286, 1989. Cote E, Laste NJ: Transvenous cardiac pacing, Clin Tech Small Anim Pract 15:165-176, 2000. Estrada AH et al: Evaluation of pacing site in dogs with naturally occurring complete heart block, J Vet Cardiol 11:79-88, 2009. Kapa S et al: Advances in cardiac pacing: beyond the transvenous right ventricular apical lead, Cardiovasc Ther 28:369-379, 2010. Lee S, Nam SJ, Hyun C: The optimal size and placement of trans­ dermal electrodes are critical for the efficacy of a transcutane­ ous pacemaker in dogs, Vet J 183:196-200, 2010. Lee S, Pak SI, Hyun C: Evaluation of changes in cardiac bio­ marker concentrations and enzyme activities in serum after short- and long-duration transcutaneous cardiac pacing in dogs, Am J Vet Res 70:599-603, 2009. Noomanova N et al: Use of transcutaneous external pacing during transvenous pacemaker implantation in dogs, Vet Rec 167:241-244, 2010. Petrie JP: Permanent transvenous cardiac pacing, Clin Tech Small Anim Pract 20:164-172, 2005. Syverud SA et al: Transcutaneous cardiac pacing: determination of myocardial injury, Ann Emerg Med 12:745-748, 1983.

SECTION II Toxicologic Diseases Chapter 20: ASPCA Animal Poison Control Center Toxin Exposures for Pets Chapter 21: Toxin Exposures in Small Animals Chapter 22: Urban Legends of Toxicology: Facts and Fiction Chapter 23: Drugs Used to Treat Toxicoses Chapter 24: Intravenous Lipid Emulsion Therapy Chapter 25: Human Drugs of Abuse and Central Nervous System Stimulants Chapter 26: Antidepressants and Anxiolytics Chapter 27: Over-the-Counter Drug Toxicosis Chapter 28: Top Ten Toxic and Nontoxic Household Plants Chapter 29: Herbal Hazards Chapter 30: Lawn and Garden Product Safety Chapter 31: Rodenticide Toxicoses Chapter 32: Insecticide Toxicoses Chapter 33: Pesticides: New Vertebrate Toxic Agents for Pest Species Chapter 34: Parasiticide Toxicoses: Avermectins Chapter 35: Human Foods with Pet Toxicoses: Alcohol to Xylitol Chapter 36: Automotive Toxins Chapter 37: Lead Toxicosis in Small Animals Chapter 38: Aflatoxicosis in Dogs

92 93 97 101 106 109 112 115 121 122 130 133 135 142 145 147 151 156 159

The following web chapters can be found on the companion website at www.currentveterinarytherapy.com Web Chapter 5: Nephrotoxicants Web Chapter 6: Reporting Adverse Events to the Food and Drug Administration–Center for Veterinary Medicine Web Chapter 7: Respiratory Toxicants of Interest to Pet Owners Web Chapter 8: Small Animal Poisoning: Additional Considerations Related to Legal Claims Web Chapter 9: Sources of Help for Toxicosis Web Chapter 10: Treatment of Animal Toxicoses: Regulatory Points to Consider

91

CHAPTER 

20 

ASPCA Animal Poison Control Center Toxin Exposures   for Pets TINA WISMER, Urbana, Illinois

C

ommon things happen commonly” is a good adage for veterinary toxicology. Knowing which toxicoses happen most frequently can help when formulating a list of differential diagnoses. The Animal Poison Control Center (APCC) of the American Society for Prevention of Cruelty to Animals (ASPCA) began as the Illinois Animal Poison Information Center (IAPIC) in November 1978 at the University of Illinois. When it first started the center averaged one call per day and dealt mostly with large animal–related inquiries (48% ruminants, swine, horses, and poultry). By 1981 it received up to six calls a day, with 63% being small animal–related inquiries (dogs 49%, cats 14%). During 2010 there were approximately 167,000 cases opened concerning possible animal poisoning. It should be noted that these data reflect exposure and not confirmed toxicosis. Domestic dogs made up the majority of exposures with 84.9%, followed by cats with 13.2%, birds and small mammals (ferrets, lagomorphs, and rodents) with 0.7%, and livestock (horses and cows) with only 0.5%. These changing demographics may reflect the  fact that animals living in a house have more opportunities for exposure to various substances than livestock, which live in a more controlled environment. It also reflects the urbanization of North America, with more pets living inside as family members. Most calls are initiated by the owner (75.9%), but 18.5% stem from veterinary personnel. The majority of dog and cat poisonings are accidental, with ingestion of dropped pills the most common scenario. Oral exposures to toxins make up 85.6% of all inquiries. Dermal exposures are next with 6.2%, followed by a combination of dermal/oral with 3.6%. Although exposures are steady throughout the year, the summer months always show an increase in calls (Figure 20-1). This may be due to pets having increased access to the outdoors and its associated toxins (plants, herbicides, insecticides), pets having increased exposure to flea and tick treatments, or children being at home on vacation and possibly not being as vigilant with keeping substances out of a pet’s reach. The 2 weeks around Christmas have a 10% increased call volume, mostly related to chocolate, a popular gift given during a hectic season in which pets may not be as carefully monitored. October, with Halloween, also has an increased call volume related to pets ingesting candy and chocolate. “

92

14000 12000 10000 8000 6000 4000 2000 0

Jan Feb Mar April May June July Aug Sept Oct Nov Dec

Figure 20-1  Monthly distribution of cases at the ASPCA APCC.

TABLE 20-1  Dog and Cat Exposures to the Most Common Categories of Substances (2010) Poison

Dog

Cat

Total

Percentage

Human prescription pharmaceuticals

7983

884

8867

16.8

Toxic foods

7790

185

7975

15.1

Insecticides

7209

3514

10723

20.4

Rodenticides

5307

218

5525

10.5

Veterinary pharmaceuticals

5022

442

5464

10.4

Human OTC pharmaceuticals

4959

300

5259

10.0

Plants

2143

1107

3250

6.2

Household*

1700

80

1780

3.4

Herbicide

1173

106

1279

2.4

Miscellaneous

697

136

833

1.6

Cleaning products

510

114

624

1.2

Lawn, garden

417

15

432

0.8

Automotive

261

45

306

0.6

Foreign body

184

8

192

0.4

Bite, sting, envenomation

134

19

153

0.3

45489

7173

52662

Totals

OTC, Over-the-counter. *Household toxins include items such as fire starter logs, mothballs, glues, paints, batteries, and coins.

CHAPTER  21  Toxin Exposures in Small Animals The previous information offers some epidemiologic bias including: 1. The APCC’s telephone number has been publicized primarily among veterinarians but is also available   to people with Internet access. 2. Calls are more likely when clinical signs develop than when no signs are apparent. 3. Calls from owners are more likely after exposure to a substance that has received media attention (see Chapter 22). 4. Once veterinarians have become familiar with the clinical signs and treatment of a toxicosis, they are less likely to call about that agent again. Despite these inherent biases, the pattern of species in­­ volvement and substance exposure trends has been quite consistent for years (Table 20-1). Dogs are most commonly exposed to human prescription pharmaceuticals. They ingest dropped pills or may

CHAPTER 

93

chew up vials of medication. Cats are overrepresented  in the insecticide category when compared with other poison categories. For example, many calls were initiated by owners who had applied non–feline-approved flea products to their cats. Other calls related to cats drooling after the application of an insecticide (a spot-on or  spray product). People may be more likely to call about  their indoor-only cats, and therefore cats are likely to be underrepresented in the outdoor toxin categories, such  as automotive products, lawn and garden chemicals,  and herbicides. The frequency of poison exposures depends on the animal’s activity level and sensitivity. An agent’s availability and prevalence of use are also important factors. Most households contain ibuprofen or acetaminophen, agents at the center of a large percentage of the calls  to the APCC involving over-the-counter medications. Pharmaceuticals, plants, and other compounds that are widely available are more likely to cause clinical poisonings; again, “common things happen commonly.”

21 

Toxin Exposures in Small Animals COLLEEN M. ALMGREN, Bloomington, Minnesota SHARON L. WELCH, Bloomington, Minnesota

P

et Poison Helpline (PPH), a division of SafetyCall International, has been providing fee-for-service animal toxicology and poison information since 2004. The help line is available to animal owners, veterinarians, veterinary students, veterinary technicians, pesticide control officers, and others 24 hours a day, 7 days a week, 365 days a year on a fee-per-case basis. The help line is staffed by board-certified veterinary toxicologists (Diplomate of the American Board of Veterinary Toxicology [DABVT], Diplomate of the American Board of Toxicology [DABT]), veterinarians, and certified veterinary technicians. A variety of board-certified veterinary specialists and allied health professionals including pharmacists, physicians, zoologists, and others with advanced training are available 24/7 for consultation. Call volumes for animal toxicology cases have increased steadily over the past several years (Figure 21-1). Whether this represents an actual increase in exposures, an increase in awareness and use of available animal toxicology services, or both is unclear. The call distribution represents a sample of the type of animal toxicology questions posed

to small animal practitioners. The source of these calls, species affected, age of animals, and toxin and foreign body types are briefly summarized.

Call Source During the 12-month period beginning July 1, 2010 and ending June 30, 2011, PPH received over 30,000 animal toxicology calls. About 60% of calls originated from pet owners and 30% from veterinarians, veterinary hospitals, or clinics. The remaining calls came from myriad sources including zoological gardens, farms, ranches, pesticide control offices, restaurants, and pet stores.

Species Affected Dog exposures accounted for 90% of the calls, with cat exposures accounting for 9%. The remaining 1% involved primarily caged birds, ferrets, rabbits, small rodents, sugar gliders, other pocket pets, potbellied pigs, goats, chickens, horses, fish, turtles, and a rare primate.

SECTION  II  Toxicologic Diseases

94

underlying disease conditions and neoplasia including hemangiosarcoma).

35000

Call volume (thousands)

30000

Age

X 25000 20000

Most of the calls involved younger animals. Of caninerelated calls, 76% concerned dogs 5 years old and younger, with 21.9% concerning dogs 6 to 12 years old. Very few calls (2.1%) involved dogs in the 13- to 19-year age range. Of cat-related calls, 67.8% involved cats in the 0- to 5-year age range and 24.6% in the 6- to 12-year age range; 7.6% of the calls involved cats 13 years and older. No agerelated data were retrieved for the other species.

X

15000

X X

X

10000 X 5000

Call Types

0 2004

2005

2006

2007

2008

2009

2010

Year Total calls

Feline

X Canine

Other species

Figure 21-1  Total call volume 2004-2011.

Plants and Mushrooms

TABLE 21-1  Category of Deaths Category

Number of Deaths

House and garden Insecticide Metaldehyde Rodenticide Ethylene glycol

2 1 2 1

Caffeine

2

Human drugs (prescription and over-the-counter)

For the purpose of investigating the specific toxin/foreign body responsible for the call, calls were divided into nine general categories (Table 21-2) Subdivisions were used in each category as needed to further classify information.

11

Household products

1

Xylitol

1

Other

10

The majority of canine exposures were attributed to the following breeds: 7014 calls pertaining to mixed breeds, followed in decreasing order by the Labrador retriever (2673), golden retriever (1065), Chihuahua (793), Yorkshire terrier (771), cocker spaniel (629), beagle (625), and boxer (614). Cats were split between domestic shorthair, domestic longhair, and mixed breed or unknown. Thirty-one deaths were reported during the 12-month period from July 1, 2010 to June 30, 2011 (Table 21-1). This number may be falsely low because some cases had unknown or undocumented outcomes. Twenty-four dogs, three cats, two guinea pigs, and one sugar glider died or were humanely euthanized. The most common cause of death in all species was from ingestion of human medications, followed by rodenticides; pesticides or other products used around the house and garden to eliminate insects, rodents, or weeds; and unknown toxins. Ten of the recorded deaths were due to unrelated causes (e.g.,

Almost all calls involving plants and mushrooms (1513) originated from the caller’s home. When corrected for increasing monthly volume, the number of calls per month was relatively steady across the calendar year. Two small spikes occurred: one in December when the number of poinsettia calls increased and one in April associated with an increase in Easter lily calls. Other common plant calls included oxalate-containing plants, azalea, sago palm, marijuana, cyclamen, and all varieties of lilies. More than 60% of the plant ingestions involved symptomatic cats and were primarily associated with some form of lily or oxalate-containing plant. Sago palm and marijuana exposures were limited to the dog population.

Human Drugs and Herbal Supplements Over 4000 human drugs and herbal supplements were identified as potential toxins. This number does not reflect the actual call volume because multidrug ingestions occurred with some frequency and were generally associated with the most serious and life-threatening ingestions. Within this category human prescription drugs constituted about 60% of calls, while exposure to overthe-counter (OTC) drugs and nutraceuticals constituted about 40% of the calls. Oral products accounted for almost all of the human prescription drug exposures, with very few calls involving ingestion of topical agents, patches, suppositories, lollipops, and inhaled or injectable substances. Within the human prescription drug division, antidepressant drugs, antianxiety drugs, newer sleep-inducing drugs, drugs for attention-deficit disorder, and cholesterol-lowering drugs were overrepresented. Despite the large number of calls generated by these drugs, few serious outcomes occurred. Two of the drug-related canine deaths were from ingestion of topical 5-fluorouracil products. Baclofen and other prescription pain medications were responsible for many of the extremely symptomatic canine patients.

CHAPTER  21  Toxin Exposures in Small Animals

TABLE 21-2  Classifications of Call Type Call Type Human drugs and nutraceuticals

Yearly Call Volume >12,000

Pesticides Rodenticides Fertilizers and plant foods Insecticides Herbicides Metaldehyde

1715 524 380 215 30

Plants

1408

Mushrooms

105

Mycotoxins

14

Food Chocolate Xylitol Vitis sp. (grapes, raisins, currants) Allium sp. (onion, garlic, chives) Coffee Tea Alcoholic beverages Macadamia nuts Bread/bread dough Household products Cleaners, disinfectants, bleach Paint, stain, varnish Soap Batteries Pool and spa chemicals Air fresheners, potpourri Deodorant Other (primarily automotive) Ethylene glycol Brake fluid Transmission fluid Veterinary drugs

1924 846 374 154 102 85 59 45 29 840 294 185 125 67 58 47 54 20 8 >2400

95

this category. Other common foreign body ingestions included batteries of all types, plastic, fireplace starter logs, pens, pencils, coins, glues, heat wraps, hand/foot warmers, ice packs, and dryer sheets. Some of the more interesting items ingested included taxidermy specimens, 40 starfish, fiberglass insulation, drywall, part of a home foundation, light bulbs, and glass.

Household Products Exposures involving household products were equally split between dogs and cats. The exposures were divided into those involving laundry products, general cleaning products, toilet products, carpet-cleaning or carpet-freshening products, and essential oils. When further analyzed, cat exposures occurred most often in the laundry and bathroom area, whereas dog ingestions occurred throughout the home and involved primarily carpet-freshening agents and general cleaning products. Clinical signs in this category for all species were usually mild and selflimiting. Essential oils were more likely to cause significant clinical signs than other agents in this category.

Food-Related Products Of the 3618 food-related calls, over half involved dogs ingesting some form of chocolate. This was consistent for every month. Other food products included nuts (almonds, macadamia nuts, and hazelnuts), onions, grapes and raisins, and xylitol-containing products (gums, mints, cough drops, and other sugar-free items). When corrected for increasing call volume, a distinct increase occurred in December and again in late March and early April. Butter, gravy, meat products, eggnog, and alcohol ingestions all increased in December, presumably because of increased availability and decreased surveillance. The number of chocolate and candy ingestions increased around Easter, Halloween, Christmas, and to a lesser extent Valentine’s Day, again presumably because of the greater availability.

House, Lawn, and Garden Products OTC drugs and nutraceuticals showed a slightly different picture, with about 10% of the ingestions involving topical medications and ophthalmic solutions. Within this category, pain medications such as acetaminophen (APAP), aspirin, ibuprofen, and naproxen were the drugs most commonly ingested, followed by cough and cold products, multivitamins, herbal supplements, and calciumcontaining supplements. With the exception of the pain medications and imidazoline decongestants (naphazoline, oxymetazoline, tetrahydrozoline, xylometazoline), clinical signs in this group were generally mild and selflimiting. Two feline drug-related deaths occurred from APAP overdose.

Foreign Bodies Surprisingly, silica gel packets made up over 50% of the calls falling into the foreign body category. Labrador and golden retrievers accounted for the majority of victims in

Almost 2900 calls involved exposures to house, lawn, and garden products (i.e., products meant to eliminate insects and other pests or rodents, herbicides, fertilizers). Pyrethrin-based insecticides accounted for over 80% of the insecticide calls, followed by avermectin or ivermectin, hydramethylnon, imidacloprid, and boric acid. Outcomes in this group varied from no clinical signs to severe, with cats having the most severe symptoms (especially when exposed to permethrin-based products formulated for dogs). Moderate to severe clinical signs (tremors, seizures) were also noted in some dogs ingesting granular bifenthrin products. Calls regarding a carbamate, organophosphate, or arsenic compound occurred much less frequently, but the outcome was generally much more critical. Deaths in the insecticide group were from exposure to either a concentrated product or very large amounts of a more dilute product. A genuine seasonal occurrence occurred with these calls, with the incidence highest in summer and lowest in winter.

96

SECTION  II  Toxicologic Diseases

Most of the rodenticide calls concerning ingestion of long-acting anticoagulant agents involved dogs. Call numbers varied little from month to month. Most calls originated from the caller’s home and were managed with no clinical signs. Calls originating from a health care facility were often associated with more severe clinical signs and required prolonged care and treatment. Brodifacoum and bromadiolone ingestions occurred with the most regularity. The remainder of the rodenticide calls included difethialone, diphacinone, and bromethalin. Several calls involved some form of sticky board exposure and typically involved cats or small dogs. The distribution of rodenticide calls is expected to change dramatically in the near future due to new regulations restricting the use of long-acting anticoagulant rodenticides. Bromethalin exposures are expected to become much more prevalent. Household herbicide and fertilizer calls were almost always of low toxicity and involved a taste, touch, or lick of a product or ingestion of treated grass. Rarely did any clinical effects develop, and signs that occurred involved primarily vomiting and mild gastrointestinal irritation. There was a distinct seasonal occurrence to these calls, with the lowest call volume in December and January and the highest in early spring and summer.

Metaldehyde Metaldehyde, although technically a pesticide, was counted separately because calls related to this product were almost always associated with a moderate-to-severe clinical outcome. This product is used for controlling snails, slugs, and other gastropods. In addition to the inherent toxicity, the product is often placed and forgotten until dug up and ingested by a curious dog. One documented canine death was attributed to metaldehyde.

Veterinary Products Dogs and cats were equally represented in calls involving veterinary products. Topical flea and tick products, including pyrethrin-based products, showed a seasonal occurrence, whereas nonsteroidal antiinflammatory drug ingestion was steady from month to month. Clinical signs and outcomes were worse with pyrethrin-based flea products, especially in cats. Other calls, primarily those involving dogs, concerned heartworm medication, prescription animal drugs, anthelmintics, and nutraceuticals. Clinical effects for almost all these categories were mild and self-limiting with the exception of avermectins including ivermectin.

Others The remaining calls were lumped into the other category. Within this group, automotive products were the most prevalent, with more than 82 exposures in the 12-month period. Of these, 54 were known exposures to ethylene

glycol, which was responsible for one reported feline death. Fortunately no reported canine deaths occurred. Personal care products such as shampoo, soap, nail polish remover, deodorant, and other items accounted for numerous calls but were all of low toxicity and generally resulted in few clinical effects. Oddly, animal and insect bites or stings occurred year-round, with two to three calls occurring each month. The outcome was generally good, and clinical signs were mild to moderate. Although dog exposures made up the vast majority of calls, clinical effects were usually mild, and the outcome was excellent. Despite the smaller number of calls, cats seemed to have a more difficult time with ingestions, often exhibiting significant clinical signs. This may be because of their relatively smaller body size or differences in metabolic pathways.

Summary In summary, PPH handled over 30,000 calls from July 1, 2010 to June 30, 2011, with 31 reported and documented deaths. The majority of calls originated from the caller’s home, and the animals involved generally had no-to-few clinical signs and were treated at home with no referral to a veterinary facility. About 90% of the calls involved young dogs, followed by cats and a variety of other species. The most commonly reported exposures were to human pharmaceuticals and OTC drugs/nutraceuticals, followed by rodenticides, pesticides, and other agents used in the lawn and garden.

References and Suggested Reading Barton J, Oehme FW: The incidence and characteristics of animal poisonings seen at Kansas State University from 1975-1980, Vet Hum Toxicol 23(2):101, 1981. Buck WB: A poison control center for animals: liability and standard of care, J Am Vet Med Assoc 302(8):1118, 1993. Forrester MB, Stanley SK: Patterns of animal poisonings reported to the Texas Poison Center Network: 1998-2002, J Am Vet Med Assoc 46(2):96, 2004. Haliburton JC, Buck WB: Animal poison control center: summary of telephone inquiries during first three years of service, J Am Vet Med Assoc 182(5):514, 1983. Hornfeldt CS, Murphy MJ: Poisonings in animals: a 1990 report of the American Association of Poison Control Centers, Vet Hum Toxicol 34(3):248, 1992. Hornfeldt CS, Jacobs MR: A poison information service for small animals offered by a regional poison center, Vet Hum Toxicol 33(4):339, 1991. Hornfeldt CS, Borys DJ: Review of veterinary cases received by the Hennepin Poison Center in 1984, Vet Hum Toxicol 27(6): 525, 1985. Klaassen CD, editor: Casarett and Doull’s toxicology: the basic science of poisons, ed 7, New York, 2008, McGraw-Hill Professional. Osweiler GD et al: Blackwell’s five-minute veterinary consult clinical companion, small animal toxicology, Ames, IA, 2011, Wiley-Blackwell. Peterson ME, Talcott PA: Small animal toxicology, ed 2, St Louis, 2006, Elsevier Saunders. Plumlee KH: Clinical veterinary toxicology, St Louis, 2004, Mosby.

CHAPTER 

22 

Urban Legends of Toxicology: Facts and Fiction FREDERICK W. OEHME, Manhattan, Kansas WILLIAM R. HARE JR., Beltsville, Maryland

T

ens of thousands of potentially toxic exposures are reported to U.S. animal poison control centers annually. Most of these exposures are not life threatening, and many do not cause harm. Understanding the realistic significance of these exposures depends on knowledge of the animal species, the actual toxicity of the chemical to which the animal was exposed, and the circumstances surrounding the exposure. All substances must be considered potentially toxic; however, whether clinical toxicity occurs is often simply a matter of whether a dose delivered to the animal is high enough to cause toxicosis. Considerations in formulating a toxicologic risk assessment include (1) the toxic substance and its chemical and physiologic characteristics such as concentration and formulation, (2) characteristics of the animal involved such as species, size, age, sex, and physiologic condition, and (3) the exposure characteristics, which include the route and duration of exposure. Ingestion is by far the most common route of exposure. Therefore, given the numerous chemical and biologic variables involved in any exposure instance, it is unsurprising that not all exposures to toxic substances result in clinical toxicosis. The role of the clinician is to review the specific circumstances surrounding an exposure and offer appropriate judgment and recommendations. Favorable outcomes depend on prompt veterinary intervention following any potentially harmful exposure. Brand name products often change ingredients through the years, which often alters the hazard. Products with similar names and intended mimicry in names can cause confusion when determining an assessment of relative risk. Therefore it is always important to read the label, determine the ingredients, and be certain that an actual exposure did occur. It is also critical to examine the patient. All too frequently, however, individuals with emotional concerns and limited chemical and medical knowledge become vocal in news and electronic media—for example, the Internet—in declaring toxic problems inappropriately. These are often blanket statements incriminating products or situations as being the absolute cause of animal illnesses or death. Once these statements become ingrained in the media and are circulated widely, they become urban legends. Such urban legends may be repeatedly presented to veterinary practitioners as inquiries, concerns, or even facts. The truth is that almost all urban legends are exaggerations of potentially risky situations or misinterpretations

of related information that are erroneously applied to everyday events or behaviors. It then becomes the responsibility of veterinarians to apply their knowledge and people skills to clarify these concerns and hopefully place the urban legend in its appropriate category. The following are a selected number of statements concerning potentially toxic exposure situations that have commonly been reported to veterinarians. In some cases the concerns may be valid, whereas in others evidence of significant risk simply does not exist. Many urban legends are rumors spread through Internet communications. It almost goes without stating to be careful of Internet misinformation. As much as we all appreciate information, to quote former President Ronald Reagan, “Information is good information only if it can be verified.” Consider how you would respond to the following statements. Are they true, false, or possible? Remember that often it is the combination of variables that ultimately affects the outcome of every chemical exposure!

Home Care and Cleaning Products • Ingestion of any small desiccant sachet “Fresh-Packet” is harmless to dogs and cats. False: These products serve as a desiccant, as the name implies, to control spoilage due to accumulation of moisture and/or oxidation. They may contain silicates (Na2SiO3), activated carbon (charcoal), iron compounds (FeN3O9), or other desiccants. In addition, sometimes the silicate products contain a color indicator (CoCl2) that turns pink when hydrated. Each of these ingredients may irritate the gastric mucosa; the iron-containing packets and color indicator–containing packets can be toxic to dogs and cats. • Ingestion of Swiffer WetJets kills dogs by liver failure. False: This product contains water (80% to 90%), propylene glycol (1% to 4%), isopropyl alcohol (1% to 4%), and preservatives (0.1%). Propylene glycol is much less toxic than ethylene glycol found in antifreeze, and this concentration of propylene glycol taken orally should not present a hazard. If there is a problem following ingestion, most likely a foreign body has been introduced or it is the result of a preexisting condition. 97

98

SECTION  II  Toxicologic Diseases

• Ultra Clorox contains lye and therefore is potentially dangerous for your dog. False: Both ultra Clorox and regular Clorox bleach formulations contain 5.25% aqueous sodium hypochlorite but not sodium hydroxide (i.e., lye). However, sodium hypochlorite is still corrosive and may cause harm from eye or skin contact, ingestion, or inhalation. It is often used as a good premise disinfectant, but it is best to keep it away from pets. • Pot-scrubbing sponges contain dangerous amounts of Agent Orange (2,4-D + 2,4,5-T). False: Packages of these commercially available sponges are moist inside because a liquid antimicrobial is included to ensure that no fungal growth develops. The antimicrobial agent is a nontoxic disinfectant and even has some perfume added. Now hands will smell nice after “doing pots and pans.” However, if the sponges become grease filled and are ingested, they could lead to gastrointestinal obstruction. It is best to properly dispose of these products following their use. • Febreze, the odor elimination product, is dangerous for household pets. False: Zinc chloride, present in the pre-1998 formulation, was removed, and now the product is sold as a pump spray rather than as an aerosol that could have been an inhalation hazard to some birds in confined spaces. Febreze contains water, alcohol, a corn-derived odor eliminator, and fragrance. Toxicity is not expected with routine use, even with exaggerated exposure. • Resolve spot and stain carpet cleaner is lethal when ingested by dogs and cats. False: This product contains soap, sodium bicarbonate, alcohols 1.5% (ethanol, 2-propanol, and carbinol), glycols 1% (propylene glycol and methyl ether), citrus/pine scent, and water. It is not a lethal formulation. It can cause temporary minor eye irritation and mild gastrointestinal upset if ingested. It is best to keep all household products out of a pet’s reach.

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Foods • Macadamia nuts produce muscle weakness in dogs. True: Weakness, depression, and vomiting usually occur 6 or more hours after ingestion of about 1 nut per kilogram of body weight, or more. Weakness and depression gradually improve after 24 hours in dogs without significant preexisting medical conditions. • Ingestion of grapes and raisins may result in acute renal failure in dogs. True: Vomiting, polydipsia, and lethargy can occur 5 to 6 hours after ingestion, followed by anorexia, anuria, tremors, and diarrhea. One to two grapes per kilogram of body weight has been reported as sufficient to induce adverse clinical signs in some dogs. Significant ingestion warrants prompt decontamination (emesis), followed by oral dosing with activated charcoal. In addition, aggressive fluid therapy within 48 hours may prevent acute renal failure from developing. Interestingly, this syndrome

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has not been reported in cats, and many dogs ingesting grapes or raisins do not develop clinical signs of toxicosis. Ingestion of sugarless candy/gum containing xylitol is poisonous to dogs. True: Weakness, ataxia, and total collapse may occur 30 to 60 minutes following ingestion of significant amounts of sugarless candy, gum, or breath-mints. Xylitol promotes insulin release by the pancreas, which results in profound hypoglycemia. Absorption is rapid, and activated charcoal is not efficacious in most instances. Acute hypoglycemia is best treated with intravenous dextrose—an initial bolus followed by continuous intravenous drip, with blood glucose concentrations being monitored over the next 12 to 24 hours (see Web Chapter 24). Tea is a good poisoning antidote for cats and dogs. False: Tea contains 300 to 1200 mg/oz of caffeine, whereas semisweet chocolate contains 22 to 138 mg/ oz, making tea on average 5 to 10 times more toxic than chocolate. Tea does have other beneficial actions, but for cats and dogs the bad effects from the high caffeine usually outweigh potential good effects. Ingestion of chocolate can poison cats and dogs. True: Chocolates contain the methylxanthines caffeine and theobromine, which can be toxic. Unsweetened baking chocolate contains the most methylxanthines (40 and 390 mg/oz for caffeine and theobromine, respectively), and white chocolate has the least (0.8 and 0.2 mg/oz, respectively). The higher the cocoa content of the chocolate, the higher the methylxanthine risk per ounce of chocolate. Hyperactivity, polydipsia, vomiting, diuresis, diarrhea, restlessness, tachycardia, cardiac arrhythmia, and seizures usually occur in a progressive fashion beginning shortly after significant ingestions. Treatment should be directed at decontamination, control of anxiety and seizures, and the support of renal elimination through fluid diuresis. Ingestion by dogs of cocoa beans, coca hulls, cola, coffee, and tea leaves may require emergency treatment. True: All contain variable but potentially toxic concentrations of methylxanthines (caffeine, theobromine, and theophylline). Depending on the dose ingested, acute vomiting, excitement, cardiac irregularities, tremors, and seizures may result. Treatment includes early digestive tract evacuation plus activated charcoal/cathartics, diazepam for seizures, and lidocaine or atropine for lifethreatening cardiac effects. Onions and garlic can be bad for dogs. True: Although bad is a relative term, too much acute exposure—or to a lesser extent, chronic, low-level dietary exposure—to onion or garlic may produce depression, rapid heart and respiratory rates, and pale mucous membranes. The anemia results from free radicals that cause Heinz bodies to form, damage to red blood cells, hemolysis, and methemoglobinemia. Effects persist for several days after exposure stops. Vitamin C and/or

CHAPTER  22  Urban Legends of Toxicology: Facts and Fiction administration of other antioxidants may have therapeutic benefits. Cooked onions and garlic are much less of a hazard than the raw food. • Ingestion of Greenies treats is enjoyable but not risk free for cats and dogs. True: Greenies are hard, green, molded boneshaped treats that contain wheat gluten, glycerin, cellulose, and other additives that are both enjoyable and nutritious for pets. Greenies are intended to be chewed before ingestion to help prevent oral odors, tartar buildup, and gingivitis. Unfortunately pets occasionally swallow large pieces of these hard treats rather than chewing them into smaller pieces. Ingestion of large pieces of Greenies has the potential of creating an esophageal or intestinal obstruction and fails to accomplish the intended use.

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Plants and Herbs • Herbal products can harm cats and dogs. True: When left open and available, potpourri, garden herbs, cooking powders, perfumes, and various odorants and similar scent products are attractive to cats. The essential oils in such materials are irritants, which cause damage to sensitive respiratory cells, skin epithelium, and mucous membranes in general. Some herbal supplements may also contain steroids, benzodiazepines, heavy metals, analgesics, nonsteroidal antiinflammatory drugs, caffeine, atropine, and other constituents that are hazardous to pets that ingest or have contact with them. • Ingestion of Easter lilies (Lilium longiflorum) is highly poisonous to cats. True: Vomiting, hypersalivation, depression, and anorexia usually occur within 1 to 2 hours after ingestion, followed by anuria and severe renal failure 2 to 4 days later. All parts of the plant should be considered poisonous, and almost all species of Lilium should be considered toxic. Dogs only appear to be affected with gastrointestinal upset. The sooner treatment is begun, the better the prognosis. • Ingestion of poinsettia flowers or leaves can make cats and dogs sick. True: Native poinsettia (Euphorbia pulcherrima) belongs to the large Euphorbia genus of flowering plants. This genus may contain a milk-like sap that contains diterpenoid esters. These compounds can act as irritants. On the other hand, cats or dogs chewing or ingesting the cultivated ornamental poinsettia flower or leaves rarely exhibit more than mild gastrointestinal upset or simply drool from the plant’s taste. Serious consequences are rarely seen. Treatment usually consists of washing away the sap with a drink of water or milk.

Other Ingestions • Ingestion of pennies and other coins is hazardous to household pets. True: U.S. pennies minted since 1982 are copper coated, weigh 2.5 g, and contain 97.5% zinc. Although the adverse clinical signs of zinc poisoning,

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characterized by severe gastroenteritis and marked intravascular hemolysis, may be delayed following the ingestion of pennies, significant lodging of pennies in the acid media of the stomach increases the risk of zinc poisoning. Coins of other value do not contain zinc but can cause foreign body GI trauma. Centipedes, if eaten by pets, can cause harm to the ingesting animal. True: All species of the order Scolopendromorpha (i.e., centipedes having 21 or 23 pairs of legs) are venomous and can inflict harm by their bites or because they have been ingested. These centipedes have a stinging apparatus connected to their first pair of legs. Little is known of their venom; however, endopeptidase, cardiotoxin (toxin-S), serotonin, histamine, lipids, and various polysaccharides have been identified. No fatalities have been reported, but ingestion can produce vomiting, anxiety, and an irregular heartbeat or may simply induce a mild digestive upset. Ingestion of caterpillars and butterflies by cats and dogs can be harmful. True: Several types of hair, setae, or bristles cover the bodies of butterflies, moths, and their caterpillars. These hairs are irritants and sometimes are associated with venomous glands. No less than 200 varieties of these insects are known to be poisonous. Harm may result as a dermatologic syndrome, an ophthalmic injury, or respiratory and digestive syndromes. Mild gastrointestinal upset appears to be the most common hazard. Parenteral administration of penicillin G procaine can cause spinal cord damage. False: Penicillin G procaine (procaine penicillin G) is an equimolar salt of procaine and penicillin G in sterile solution. Penicillin G is one of the safest parenteral antimicrobial drugs available for use in animals. It has been used successfully for more than 50 years. However, there are always exceptions. A significant amount of penicillin G procaine injected directly into the spinal cord or even injected epidurally could cause spinal cord damage. Likewise, use of penicillin in animals known to be hypersensitive to penicillin is problematic. Use is contraindicated in guinea pigs and chinchillas, as well as in certain species of birds, snakes, turtles, and lizards. Vitamins A and D have toxic potential for most animals. True: Excessive amounts of vitamin A promote bone lesions with potential development of exostoses, which in turn may cause pressure on spinal nerves, resulting in paresis or other nerve deficits. Excessive amounts of vitamin D lead to hypercalcemia and calcium deposition of soft tissues, resulting in gastrointestinal, cardiopulmonary, and renal pathophysiology. Ingestion of lipstick by cats or dogs results in lead poisoning. False: The formulation of lipstick and other cosmetics is closely regulated and does not include lead as a constituent. However, many of the paints used in arts and crafts still contain potentially

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SECTION  II  Toxicologic Diseases

dangerous levels of heavy metals (including lead, barium, cadmium, and mercury). Red, yellow, orange, green, violet, vermillion, white, and black paints may contain toxic heavy-metal pigments and may also be potentially carcinogenic. • DEET mosquito repellent products are safe for use on cats and dogs. False: All DEET (N,N-diethyl-meta-toluamide)– containing mosquito repellent products are potentially toxic to cats and dogs. Hypersalivation, vomiting, anxiety, tremors, ataxia, and seizures may occur within 6 hours following excessive exposure. Animals need to be decontaminated (dermal washing, oral-activated charcoal), their hydration monitored, and supportive therapy initiated as soon as possible following exposure. There is no antidote. • Ingestion of environmental mosquito larvicides containing Bacillus thuringiensis israelensis (BTI) is deadly to cats and dogs. False: All mosquito prevention products containing BTI for use around the home (e.g., floating donuts, granules, liquids, briquettes) are generally safe. They may potentially cause gastrointestinal upset 3 to 6 hours following ingestion, and on rare occasions ingestion of floating donuts could result in formation of a gastrointestinal obstruction. However, they do help eliminate mosquito pests. • Human drugs tend to be less toxic to dogs and cats and therefore accidental ingestion is not usually a problem. False: Human medications have a much narrower margin of safety in animals and any accidental ingestion should therefore be regarded as potentially toxic. Among the most hazardous are pain relief medications and antidepressants. However, all human medications should be regarded as hazardous to animals, unless prescribed by a veterinarian.

• Anything and everything can be potentially toxic for a companion animal. True: DOSE ALONE CAN MAKE ALL THE DIFFERENCE! As may be seen from the previous examples of urban legends taken from various Internet sites, some have selected validity, some are clearly erroneous, and others are half-truths and depend on the circumstances of exposure. Veterinarians called on to respond to clients’ concerns about such electronic postings or related neighborhood rumors must use their knowledge, experience, and common sense to provide appropriate, realistic, and professional clarifying information. In some instances questions about the real toxicologic facts may develop, and other professional resources may be researched. Colleagues certified by the American Board of Veterinary Toxicologists (www.abvt.org) are widely available and can be contacted at nearby universities or animal poison centers. Clarification of related chemical details and the expertise of veterinary toxicologists are usually no more than a telephone call or computer keyboard click away; once the networking has been initiated, keep the phone number or online address in a readily available and visible place. Misconceived or erroneous urban legends fade away slowly!

References and Suggested Reading Gupta RC: Veterinary toxicology: basic and clinical principles, New York, 2007, Academic Press. Material Safety Data Sheets (MSDS): For commercial products MSDSs are available from manufacturers off their websites. Peterson ME, Talcott PA: Small animal toxicology, ed 2, St Louis, 2006, Elsevier. Plumlee KH: Clinical veterinary toxicology, St Louis, 2004, Mosby.

CHAPTER 

23 

Drugs Used to Treat Toxicoses SHARON M. GWALTNEY-BRANT, Mahomet, Illinois

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aracelsus, who some consider the “Father of Toxicology,” declared in the sixteenth century, “All substances are poisons; there is none which is not a poison. The right dose differentiates a poison from a remedy.” Given the large number of potential poisons (toxicants) in the world and the wide variety of clinical effects these toxicants have on biological systems, it is not surprising that a vast range of compounds have been used in attempting to treat the effects of these toxicants on the body.

Antidotes In the broadest definition, any compound that is used to counteract the effects of a toxicant is an antidote. The compound can interfere with the absorption, distribution, metabolism, or elimination of a toxicant; reduce or eliminate the adverse effects of that toxicant; or perform any combination of these biological effects. As our understanding of the mechanisms of action of various compounds increases, so does our ability to choose the most appropriate drugs to counter the adverse effects of toxicoses. This knowledge puts to rest the legend of the “universal antidote,” that mythical compound that can counter the effects of any poison. Table 23-1 lists drugs commonly used in the management of toxicoses.

Mechanisms of Action Antidotes are frequently classified into two groups based on their mechanisms of action: chemical antidotes and pharmacologic antidotes. Chemical antidotes, which interact directly with a toxicant to alter the toxicant’s action in the body, include metal chelators, antibodies, and agents causing pharmacologic compartmentalization, as well as some other drugs. Metal chelators bind to metal ions, forming complexes that prevent the metal from reaching its target tissue and enhancing elimination of the chelate-metal complex. Immunologic products in­­ clude intact immunoglobulins, such as IgG, and isolated F(ab′) fragments, such as digoxin-specific F(ab’) fragments, antivenoms, and antivenins. These drugs also bind target compounds, which prevents or reduces toxicant action and enhances excretion. Chemical chelators also may act as sinks by forming pharmacologic compartments that sequester toxicants, thereby reducing their ability to react with target tissues. Cholestyramine and intravenous lipid emulsions are examples of drugs thought to act in this fashion.

Pharmacologic antidotes neutralize or antagonize the effects of toxicants. Some such as fomepizole block metabolic enzymes and thereby reduce the formation of toxic metabolites; others such as naloxone act as receptor antagonists; and still others such as methocarbamol counter the effects of the toxicant.

Clinical Use of Antidotes Although antidotes can be valuable assets in the management of toxicoses, there can be challenges when attempting to use them in veterinary practice. Some antidotes can be difficult to obtain; for example, botulinum antitoxin is only available through the Centers for Disease Control and Prevention and a few researchers. Others may be too expensive for some animal owners; for example, F(ab’) crotalid antivenin costs more than $1,000. Furthermore, not all antidotes are innocuous; injudicious use of excessive or inappropriate antidotes may result in clinical consequences that are more serious than those caused by the original toxicant. For example, methylene blue is an oxidation-reduction agent that has been used to treat methemoglobinemia; however, its precise dosing is required to prevent worsening of methemoglobinemia, especially in cats.

Approach to Patient Management The veterinary clinician faced with a case of potential poisoning must carefully evaluate the patient and manage the clinical signs that are present in a systematic manner (i.e., “treat the patient, not the poison”). Because we lack specific chemical or pharmacologic antidotes for many toxicants, veterinarians are frequently forced to rely on “symptomatic and supportive” care when dealing with patients with toxicoses. The good news is that in many cases, successful outcomes can be attained by using good clinical judgment.

Initial Assessment Patients should be assessed on presentation for any immediate life-threatening signs that need to be ad­­ dressed. An efficient but thorough physical examination should be completed and vital signs carefully recorded. Specific tests, such as fluorescein staining for corneal ulcers, electrocardiography to identify heart rhythm disturbances, and thoracic radiography for pulmonary injury or a risk of aspiration, and routine 101

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SECTION  II  Toxicologic Diseases

TABLE 23-1  Drugs Used in Toxicology* Drug

Indication

Acepromazine

Sedation for agitation caused by psychotropic drugs (e.g., amphetamines, phenylpropanolamine, pseudoephedrine)

N-acetylcysteine (Mucomyst,   Acetadote)

Management of acetaminophen toxicosis Hepatoprotectant

Activated charcoal

Adsorption of ingested toxicants (poor adsorption of many metals and minerals, small molecules [e.g., alcohols]) Multidose protocols: monitor for hypernatremia

Aluminum hydroxide

Antacid; use for ingestion of corrosives or ulcerogenic drugs (e.g., NSAIDs)

Anti-digoxin Fab fragments,   ovine origin (Digibind, DigiFab)

Management of cardiac glycoside toxicosis (drugs, plants, toads) in which life-threatening arrhythmias have not resolved with symptomatic therapy or serum potassium levels   > 5 mmol/L

Antitoxin, botulinum, equine origin

Management of clinical signs of botulism

Antitoxin, tetanus, equine origin

Management of clinical signs of tetanus

Antivenin Crotalidae polyvalent, equine origin Polyvalent, immune Fab, ovine origin (Cro Fab)

Management of North American crotalid envenomation (rattlesnake, copperhead, water moccasin)

Antivenin Micrurus (Wyeth)

Management of North American elapid envenomation (coral snake)

Antivenin Latrodectus (Merck)

Management of envenomation by black widow spider

Antivenom, Centruroides immune F(ab′)2, equine origin (Anascorp)

Treatment of clinical signs of North American scorpion envenomation

Apomorphine

Induction of emesis; may not be effective in cats because they have few dopaminergic receptors in their CNS emetic center

Ascorbic acid

Antioxidant Urinary acidifier

Atipamezole hydrochloride   (Antisedan)

Reversal of bradycardia, hypotension, and sedation from α-agonists (e.g., amitraz, xylazine, imidazole decongestants)

Atropine

Test dose for suspected organophosphorus (OP) or carbamate toxicosis Management of bradycardia or excessive bronchial secretions from OP or carbamate toxicosis Treatment of bradycardia from cardiac depressant drugs (e.g., digoxin)

Bicarbonate, sodium

Management of acidosis (e.g., ethylene glycol)

Blood, whole

Replacement therapy for anemia (e.g., anticoagulant rodenticides)

Buprenorphine

Management of pain

Calcitonin, salmon

Treatment of hypercalcemia (e.g., vitamin D or analogs)

Calcium EDTA

Heavy metal chelator (lead)

Calcium gluconate, calcium chloride

Management of fluoride or calcium channel blocker toxicosis Management of hypocalcemia

Cholestyramine resin polystyrene

Ion-binding resin; may help remove agents that undergo extensive enterohepatic recirculation Hepatotoxic mushroom ingestion

Chlorpromazine

Antiemetic Sedation for agitation caused by psychotropic drugs (e.g., amphetamines, pseudoephedrine)

Cyproheptadine

Assist in management of serotonin syndrome and serotonergic effects of psychotropic drugs (e.g., SSRI)

Dantrolene

Management of Latrodectus (black widow spider) bites; management of malignant hyperthermia from hops

Dapsone

Management of dermal necrosis from Loxosceles (recluse spider) bites

Deferoxamine mesylate (Desferal, Novartis)

Heavy metal chelator (iron)

Dextrose

Treatment of hypoglycemia due to xylitol, α-lipoic acid, or antidiabetic drug (e.g., sulfonylurea) toxicosis

CHAPTER  23  Drugs Used to Treat Toxicoses

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TABLE 23-1  Drugs Used in Toxicology*—cont’d Drug

Indication

Diazepam

Sedation for CNS stimulation or seizures; use with caution with sympathomimetic   (e.g., amphetamine) intoxication because paradoxical excitation may occur

Dimercaprol (BAL)

Heavy metal chelator (arsenic, lead, mercury)

Diphenhydramine

Management of acute allergic reactions; antiemetic

Epinephrine

Systemic treatment of acute anaphylaxis

Esmolol

Management of ventricular arrhythmias; ultra–short acting β-blocker

Ethanol

Prevent formation of toxic metabolites in ethylene glycol toxicosis

Etidronate

Treatment of hypercalcemia (e.g., vitamin D or analogs)

Flumazenil

Benzodiazepine antagonist used to aid in severe benzodiazepine overdose

Fomepizole (Antizol-Vet)

Prevent formation of toxic metabolites in ethylene glycol toxicosis

Furosemide

Diuretic for use in management of pulmonary edema secondary to inhaled toxicants Enhance calcium excretion in hypercalcemia (e.g., cholecalciferol toxicosis)

Glucagon

Manage hypotension (e.g., β-adrenergic blocker, calcium channel blocker, tricyclic antidepressant toxicosis); manage hypoglycemia (e.g., antidiabetic drug toxicosis)

H2-blockers (cimetidine, famotidine, nizatidine, ranitidine)

Reduce gastric acid production Prevention and healing of gastrointestinal ulcers (e.g., NSAIDs)

Hemoglobin glutamer-200, bovine (Oxyglobin)

Replacement therapy for anemia (e.g., anticoagulant rodenticides); does NOT provide clotting factors Improved perfusion of tissues with pressure hypoperfusion (e.g., snakebite swelling)

Hydroxocobalamin (Cyanokit)

Management of cyanide toxicosis

Hydrogen peroxide USP, 3%

Induction of emesis; CAUTION: overuse can result in esophagitis or gastritis

Intravenous lipid solution, intravenous fat emulsion (20%; Liposyn, Intralipid)

Management of intoxication by highly lipid-soluble compounds (e.g., avermectins, baclofen, calcium channel blockers); emerging modality that some consider experimental; should be reserved for severe cases that are poorly responsive to other therapy

Kaolin-pectin

Demulcent and putative adsorbent; CAUTION: many formulations now contain salicylates

Lactulose

Laxative and reduces blood ammonia levels Management of liver insufficiency (e.g., Cycas toxicosis)

Leucovorin calcium

Management of folate antagonist (methotrexate, trimetrexate) overdoses

Lidocaine

Management of ventricular arrhythmias

Magnesium hydroxide

Antacid; use for ingestion of corrosives or ulcerogenic drugs (e.g., NSAIDs)

Magnesium sulfate

Cathartic

Mannitol

Management of oliguric renal failure Treatment of cerebral edema

Maropitant (Cerenia)

Antiemetic

Methocarbamol

Management of muscle tremors, rigidity, convulsive activity (e.g., permethrin toxicosis, metaldehyde toxicosis)

Methylene blue

Treatment of methemoglobinemia; use with extreme caution, especially in cats (many clinicians no longer recommend); DO NOT USE new methylene blue from staining kits

Metoprolol

Management of tachycardia

Milk

Diluent May reduce pain from exposure to insoluble calcium oxalate–containing plants

Misoprostol (Cytotec)

Synthetic prostaglandin; prevention and healing of gastrointestinal ulcers (e.g., NSAIDs)

Naloxone

Opiate antagonist; management of opioid toxicosis

Neostigmine, physostigmine, pyridostigmine

Management of toxicosis from non-depolarizing neuromuscular blocking agents, botulism, atropine, coral snake envenomation, and anticholinergics

Nitroprusside

Treatment of hypertension

Norepinephrine

Treatment of hypotension Continued

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SECTION  II  Toxicologic Diseases

TABLE 23-1  Drugs Used in Toxicology*—cont’d Drug

Indication

Ondansetron (Zofran)

Antiemetic

Pamidronate (Aredia)

Treatment of hypercalcemia (e.g., vitamin D or analogs)

D-Penicillamine

Heavy metal chelator (arsenic, copper, lead)

Pentobarbital

Management of seizures

Phenobarbital

Management of seizures

Plasma, frozen plasma, fresh frozen

Management of coagulopathy from anticoagulant rodenticides; provide clotting factors

Pralidoxime chloride (Protopam)

Treatment of nicotinic signs of OP insecticide intoxication

Prednisone

Adjunct therapy in hypercalcemia (e.g., cholecalciferol)

Propofol

Management of seizures

Propranolol

Management of tachycardia or other cardiac arrhythmias; management of hypokalemia in albuterol toxicosis

Protamine sulfate

Management of heparin overdoses

Proton pump inhibitors (e.g.,   omeprazole, lansoprazole, pantoprazole)

Reduce gastric acid production Prevention and healing of gastrointestinal ulcers (e.g., NSAIDs)

Prussian blue

Management of thallium toxicosis

Pyridoxine (vitamin B6)

Management of seizures from penicillamine, Gyromitra mushroom, isoniazid, and hydrazines; adjunct therapy for ethylene glycol toxicosis

SAMe

Hepatoprotectant

Silymarin

Hepatoprotectant

Sodium sulfate

Cathartic

Sorbitol

Cathartic

Succimer (Chemet, Lundbeck)

Heavy metal chelator (arsenic, lead, mercury)

Sucralfate

Management and prevention of esophageal (slurries) and gastrointestinal ulceration

Trientine (Syprine)

Heavy metal chelator (copper)

Vitamin K1 (phytonadione)

Treatment of anticoagulant rodenticide coagulopathy

Xylazine

Emetic, especially for cats

Yohimbine

Reversal of bradycardia, hypotension, and sedation from α-agonists (e.g., amitraz, xylazine, imidazole decongestants)

*See Appendix for dosages. CNS, Central nervous system; EDTA, ethylenediaminetetraacetic acid; NSAIDs, nonsteroidal antiinflammatory drugs; SAMe, s-adenosyl methionine; SSRI, selective serotonin reuptake inhibitor; USP, United States Pharmacopeia.

clinical laboratory tests should be performed as clinically indicated.

Initial Treatments Critical problems require immediate management. Seizures and convulsions generally respond well to standard anticonvulsants such as barbiturates and benzodiazepines; general anesthetics should be considered in refractory cases. Life-threatening cardiac arrhythmias or respiratory issues should be managed with appropriate antiarrhythmic medications (see Chapters 171 and 172), oxygen (see Chapter 10), and other drugs as needed (see Chapter 8). Severe hemorrhage or anemia may require blood transfusion (see Chapter 67) and oxygen supplementation. Severe hyperthermia (see Chapter 14), electrolyte

abnormalities, hypoglycemia or hyperglycemia, and other metabolic derangements should be managed as needed (see Section I). Supportive care could include control of non–life-threatening signs, such as vomiting, maintenance of hydration, thermoregulation, and pain management (see Chapter 12).

Decontamination Decontamination of clinically stable patients may be considered depending on the time frame of the exposure, the toxicant involved, and the potential for adverse effects from the decontamination procedure. Decontamination most commonly applies to surface exposures and to oral ingestions of potential toxicants. Grooming behavior can extend a topical exposure to a systemic exposure. Surface

CHAPTER  23  Drugs Used to Treat Toxicoses exposures are usually treated by irrigation of the skin, hair, or eyes with copious volumes of water, along with washing using a mild detergent. Care must be directed to effects on body temperature, especially in depressed or sedated animals. In cases of ocular contact, the cornea and eyelids should be gently irrigated with eyewash or sterile saline. When a toxic substance is ingested consideration should be given to inducing emesis, administration of activated charcoal, and administration of a cathartic. However, as discussed in other chapters in this section, these treatments should not be administered to every animal or for every toxicant. Emetics include (1) xylazine (0.44 mg/kg IM for cats; 1.1 mg/kg IM for dogs; note: xylazine can be reversed with yohimbine); (2) apomorphine in dogs (0.25 mg/kg of the crushed tablet in the conjunctival sac; rinse the conjunctival sac after vomiting; note: apomorphine can be reversed with naloxone); and (3) hydrogen peroxide (3%) in dogs (1 to 2 ml/kg PO to a maximum of 45 ml). Emesis should not be induced if the animal has been vomiting or if toxicant exposure has occurred over 3 hours before admission to the hospital. Moreover, it is not recommended to induce vomiting when a corrosive chemical has been ingested, if the animal cannot gag, or when there is evidence of preexistent or developing esophageal, cardiac, respiratory, or central nervous system disease. Marked sedation or loss of consciousness is a contraindication for emetics. Activated charcoal (1 to 4 g/kg) may be beneficial as a nonspecific adsorbent for specific toxicoses (see Chapters 26 and 27). Activated charcoal will adsorb many larger molecules such as many pharmaceutical products, pesticides, and plant toxins. However, it is not indicated for ingestion of caustic (alkaline) chemicals, petroleum distillates, or small molecules such as alcohols, some mineral acids, or ionized metals or minerals (e.g., sodium, lithium). Administration can proceed by the oral route (in conscious animals that can swallow) or by orogastric tubing in dogs or nasogastric tubing in cats (the commonly used route in most emergency practices). In conscious animals, if emesis has been induced, administration of activated charcoal should be delayed for about 30 minutes to minimize the risk of spontaneous vomiting of charcoal or aspiration. If the patient is anesthetized or comatose, a

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cuffed endotracheal tube should be inserted to protect the airway. Re-dosing at one half of the original dose can be considered at 4- to 8-hour intervals for toxicants that undergo enterohepatic recirculation including phenobarbital, methylxanthines (chocolate), theophylline, marijuana, ivermectin (see Chapter 34), and nonsteroidal antiinflammatory drugs (see Chapter 27), among others. Potential risks include aspiration of activated charcoal, peritonitis if there is gastrointestinal ulceration or perforation, discoloration of the alimentary mucosa thereby complicating endoscopic evaluation, and hypernatremia due to fluid shifts following multidose activated charcoal regimens. A cathartic reduces the time a toxicant is exposed to the gastrointestinal tract. These may be administered with the first dose of activated charcoal; in multidose activated charcoal regimens, cathartics are generally given with every third charcoal dose. Cathartics include sorbitol and magnesium or sodium sulfate salts. These may be incorporated into some commercial activated charcoal products or administered separately. The dosage of magnesium sulfate is approximately 5 to 20 g per dog and 2 to 4 g per cat. Magnesium sulfate is not administered in patients with kidney failure.

Specific Treatments Table 23-1 list some of the specific drug treatments used when managing pets with toxicosis. Clinicians are advised to check dosages carefully and to appreciate differences between canine and feline dosing (see Appendix). Some of the specific uses of these drugs are described in greater detail in other chapters within this section.

References and Suggested Reading American Board of Veterinary Toxicology: Review of veterinary antidotes. Available at: http://www.abvt.org/public/docs/ reviewofveterinaryantidotes.pdf. Accessed Dec 1, 2011. Bright SJ, Post LO: Veterinary antidotes and availability: an update, Center for Veterinary Medicine, US Food and Drug Administration. Available at: http://www.abvt.org/public/docs/ antidoteupdate08.pdf, 2008. Accessed Dec 1, 2011. Gwaltney-Brant SM, Rumbeiha WR: Newer antidotal therapies, Vet Clin North Am Small Anim Pract 32:323-339, 2002.

CHAPTER 

24 

Intravenous Lipid Emulsion Therapy JUSTINE A. LEE, Minneapolis, Minnesota ALBERTO L. FERNANDEZ MOJICA, St. Georges, West Indies, Grenada

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ntravenous lipid emulsion (ILE), also known as intravenous fat emulsion (IFE), has been used in human and veterinary medicine as a part of total parenteral nutrition (TPN) or partial parenteral nutrition (PPN) for the past several decades. It also has been used as a vehicle for drug delivery for emulsions, such as propofol. More recently, ILE has been recommended as a potential antidote for lipophilic drug toxicosis. In the 1970s and 1980s, studies that evaluated the effects of ILE on the pharmacokinetics of chlorpromazine and cyclosporine in rabbits and phenytoin in rats demonstrated potential support for use of ILE in certain drug toxicities. Almost 2 decades later, Weinberg and colleagues reintroduced the potential beneficial effects of ILE in the treatment of the fat-soluble, local anesthetic bupivacaine toxicosis. Since then, several animal studies and human and animal case reports have reported successful use of ILE. Toxicoses that are reportedly responsive to ILE treatment include bupivacaine, lidocaine, clomipramine, verapamil, bupropion, mepivacaine, ropivacaine, haloperidol, quetiapine, doxepin, carvedilol, carbamazepine, flecainide, hydroxychloroquine, amlodipine, propranolol, calcium channel blockers (e.g., diltiazem), and macrocyclic lactones (e.g., moxidectin, ivermectin). However, success with ILE has been variable, ranging from no improvement to complete resolution of clinical signs. That said, ILE is considered a potential antidote in cases of lipid-soluble toxicities in which cardiopulmonary arrest (CPA) and standard resuscitation have failed to result in return of spontaneous circulation (ROSC). Currently, no prospective, randomized studies are available in human or veterinary medicine regarding the use of ILE because it is currently reserved for catastrophic toxicities and severe clinical signs. In veterinary medicine, recent publications describe the use of ILE for macrocyclic lactones, lidocaine, pyrethrins, and calcium channel blocker toxicoses (Crandell et al, 2009; O’Brien et al, 2010; Clarke et al, 2011; Brückner et al, 2012; Maton et al, 2013). A state-of-the-art review was recently published introducing the first recommendations on the use of ILE in veterinary medicine (Fernandez et al, 2011). Pet Poison Helpline, an animal poison control center based in Minneapolis, has experienced anecdotal success with the use of ILE for certain additional medications with a narrow margin of safety (e.g., baclofen, cholecalciferol, β-blockers). 106

Mechanism of Action The precise mechanism of action through which ILE increases the rate of recovery and augments conventional resuscitation efforts in various cases of lipophilic drug toxicosis is currently unknown. It is possible that the potential antidotal effects of ILE vary with the lipophilicity of the toxic agent or that more than one mechanism of action is operative. Current theories regarding ILE’s mechanism of action are: • Providing myocytes with energy substrates, thereby augmenting cardiac performance. • Restoring myocardial function by increasing intracellular calcium concentration. • Acting as a lipid sink by sequestration of lipophilic compounds into the newly created intravascular lipid compartment (a lipid or pharmacologic sink). With this lipid sink hypothesis, compartmentalization of the drug into the lipid phase results in a decreased free drug concentration available to tissues. • Increasing the overall fatty acid pool, which overcomes inhibition of mitochondrial fatty acid metabolism (e.g., bupivacaine toxicosis). Currently, the most supported hypotheses are that ILE improves cardiac performance and provides a lipid sink effect in the vascular compartment.

Current Published Human Research Information and Data The vast majority of ILE publications in human medicine stem from case reports. Initial human case reports related to the use of ILE as a treatment in local anesthesia-related CPA that was unresponsive to cardiopulmonary resuscitation (CPR). In 2006, the first case study was published involving a patient who developed seizures and cardiac arrest shortly after receiving a nerve block with a mixture of bupivacaine and mepivacaine (Rosenblatt et al, 2006). After 20 minutes of unsuccessful CPR and advanced cardiac life support (ACLS), 100 ml of a 20% ILE was administered (1.2 ml/kg IV bolus), followed by an additional constant rate infusion (CRI) (0.5 ml/kg/min, IV, over 2 hours). Sinus rhythm and ROSC occurred shortly after administration of the ILE bolus. The patient recovered uneventfully. Similar reports have since been

CHAPTER  24  Intravenous Lipid Emulsion Therapy published demonstrating an amelioration or reversal of the adverse effects of bupivacaine, mepivacaine, and ropivacaine with ILE. However, ILE has not proven to be consistently effective in all cases of lipophilic drug toxicosis, presumably related to the lipid solubility of the toxin in question.

Current Published Veterinary Information Experimental studies: In contrast to the available human data, most of the animal publications are in the form of experimental studies. One of the first investigations performed in 1974 evaluated in vivo and ex vivo rabbit models of chlorpromazine toxicosis. In the in vivo arm of the study, all control rabbits dosed with 30 mg/kg IV chlorpromazine died, whereas all control rabbits in the ILE pretreatment group lived. The study also reported significantly decreased free chlorpromazine after the addition of ILE to rabbit blood. A similar study evaluating coadministration of 20% ILE on the pharmacokinetics of cyclosporine in rabbits reported decreased total body clearance and volume of distribution of cyclosporine with ILE administration. In 1998, Weinberg and colleagues evaluated the effects of pretreatment with ILE in a rodent model of bupivacaineinduced asystole and reported a 48% increase in median lethal dose (LD50) in the ILE-treated group. Several years later, this author evaluated the effect of saline fluid versus ILE in the treatment of bupivacaine-induced cardiotoxicity in 12 dogs in which all animals in the saline control group failed to develop ROSC and died, whereas all the ILE-treated patients survived. Additional details of these and related studies can be found in the review of Jamaty et al.

Case Reports The first clinical case using 20% ILE in veterinary medicine was described by Crandell et al in a 16-week-old Jack Russell terrier with moxidectin toxicosis. In this case, 2 ml/kg of ILE (IV, bolus) was administered, followed by 4 ml/kg/hr (0.07 ml/kg/min, IV) for 4 hours. ILE treatment began 10 hours after moxidectin exposure, and then was repeated approximately 25 hours after exposure (0.25 ml/kg/min, IV, for 30 minutes). Several subsequent cases reported ILE use. In 2010, O’Brien et al reported on ILE-treated lidocaine toxicosis. A 5-year-old cat received a SC injection of about 20 mg/kg of lidocaine for surgical closure of a wound in the left hind limb. Less than 5 minutes after administration, severe lethargy and respiratory distress were noticed. Marked cardiovascular, respiratory, and neurologic ab­­ normalities were seen on arrival to the emergency room approximately 25 minutes later. Initial therapy consisted of oxygen support, crystalloid fluid resuscitation, and a 20% ILE bolus administered at 1.5 ml/kg [0.68 ml/lb]) over a 30-minute period. Shortly after initiation of ILE administration, the cat was more responsive to stimuli and was able to hold its head up. Significant neurologic improvement was noticed by the end of the lipid infusion. The cat survived to discharge with no adverse effects reported. In this case it is likely that the toxic effects of

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lidocaine may have improved without the use of ILE; however, its use appeared to reduce the duration of clinical signs and minimize the overall morbidity associated with this toxicosis. Later, Clarke et al reported the use of ILE in a Border collie that developed ivermectin toxicosis after ingesting 6 mg/kg of equine ivermectin paste. Treatment with a 20% ILE bolus administered at 1.5 ml/kg over 10 minutes, followed by a CRI of 0.25 ml/kg/min for 60 minutes was performed. This was the first clinical study to demonstrate the lipid sink hypotheses based on serial ivermectin serum levels. Since then, numerous case reports have been published demonstrating the use of ILE in dogs and cats (Brückner and Schwedes, 2012), some with successful resolution of clinical signs and some demonstrating lack of efficacy (Wright et al, 2011).

When to Use ILE ILE therapy is generally considered relatively safe. Nevertheless, in human medicine ILE is reserved for severe toxicosis and life-threatening clinical signs when conventional therapies have failed. This differs from veterinary medicine, in which ILE is generally initiated earlier in the course of treatment. In veterinary medicine, ILE is warranted for toxicities associated with lipid-soluble compounds in which a high morbidity has been reported, the patient is symptomatic, and traditional therapies have failed or are cost-prohibitive.

Dosing of ILE Initial human dosing guidelines for ILE administration stem from two main sources: a publication entitled Guidelines for the Management of Severe Local Anesthetic Toxicity by the Association of Anaesthetists of Great Britain and Ireland (AAGBI) and publications authored by Dr. Guy Weinberg, who created a website (www.lipidrescue.org) in which the use of ILE is well described. Following the publication of these guidelines, there was an increase in both the availability of and the willingness to use ILE in hospitals for humans, particularly in areas in which local anesthetic drugs were administered. These dosing recommendations were based on experimental animal studies and human case reports. Currently in veterinary medicine, the dosing of ILE is extrapolated from human data and the use of ILE is considered extralabel. The current human guidelines for the use of ILE recommend that infusion with ILE should only be attempted when standard resuscitation protocols have failed to establish adequate ROSC and that CPR should continue during ILE administration. Dosage recommendations for 20% ILE are 1.5 ml/kg (IV, bolus over 1 minute), followed by a CRI of 0.25 ml/kg/min (IV, for 30 to 60 minutes). The bolus dose can be repeated twice in 5-minute intervals if CPA persists. If progressive hypotension is noticed, the CRI rate of administration can then be further increased to 0.5 ml/kg/min (IV). A total limit of 8 to 12 ml/kg/day has been suggested.

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Fernandez et  al recommended the following dosage in veterinary medicine based on extrapolation from human dosing and the dose used for TPN and PPN administration in veterinary medicine: administration of an initial 20% ILE bolus in the range between 1.5  ml/ kg and 4  ml/kg (between 0.3  g/kg and 0.8  g/kg, IV, over 1 minute), followed by a CRI of 0.25  ml/kg/min (0.05  g/ kg/min, IV, over 30 to 60 minutes) as a generally conservative start in dogs. In patients that are nonresponsive after this traditional dosing, additional individual bolus aliquots can be given slowly at up to 7  ml/kg (1.4  g/kg, IV). The authors recommended intermittent bolusing at 1.5  ml/kg q4-6h for 24 hours with anecdotal success. In addition, follow-up CRI doses of 0.5  ml/kg/ hr (0.1  g/kg/hr) can be continued until clinical signs improve (not to exceed 24 hours) or until serum is lipemic. That said, there have been no safety studies evaluating the use of ILE in the clinically poisoned veterinary patient, and careful monitoring and risk assessment is imperative.

Fat Overload Syndrome Rare complications exist with ILE therapy. Delayed or subacute reactions to ILE are commonly referred to as fat overload syndrome (FOS). Reactions are often the result of accidental administration of excessive volumes or rates that overwhelms the endogenous lipid clearance mechanisms. FOS is characterized by hyperlipidemia, hepatomegaly, icterus, splenomegaly, thrombocytopenia, increased clotting times, hemolysis, and variable end-organ dys­ function. In humans, long-chain triglyceride emulsions administered at rates above 0.11 g/kg/hr (ILE 20% = 0.55 ml/kg/hr) can be associated with adverse effects. The syndrome can also occur when ILE is administered to patients with decreased plasma clearance of lipids. This complication appears to be reported in the literature more often with the use of soybean oil-based emulsions than with other formulations. However, this could be because these types of emulsions are more frequently used for parenteral nutrition. Management of FOS consists of both discontinuation of ILE administration and supportive care. Resolution of clinical signs is expected after the ILE is metabolized, but permanent organ damage has been reported. Plasma exchange has been recommended for cases of FOS that failed to respond to conservative therapy. Heparin, which elicits significant effects in lipid me­­ tabolism, has been clinically used to prevent adverse events from ILE administration. Although heparin can potentially minimize hyperlipidemia, its routine use with ILE therapy is not currently recommended. By enhancing the release of lipoprotein lipase (LPL) and hepatic lipase, heparin may reduce the lipid compartment in the blood and, potentially, the beneficial properties of ILE when used for the treatment of a lipid-soluble toxicant. Until further studies evaluate the underlying mechanisms of action of how ILE therapy works and is influenced by LPL, heparin should be reserved only for those patients at risk to develop FOS or other adverse events. If heparin administration is considered for the treatment of FOS, it should ideally be used as a CRI to have continued effects on LPL levels.

Controversies of ILE If an effective therapy or antidote is already well established in the field of veterinary toxicology, its continued use is recommended over ILE due to the unknown effects of ILE administration. Keep in mind that certain therapeutics (e.g., anticonvulsants) may be made ineffective with the administration of ILE; hence supportive therapy is always warranted prior to experimental use of ILE. However, if the patient has undergone cardiovascular collapse secondary to toxicosis or demonstrates significant clinical signs of toxicosis (e.g., from baclofen, ivermectin, or moxidectin), ILE should be considered. As administration of ILE increases the free fatty acid concentration, it may have negative inotropic effects and induce cardiac arrhythmias in the hypoxic myocardium. Therefore appropriate medical management, volume resuscitation, and adequate oxygenation are imperative as the first-line defense in the treatment of the critically ill patient with a lipophilic compound intoxication prior to any consideration of the use of ILE. The administration of ILE for the treatment of local anesthetic or other lipophilic drug toxicosis in veterinary medicine is still in its infancy and the potential is currently unknown. The judicious use of this new potential antidote should be considered based on the lipophilic nature of the drug. The higher the affinity of a drug for lipids and the higher the volume of distribution, the more suitable it is to be potentially reversed by administration of ILE. An animal poison control helpline should ideally be consulted prior to administration of ILE to ensure appropriate use and fat-solubility for the toxicant.

References and Suggested Reading Association of Anaesthetists of Great Britain and Ireland. Available at: http://update.anaesthesiologists.org/wp-content/uploads/ 2009/12/Management-of-local-anaesthetic-toxicity.pdf Ac­cessed November 25, 2012. Brückner M, Schwedes CS: Successful treatment of permethrin toxicosis in two cats with an intravenous lipid administration, Tierärztl Prax 40:129-134, 2012. Clarke DL et al: Use of intravenous lipid emulsion to treat ivermectin toxicosis in a Border collie, J Am Vet Med Assoc 239:(10):1328-1333, 2011. Crandell DE, Weinberg GL: Moxidectin toxicosis in a puppy successfully treated with intravenous lipids, J Vet Emerg Crit Care 19(2):181-186, 2009. Fernandez AL et al: The use of intravenous lipid emulsion as an antidote in veterinary toxicology, J Vet Emerg Crit Care 21(4):309-320, 2011. Jamaty C et al: Lipid emulsions in the treatment of acute poisoning: a systematic review of human and animal studies, Clin Toxicol 48:1-27, 2010. Kollef MH et al: The fat overload syndrome: successful treatment with plasma exchange, Ann Intern Med 112(7):545-546, 1990. Krieglstein J, Meffert A, Niemeyer DH: Influence of emulsified fat on chlorpromazine availability in rabbit blood, Experientia 30(8):924-926, 1974. LipidRescue: Resuscitation for cardiac toxicity. Available at: http://lipidrescue.org. Accessed November 10, 2011. Maton BL et al: The use of high-dose insulin therapy and intravenous lipid emulsion to treat severe, refractory diltiazem toxicosis in a dog, J Vet Emerg Crit Care 23(3):321-327, 2013. O’Brien TQ et al: Infusion of a lipid emulsion to treat lidocaine intoxication in a cat, J Am Vet Med Assoc 237:1455-1458, 2010.

CHAPTER  25  Human Drugs of Abuse and Central Nervous System Stimulants Rosenblatt MA et al: Successful use of a 20% lipid emulsion to resuscitate a patient after a presumed bupivacaine-related cardiac arrest, Anesthesiology 105(1):217-218, 2006. Turner-Lawrence DE, Kerns W II: Intravenous fat emulsion: a potential novel antidote, J Med Toxicol 4(2):109-114, 2008. Weinberg GL et al: Pretreatment or resuscitation with a lipid infusion shifts the dose-response to bupivacaine-induced asystole in rats, Anesthesiology 88:1071-1075, 1998.

CHAPTER 

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Weinberg G et al: Lipid emulsion infusion rescues dogs from bupivacaine-induced cardiac toxicity, Reg Anesth Pain Med 28:198-202, 2003. Weinberg G: Lipid infusion resuscitation for local anesthetic toxicity, Anesthesiology 105:7-8, 2006. Wright HM et al: Intravenous fat emulsion for treatment for ivermectin toxicosis in three dogs homozygous for the ABCB11Δ gene mutation, J Vet Emerg Crit Care 21(6):666-672, 2011.

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Human Drugs of Abuse and Central Nervous System Stimulants PETRA A. VOLMER, Champaign, Illinois

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nimal exposures to human drugs of abuse occur periodically in veterinary medicine. In many cases the owners are reluctant to admit that the animal was exposed until it is in severe distress. Often illicit drugs are contaminated with other compounds that may possess pharmacologic activity, causing unique combinations of clinical signs. Diagnosis of a toxicosis is often based on characteristic clinical signs and history of exposure. Overthe-counter drug-testing kits are available at most pharmacies. These kits are designed for rapid determination of drug presence in urine and, although designed for in-home human use, may provide important diagnostic information in the veterinary clinical setting. Some kits may test for as many as 12 drugs. Although these kits are often useful clinically, further confirmation may be needed in medicolegal circumstances.

Amphetamines Amphetamines are a class of compounds that includes a number of prescription and illicit products, all derivatives of the parent compound amphetamine. Most animal exposures are a result of the accidental ingestion of human prescription products used for the treatment of obesity, narcolepsy, and attention-deficit hyperactivity disorder. Examples include dextroamphetamine (Dexedrine), methylphenidate (Ritalin, Concerta), pemoline (Cylert), phentermine (Fastin), and the combination of dextroamphetamine and amphetamine (Adderall). Exposure to unlawful amphetamine compounds can also occur. Street names for amphetamines can include speed,

uppers, dex or dexies, and bennies. Methamphetamine production is on the rise in clandestine laboratories in many areas of the United States. Street names for methamphetamine can include ice and glass for the clear, translucent crystals and crystal, crank, and meth for the white or yellow powder form. Designer amphetamines include 4-methylaminorex (ice, U4EUh), methcathinone (cat), 3,4-methylenedioxy-N-methylamphetamine (MDMA [ecstasy, XTC, Adam, MDA]), and 3,4-methylenedioxy-Nethylamphetamine (MDEA [Eve]) (Volmer, 2006; Llera and Volmer, 2006). The amphetamines as a class are well absorbed orally, with peak plasma levels occurring by 1 to 3 hours; thus clinical signs can develop rapidly. Some pharmaceutical products are extended-release preparations, with the result of prolonging absorption and delaying the onset of signs. Amphetamine and its metabolites are excreted in the urine in a pH-dependent manner, so that a lower pH enhances excretion (Baggot and Davis, 1972). Amphetamines have a stimulant effect on the cerebral cortex through release of catecholamines, acting as a dopamine excitatory receptor agonist and enhancing release of serotonin. Toxic dosages of amphetamine products are low: the oral median lethal dosage for amphetamine sulfate in the dog is 20 to 27 mg/kg; for methamphetamine hydrochloride it is 9 to 11 mg/kg (Zalis et al, 1965). Signs in field cases can be seen at dosages much lower than experimental lethal dosages. Exposed animals exhibit signs associated with stimulation. Behavioral effects can include initial restlessness, pacing, panting, and an inability to sit still. These signs

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can progress to pronounced hyperactivity, hypersal­ ivation, vocalization, tachypnea, tachycardia, tremors, hyperthermia, seizures, and potentially death. In some cases animals may exhibit depression, weakness, and bradycardia. Diagnosis is based on clinical signs and history of exposure. Amphetamines can be detected in urine. Overthe-counter drug-testing kits may be of use in diagnosing an exposure in the acute clinical setting. Animals should be stabilized and then decontaminated. Animals with known ingestions of amphetamine products less than 30 minutes prior can undergo induction of emesis followed by administration of activated charcoal and a cathartic. Animals already exhibiting signs of stimulation such as restlessness or worse should not be induced to vomit because of the risk of aspiration. Similarly, if the product is rapidly absorbed with the possible rapid onset of signs, emesis is not recommended. For those cases gastric lavage followed by the instillation of activated charcoal and a cathartic is a safer approach. Sustained-release medications may require repeated doses of activated charcoal. Excitability, tremors, seizures, and other stimulant signs associated with amphetamine intoxication can be treated with acepromazine (0.5 to 1 mg/kg slowly intravenously [IV]; allow 15 minutes for onset of action; repeat as needed and monitor arterial blood pressure) or chlorpromazine (10 to 18 mg/kg IV repeated as needed with blood pressure monitoring). Phenothiazine tranquilizers have been shown to have a protective effect when used to treat amphetamine toxicoses (Catravas et al, 1977). Diazepam is not recommended because it can exacerbate the stimulatory signs in some animals. Phenobarbital, pentobarbital, and propofol (dosed carefully “to effect”) may also be used to treat or mitigate severe central nervous system (CNS) signs. In addition, cyproheptadine, a serotonin antagonist, may help reduce the CNS signs. It has been used successfully to dampen the excessive stimulation from overexposure to antidepressant medications designed to increase serotonin in nerve synapses. Cyproheptadine is dosed at 1.1 mg/kg rectally in dogs. Tachyarrhythmias should be treated with a β-blocker such as propranolol, esmolol, atenolol, or metoprolol. Hyperthermia should be corrected using a water mist and fans. Animals should be monitored to prevent subsequent hypothermia and housed in a dark, quiet environment to avoid external stimulation. Intravenous fluids act to protect the kidneys and enhance elimination. Tremendous muscle stimulation can result in rhabdomyolysis and subsequent myoglobinuria, as well as a metabolic acidosis. Urinary acidification can promote elimination of amphetamines but must not be undertaken if the animal has compromised renal function or if acidosis is already present.

Cocaine There are two main forms of cocaine: the hydrochloride salt and the pure cocaine alkaloid or freebase. The hydrochloride salt is a powder that readily dissolves in water and is usually self-administered by humans either intravenously or intranasally. Some street names for cocaine

powder include coke, girl, gold or star dust, snow, blow, nose candy, and white lady. Freebase is the conversion of the hydrochloride salt form to the pure cocaine alkaloid. The pure alkaloid thus created exists in a flake, crystal, or rock form that vaporizes when heated, making a popping or cracking sound (i.e., crack, rock, or flake). Freebase is usually smoked but is sometimes taken orally (Volmer, 2006). Cocaine is rapidly and well absorbed from all mucosal surfaces. Inflamed or irritated surfaces may promote absorption. Cocaine is rapidly and extensively metabolized in the liver and excreted in the urine. Cocaine is a strong CNS stimulant. It acts to block the reuptake of serotonin and norepinephrine and has the ability to block cardiac sodium channels (Parker et al, 1999). The overall effect of cocaine intoxication is one of stimulation. Animals initially become restless and hyperactive. Signs can progress rapidly to tremors, tachycardia, hypotension, prolongation of QRS intervals, tachypnea, and seizures. Diagnosis is usually based on clinical signs and history of exposure. Over-the-counter drug-testing kits may be helpful in diagnosing a cocaine toxicosis. Treatment is aimed at stabilizing the patient, followed by decontamination. Because clinical signs can develop rapidly, increasing the risk of aspiration, caution should be used if inducing emesis. A safer approach may be to perform gastric lavage with administration of activated charcoal and a cathartic. Tremors and seizures can be controlled with diazepam, chlorpromazine, or a barbiturate. Pretreatment with chlorpromazine effectively antagonized the effects of cocaine in experimentally dosed dogs (Catravas and Waters, 1981). Administration of sodium bicarbonate decreases the likelihood of development of ventricular arrhythmias, shortens the prolonged QRS complex duration, counteracts the reduction in mean arterial blood pressure, and reverses cocaineinduced sodium channel blockade (Llera and Volmer, 2006). Severe tachyarrhythmias can be treated with a β-blocker such as propranolol or esmolol. Intravenous fluids should be administered to maintain renal blood flow and promote excretion. Acid-base and electrolyte status should be monitored and corrected. Hyperthermia can be severe in cocaine intoxications. Correction of body temperature can be achieved with evaporative cooling measures such as misting the animal with cool water and placing the patient in front of a fan until normal body temperature is reached. Alternatively the patient can be immersed in a tepid water bath while monitoring body temperature.

Marijuana Tetrahydrocannabinol (THC), the major active cannabinoid in marijuana, can be found in all parts of the marijuana plant. Street names include pot, Mary Jane, MJ, weed, grass, puff, and hemp. Hashish is the dried resin from flower tops and can contain up to 10% THC. Hashish oil can contain up to 20% THC. Sinsemilla is seedless marijuana (Volmer, 2006). THC is highly lipophilic, is highly protein bound, has a large volume of distribution, and undergoes

CHAPTER  25  Human Drugs of Abuse and Central Nervous System Stimulants enterohepatic recirculation. All these characteristics result in slow elimination from the body (Otten, 2002). Only 10% to 15% of THC or its metabolites are excreted in the urine, with the remainder through the feces via the bile. Marijuana has a wide margin of safety, with a minimum oral lethal dose in the dog of greater than 3 g/kg. However, clinical signs can occur at 1000 times less than this dose (Thompson et al, 1973). Onset of clinical signs can occur within 30 to 60 minutes and can include depression, disorientation, lethargy, ataxia, bradycardia, vomiting, tremor, mydriasis, hypothermia, and urine dribbling. Analysis for THC can be performed on stomach contents and urine. Treatment is primarily symptomatic and supportive. The cannabinoids have a wide margin of safety, and toxicoses are rarely fatal. If the animal is not exhibiting any clinical signs and no other contraindications exist, emesis should be induced. Because enterohepatic recirculation may prolong the residence time of the cannabinoids in the body, repeated doses of activated charcoal are recommended. Body temperature should be monitored for hypothermia and corrected. In most cases recovery should occur within 24 to 72 hours.

Opioids Opium, the dried milky exudate of the poppy plant, contains 24 alkaloids, including morphine, codeine, and thebaine. The opioids are synthetic compounds that bind to the opioid receptor and are classed as agonists, partial agonists, or antagonists. They differ in their specificity and efficacy at different types of receptors. Four major opioid receptors have been identified, with most of the clinically useful opioids binding to mu receptors. Naloxone is a pure competitive antagonist with no agonist activity and has a high affinity for the mu receptor (Volmer, 2006). Most animal exposures involve ingestion of pharmaceutical preparations. Some common opioids include codeine, fentanyl, hydrocodone, hydromorphone, levorphanol, loperamide, meperidine, methadone, and oxy­ codone. The opioids are well absorbed from the gastrointestinal tract and rapidly metabolized in the liver. Morphine is glucuronidated, and the glucuronide is then excreted by the kidney. Clinical signs can include vomiting, defecation, salivation, lethargy and depression, and ataxia. In severe cases respiratory depression, constipation, hypothermia, coma, seizures, and pulmonary edema are possible. Emesis is recommended for recent ingestions in animals that are not exhibiting clinical signs. Pylorospasm produced by the opioid may cause much of the drug to remain in the stomach; thus gastric lavage, activated charcoal, and a cathartic may be effective even several hours after ingestion. Respiratory depression is the most common cause of death with opioid overexposure and should be treated by establishment of a patent airway, assisted ventilation, and oxygen. Naloxone (0.01 to 0.02 mg/kg IV, intramuscularly, or subcutaneously) reverses respiratory depression but does not restore full consciousness. Naloxone may need to be repeated as clinical signs indicate.

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Barbiturates Members of barbiturates are all derivatives of barbituric acid. The barbiturates are used therapeutically as sedatives and anticonvulsants. Animal exposures can result from iatrogenic overdose, ingestion of illicit preparations, accidental administration of euthanasia solutions, and ingestion of euthanized carcasses. Illicit products are known as downers, reds, Christmas trees, and dolls (Volmer, 2006). The barbiturates are well absorbed orally or following intramuscular injection. Lipid solubility of the drug determines the distribution of the barbiturate in the body and the duration of effect. The barbiturates are metabolized in the liver by hepatic microsomal enzymes and excreted in the urine. Acutely the barbiturates may interfere with metabolism of other drugs by binding to hepatic P-450 enzymes, preventing their action on other compounds. Chronic exposure to barbiturates acts to increase microsomal enzyme activity (enzyme induction), thus enhancing the biotransformation of both exogenous and some endogenous substances. Approximately 25% of phenobarbital is excreted unchanged in the urine. It can be ion trapped in the urine by urinary alkalinization, increasing excretion fivefold to tenfold (Haddad and Winchester, 1998). The efficacy of ion trapping for other barbiturates is not as distinct. Barbiturates activate γ-aminobutyric acid A receptors and inhibit excitatory glutamate receptors. Clinical signs can include depression, ataxia, incoordination, weakness, disorientation, recumbency, coma, hypothermia, tachycardia or bradycardia, and death. Barbiturates can be detected in stomach contents, blood, urine, liver, and feces. For recent ingestions in animals exhibiting no other clinical signs, emesis followed by repeated dosages of activated charcoal and a cathartic is recommended. Activated charcoal acts as a sink, encouraging the barbiturate to diffuse back into the intestine from the circulation, even for compounds administered parenterally (Plumb, 2005). Gastric lavage followed by activated charcoal and a cathartic is a safer alternative for animals exhibiting clinical signs (and risking aspiration from induction of emesis). Death is usually the result of respiratory depression; therefore intubation, administration of oxygen, and assisted ventilation may be required. Body temperature should be monitored and corrected. Ventricular fibrillation and cardiac arrest can result from some barbiturates and be exacerbated by profound hypothermia (Haddad and Winchester, 1998). Supportive care, including intravenous fluids, is recommended. Forced alkaline diuresis may facilitate the excretion of some barbiturates, especially phenobarbital.

References and Suggested Reading Baggot JD, Davis LE: Pharmacokinetic study of amphetamine elimination in dogs and swine, Biochem Pharmacol 21:1967, 1972. Catravas JD et al: The effects of haloperidol, chlorpromazine and propranolol on acute amphetamine poisoning in the conscious dog, J Pharmacol Exp Ther 202:230, 1977.

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Catravas JD, Waters IW: Acute cocaine intoxication in the conscious dog: studies on the mechanism of lethality, J Pharmacol Exp Ther 217:350, 1981. Haddad LM, Winchester JF: Barbiturates. In Haddad LM, Shannon MW, Winchester JF, editors: Clinical management of poisoning and drug overdose, ed 3, Philadelphia, 1998, Saunders, p 521. Llera RM, Volmer PA: Hazards faced by police dogs used for drug detection, J Am Vet Med Assoc 228:1028, 2006. Otten EJ: Marijuana. In Goldfrank LR, et al, editors: Toxicologic emergencies, ed 7, New York, 2002, McGraw-Hill, p 1055. Parker RB et al: Comparative effects of sodium bicarbonate and sodium chloride on reversing cocaine-induced changes in the electrocardiogram, J Cardiovasc Pharmacol 34:864, 1999.

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Plumb DC: Phenobarbital. In Plumb DC, editor: Plumb’s veterinary drug handbook, ed 5, Ames, IA, 2005, Blackwell Publishing, p 620. Thompson GR et al: Comparison of acute oral toxicity of cannabinoids in rats, dogs, and monkeys, Toxicol Appl Pharmacol 25:363, 1973. Volmer PA: Recreational drugs. In Peterson M, Talcott P, editors: Small animal toxicology, ed 2, Philadelphia, 2006, Saunders, p 273. Zalis EG et al: Acute lethality of the amphetamines in dogs and its antagonism by curare, Proc Soc Exp Biol Med 118:557, 1965.

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Antidepressants and Anxiolytics AHNA G. BRUTLAG, Minneapolis, Minnesota

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rescription antidepressants and anxiolytic drugs routinely rank among the most commonly prescribed agents in the United States. Additionally, they are commonly used in veterinary medicine for a variety of behavioral disorders including separation anxiety, storm phobias, inappropriate urine marking, stereotypic behaviors, and psychogenic alopecia (see Chapter 117). Although mild adverse effects may be noted at therapeutic doses, severe toxicosis and death may result following overdose, especially if these drugs are ingested with other drugs with serotonergic properties (such as monoamine oxidase inhibitors or 5-hydroxytryptophan). Because of their frequent use, the palatability of some flavored veterinary formulations, and the potential for severe intoxication, unintentional overdoses of antidepressants rank among the most commonly reported cases to Pet Poison Helpline. Antidepressants and anxiolytics encompass several drug classes, the most common of which include selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), benzodiazepines (BZDs), and nonbenzodiazepine (non-BZD) hypnotic agents. The pharmacologic and pharmacokinetic properties of these different classes vary greatly and account for a wide range of toxicities and mechanisms of action. Although some drugs, such as many SSRIs or TCAs, may cause severe intoxication in smaller dosages, others, such as BZDs, have a wider margin of safety and are less likely to

result in severe toxicosis or death. Thus obtaining the exact name of the medication ingested by the pet is crucial to determine a proper course of treatment and guide prognosis. Due to the wide variability in clinical signs and treatments available for these drugs, along with the potential for severe intoxication, consultation with an animal poison control center is recommended (see Chapters 20 and Web Chapter 9).

Considerations for Decontamination Appropriate decontamination procedures are paramount to successful treatment for most poisonings. Because many antidepressants and anxiolytics are rapidly absorbed, resulting in central nervous system (CNS) depression within 15 to 30 minutes of ingestion, decontamination must be judicious. For agents discussed in this chapter, the induction of emesis at home is not always advisable due to the increased risk of aspiration secondary to CNS depression. Additionally, emesis should never be induced in a symptomatic animal. Often, decontamination is most safely performed in a veterinary setting. Therefore educating receptionists, technicians, and other “front-line” agents about contraindications to emesis induction is imperative. In cases of very recent ingestion (less than 5 minutes), the induction of emesis may be attempted at home in dogs (not cats) by administering fresh hydrogen peroxide, 3% (1 to 5 ml/kg, PO). Pet Poison Helpline typically

CHAPTER  26  Antidepressants and Anxiolytics recommends administering 1 ml/kg as the first dosage. If the dog has not vomited within 5 to 10 minutes and remains asymptomatic, a second dosage of 2 ml/kg may be administered. Offering a small amount of food prior to the administration of hydrogen peroxide may increase its effectiveness. Unfortunately, there are currently no safe and effective at-home emetic agents for cats. Products such as table salt, mustard, and syrup of ipecac are no longer recommended in any veterinary species. If emesis cannot be safely induced in the dog at home, apomorphine (0.03 to 0.04 mg/kg) should be administered IV, IM, or by placing the tablet directly into the subconjunctival sac. If subconjunctival apomorphine is used, the subconjunctival sac must be flushed thoroughly after emesis or protracted vomiting may occur. Apomorphine use in cats is not recommended due to poor efficacy and the potential for CNS stimulation. Instead, xylazine (0.44 mg/kg, IM) may be administered. Reversal with yohimbine (0.1 mg/kg, IM, SC, or slowly IV) or atipamezole (Antisedan, 25 to 50 µg/kg, IM or IV) should be performed if severe CNS and/or respiratory depression develop from this treatment. If the patient is symptomatic, the induction of emesis is contraindicated, but gastric lavage may still be effective provided the ingestion was recent (2 g/kg) may cause vomiting, restlessness, and hyperemia. Higher doses may depress cardiovascular function and lead to circulatory collapse. Nizatidine is well absorbed (>90%) in humans PO. Overdose in humans is characterized by cholinergic signs including lacrimation, salivation, emesis, miosis, and diarrhea. The oral LD50 of nizatidine in dogs is 2600 mg/ kg. In acute toxicity studies, however, a single oral dose of 800 mg/kg was not lethal in dogs. Ranitidine, unlike cimetidine, has apparently minimal effects on hepatic metabolism. In laboratory species doses over 200 mg/kg/day have been associated with muscular tremors, vomiting, and rapid respiration (Plumb, 2011). Overdose with H2-antagonists may be treated by limiting intestinal absorption and symptomatic therapy. If tachycardia and respiratory failure develop after cimetidine exposure, β-adrenergic blockers (a trial dose of esmolol to start) and ventilatory support are suggested. Cholinergic signs seen with nizatidine may be treated with atropine and supportive therapy.

Nicotine Several OTC nicotine-based 2 or 4 mg polacrilex chewing gums and replacement transdermal patches are available in the United States as nicotine replacement therapy used in smoking cessation. Nicotine polacrilex is a resin complex of nicotine and polacrilin, which is a cationexchange resin prepared from methacrylic acid and divinylbenzene. The gum may also contain sorbitol as a sweetener and buffering agents to enhance buccal absorption of nicotine. The rate of release of nicotine from the resin complex in chewing gum is variable and depends on the vigor and duration of chewing. Nicotine transdermal patches typically contain 8.3 to 114 mg of the free alkaloid. All patches have significant residues of nicotine (2 to 83 mg) even after 24 hours of application. Some patches consist of a drug reservoir containing nicotine in an ethylene-vinyl acetate copolymer matrix that delivers the drug via a rate-controlling polyethylene membrane. Other sources of nicotine include smokeless tobacco, cigarettes (these contain approximately 15 to 25 mg nicotine), cigars, and related products. Nicotine is a cholinergic (nicotinic) receptor agonist that exhibits both stimulant (low-dose) and depressant (high-dose) effects in the peripheral nervous system and CNS. Nicotine’s cardiovascular effects are usually dose dependent. Nicotine may increase circulating levels of cortisol and catecholamines. The drug is quite toxic

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(the minimal oral lethal dose in dogs and cats is ap­­ proximately 10 mg/kg), and the toxic effects develop rapidly after ingestion. Nicotine-induced clinical effects may include muscle tremors, hypertension, tachycardia, tachypnea, vomiting, hypersalivation, CNS depression or excitation, mydriasis, ataxia, weakness, seizures, and death from respiratory paralysis. Management of nicotine overdose generally involves gastric decontamination followed by symptomatic and supportive therapy. If vomiting has not occurred following an acute ingestion of nicotine, the stomach should be emptied immediately by inducing emesis or by gastric lavage. Activated charcoal and a saline cathartic should be given immediately following gastric emptying. Activated charcoal should be given every 6 to 8 hours following ingestion of transdermal patches because delayed nicotine release may occur. Vigorous intravenous fluid support and additional therapy should be instituted if hypotension or cardiovascular collapse occurs. Seizures should be treated with standard anticonvulsants such as diazepam. Atropine may be given for bradycardia, excessive bronchoconstriction, or diarrhea. Assisted pulmonary ventilation may be necessary for the management of respiratory paralysis.

Herbal Supplements Accidental ingestion of herbal supplements by dogs and cats may result in toxicity. Herbal products are often heterogeneous, may produce multiple effects, and may affect multiple organ systems, including the nervous, cardiovascular, gastrointestinal, hepatic, renal, and hematologic systems (see Chapter 29).

References and Suggested Reading Cavanagh RL, Buyniski JP, Schwartz SE: Prevention of aspirininduced gastric mucosal injury by histamine H2 receptor antagonists: a crossover endoscopic and intragastric pH study in the dog, J Pharmacol Exp Ther 243:1179-1184, 1987. Fernandez AL et al: The use of intravenous lipid emulsion as an antidote in veterinary toxicology, J Vet Emerg Crit Care 21:309320, 2011. Fitzgerald KT, Bronstein AC, Flood AA: “Over-the-counter” drug toxicities in companion animals, Clin Tech Small Anim Pract 21:215-226, 2006. Forrester MB: Pattern of proton pump inhibitor calls to Texas poison centers, 1998-2004, J Toxicol Environ Health A 70:705714, 2007. Gwaltney-Brant S, Meadows I: Use of intravenous lipid emulsions for treating certain poisoning cases in small animals, Vet Clin North Am Small Anim Pract 42:251-262, 2012. Kaplan A, Whelan M: The use of IV lipid emulsion for lipophilic drug toxicities, J Am Anim Hosp Assoc 48:221-227, 2012. Papich MG: Toxicoses from over-the-counter human drugs, Vet Clin North Am Small Anim Pract 20:431, 1990. Parikh N, Howden CW: The safety of drugs used in acid-related disorders and functional gastrointestinal disorders, Gastroenterol Clin North Am 39:529-542, 2010. Physicians’ desk reference for nonprescription drugs, dietary supplements, and herbs 2011, ed 32, Montvale, NJ, 2011, Physicians’ Desk Reference Inc. Plumb DC: Plumb’s veterinary drug handbook, ed 7, Hoboken, 2011, Wiley, John & Sons. Poortinga EW, Hungerford LL: A case-control study of acute ibuprofen toxicity in dogs, Prev Vet Med 35:115-124, 1998. Simons FE: Advances in H1-antihistamines, N Engl J Med 351:22032217, 2004. Ward DM et al: The effect of dosing interval on the efficacy of misoprostol in the prevention of aspirin-induced gastric injury, J Vet Intern Med 17:282-290, 2003.

CHAPTER 

28 

Top Ten Toxic and Nontoxic Household Plants A. CATHERINE BARR, College Station, Texas

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ogs and cats often eat lawn grass and then vomit, but otherwise they are not considered sick. Similarly, there are other house and yard plants that if ingested may or may not cause a pet to vomit but do not typically induce serious adverse effects. Many veterinary practitioners handle calls about these plants and manage the situation by having the owner observe the animal at home. In most cases, if the pet is interested in eating at its next normal feeding time, follow-up medical care is not needed. However, other common house and yard plants contain potentially toxic agents; if a pet eats any of these, it may require medical management and closer observation. This chapter lists the “top 10” nontoxic and toxic plants encountered by veterinary toxicologists in the United States with the hope that the information provided will be of practical use to the clinician or technical staff dealing with a concerned owner about a potential intoxication.

Nontoxic Plants Using the popular “top 10” approach, Box 28-1 lists in alphabetical order (by common name) plants for which no reference to toxicity in dogs or cats has been found.

Toxic Plants In contrast, a number of plants or plant groups are more likely to result in serious adverse effects if ingested by dogs and cats. The “top 10” toxic home and yard plants most frequently encountered by veterinary toxicologists across the United States are listed in Box 28-2. These are subdivided by the major form of clinical toxicosis. There are very few true antidotes for plant intoxications. In the majority of cases, care consists mostly of decontamination and symptomatic/supportive measures. Management of some of these toxicoses is discussed elsewhere in this volume.

References and Suggested Reading Barr AC: Household and garden plants. In Peterson ME, Talcott PA, editors: Small animal toxicology, ed 2, St Louis, 2006, Saunders, pp 345-410. Milewski LM, Khan SA: An overview of potentially lifethreatening poisonous plants in dogs and cats, J Vet Emerg Crit Care 16(1):25-33, 2006.

BOX 28-1  Top 10 Nontoxic Plants African violets: Ionantha saintpaulia hyb. Boston ferns: Nephrolepis exaltata Camellias: Camellia spp./hyb. Chrysanthemums: Chrysanthemum spp./hyb. Geraniums: Pelargonium spp./hyb. Grass, turf: Common lawn grasses (e.g., fescue, Bermuda, St. Augustine, Kentucky bluegrass) Hibiscus, althea: Hibiscus rosa-sinensis hyb. Orchids: Cattleya, Bletia, Brassia, Cymbidium, Dendrobium, Laeliocattleya, Oncidium, Phalaenopsis spp./hyb. Roses: Rosa spp./hyb. Sedums: Sedum spp./hyb.

BOX 28-2  Top 10 Toxic Plants Oral Irritation Araceae: Members of this family include Alocasia spp./hyb. (e.g., elephant ear), Anthurium spp./hyb. (e.g., flamingo flower), Caladium spp./hyb., Dieffenbachia spp./hyb. (e.g., dumb cane), Philodendron spp./hyb., Zantedeschia spp./hyb (e.g., calla lily), and many others Cardiovascular Effects Kalanchoe: Kalanchoe spp. Rhododendron: Azalea spp./hyb, Rhododendron spp./hyb. Oleander: Nerium oleander Yew: Taxus spp. Renal Effects Lilies: Lilium spp./hyb., Hemerocallis spp./hyb. Grapes/raisins: Vitis spp./hyb. Severe Gastrointestinal/Hepatic Effects Autumn crocus: Colchicum autumnale Castor beans: Ricinus communis Sago palms: Cycas spp./hyb.

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CHAPTER 

29 

Herbal Hazards ELIZABETH A. HAUSNER,* Beltsville, Maryland ROBERT H. POPPENGA, Davis, California

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any people use herbal medicines and dietary supplements for their own health, and increasingly these products are administered for the health of their pets. The increasing popularity of herbals may be seen in the volume of sales. Despite economic difficulties, sales in 2010 increased by 3.3% over 2009, with receipts totaling about $5 billion (American Botanical Council). In addition to herbs sold in mass-market, chain, health food, and specialty stores, on-line sales of these products are substantial. The Internet has evolved into a powerful tool for offering information, misinformation, and access to a plethora of products from virtually every corner of the world. Accordingly, toxicities from plants not indigenous to this country can and should be considered in differential diagnoses of possible plant toxicosis.

Regulations In 1994 Congress passed the Dietary Supplement and Health Education Act (DSHEA), creating a new category of substances termed dietary supplements. Dietary supplements include minerals, vitamins, amino acids, herbs, and any product sold as a dietary supplement before October 15, 1994. The Food and Drug Administration (FDA) Center for Veterinary Medicine interpreted the DSHEA as not applying to substances used in animals, leaving veterinary herbals and dietary supplements regulated as foods, food additives, or new animal drugs, depending on the ingredients and their intended use. DSHEA was followed by the Dietary Supplement and Nonprescription Drug Consumer Protection Act, effective December, 2007. This law requires collection of adverse event (AE) reports by manufacturers, distributors, and retailers, with reporting of serious AEs to the FDA. Dietary supplement labels are also required to provide information to facilitate reporting of AEs (Abdel-Rahman et al, 2011). Because there is an assumption of underreporting of AEs for prescription pharmaceuticals, it is reasonable to assume that underreporting of AEs for herbals will occur. Of course, nothing prevents a product intended for human use from being used in or on animals, and at this time there is scant information on AEs of dietary supplements in animals. Ultimately of equal or greater concern than intoxication from herbal remedies is the potential delay in seeking treatment for otherwise treatable diseases handled inappropriately with a supplement or herb.

*The views and opinions expressed are those of the authors and do not represent the FDA.

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Intoxication Scenarios There are a number of scenarios in which animals may experience an adverse reaction to or toxicosis from an herbal preparation. It is worth noting that in several reports the incidence of animal intoxication from an herb, herbal preparation, or dietary supplement seems to parallel its popularity (Ooms, Khan, and Means, 2001; Gwaltney-Brant, Albretsen, and Khan, 2000). The following list provides situations in which toxicosis may occur: 1. The components of a supplement are correctly identified and the preparation contains a known toxicant. For example, the dried rootstocks of Aconitum spp. contain several constituents that are acutely cardiotoxic (Lin, Chan, and Deng, 2005). Pennyroyal oil containing the putative toxin pulegone was responsible for the death of a dog after dermal application to control fleas (Sudekum et al, 1992). 2. The intoxication may be chronic rather than acute as in the case of pyrrolizidine alkaloids, which are found in many plant species and when ingested over time cause severe liver disease (Prakash et al, 1999; Stedman, 2002). 3. Errors may be made when preparing a remedy. For example, human illness was caused when an anise seed preparation was contaminated with the highly toxic Conium maculatum (poison hemlock) seed (deSmet, 1991). An outbreak of renal interstitial fibrosis in women taking Chinese herbs for weight loss was attributed to the use of Aristolochia fangchi instead of Stephania tetrandra in imported powdered extracts (Vanherweghem, 1998). 4. Herbal preparations may unintentionally contain contaminants or intentionally contain chemical adulterants. Many Chinese herbal patent medicines contain drugs such as nonsteroidal antiinflammatory drugs (NSAIDs) or sedatives (Ko, 1998). Also, heavy metal and pesticide contamination has been reported (Ernst, 2002b; Saper et al, 2004; Harris et al 2011). Salmonellosis has been reported in humans taking rattlesnake capsules contaminated with Salmonella arizonae (Fleischman, Haake, and Lovett, 1989). 5. The active constituents in herbal preparations can interact with other concurrently administered drugs, resulting in adverse interactions. For example, buckthorn bark and berries taken chronically can increase the loss of potassium, thus potentiating the action of cardiac glycosides and antiarrhythmic agents (DerMarderosian, 2001). Potassium loss may

CHAPTER  29  Herbal Hazards be exacerbated by simultaneous use of thiazide diuretics, corticosteroids, and licorice root (DerMarderosian, 2001). In addition, active constituents in herbal preparations can induce liver-metabolizing enzymes, which can alter the metabolism and kinetics of coadministered conventional drugs. For example, eucalyptus oil induces liver enzyme activity (DerMarderosian, 2001). This scenario of adverse pharmacologic interactions may occur when the owner does not inform the veterinarian of the intentional use of herbal preparations. 6. Finally, pets may consume improperly stored remedies, resulting in ingestion of a large quantity of a product.

Active Herbal Constituents There are many different ethnic traditions of herbal medicine use, with many plants having roles in these remedies. The following broad classes of active chemical constituents occur in plants: volatile oils, resins, alkaloids, polysaccharides, phenols, glycosides, and fixed oils (Hung, Lewin, and Howland, 1998). Volatile oils are odorous plant ingredients (e.g., catnip, garlic, citrus). Resins are complex chemical mixtures that can be strong gastrointestinal irritants. Alkaloids are a heterogeneous group of alkaline, organic, and nitrogenous compounds. Glycosides are sugar esters containing a sugar (glycol) and a nonsugar (aglycon). In some cases the glycosides are not toxic. However, hydrolysis of the glycosides after ingestion can release toxic aglycons. Fixed oils are esters of long-chain fatty acids and alcohols. Herbs containing fixed oils are often used as emollients, demulcents, and bases for other agents; in general these are the least toxic of the plant constituents. There is a misperception that preparations from plants are inherently safe because they occur in nature compared with synthesized chemicals. However, many plantderived chemicals are biologically active and therefore potentially toxic. Concentrated extracts of a number of herbs have proven to be toxic even if the entire plant may be used with relative safety. Although green tea is consumed by many people with apparent safety, an extract of green tea marketed in Europe caused a significant number of adverse hepatic events, including fulminant hepatitis. The extract was withdrawn from the market (Gloro et al, 2005).

Toxicity of Specific Herbs or Other Natural Products Some of the most commonly encountered herbals are discussed in the following paragraphs; others are listed in Table 29-1.

Blue-Green Algae Blue-green (BG) algae are single-celled organisms that have been promoted for their nutritional properties. Several BG algal species produce potent toxins. Microcystis

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aeruginosa produces the hepatotoxic microcystins. Anabaena flos-aquae produce the neurotoxins anatoxin-a and anatoxin as. Aphanizomenon flos-aquae produce the neurotoxins saxitoxin and neosaxitoxin. Efforts are underway to better define the risks associated with ingestion of potentially toxigenic BG algae and to establish safe concentrations of total microcystins in marketed products. Spirulina has also been promoted as a nutritional supplement and is not considered a toxigenic BG algae genus. However, some products have been found to be contaminated with mercury. Microbial contamination could possibly be a concern if harvested algae grow in water contaminated with human or animal wastes.

Ephedra or Ma Huang The dried young branches of ephedra (Ephedra spp.) have been used for their stimulating and vasoactive effects. In addition, ephedra has been used in several products promoted for weight loss. The plant constituents responsible for biologic activity are the sympathomimetic alkaloids ephedrine and pseudoephedrine. A case series involving intoxication of dogs following ingestion of a weight-loss product containing guarana (caffeine) and ma huang (ephedrine) has been reported (Ooms, Khan, and Means, 2001). Estimated doses of the respective plants associated with adverse effects were 4.4 to 296.2 mg/kg for guarana and 1.3 to 88.9 mg/kg for ma huang. Symptomatology included hyperactivity, tremors, seizures, behavioral changes, emesis, tachycardia, and hyperthermia. Ingestion was associated with mortality in 17% of the cases. North American species of ephedra (also called Mormon tea) have not been shown to contain the sympathomimetic alkaloids. Citrus aurantium (“bitter orange” or “Seville orange”) has appeared in many products labeled as “ephedrinefree” and is also combined with caffeine and/or guarana. The primary active components of C. aurantium are synephrine (structurally similar to epinephrine), octo­ pamine (structurally similar to norepinephrine), and N-methyltyramine. The overall effect is that of stimulation (Fugh-Berman and Myers, 2004). Studies in humans have shown that bitter orange–containing preparations cause tachycardia and increases in systolic and diastolic pressure (Haller, Benowitz, and Jacob, 2005). Signs of intoxication are similar to those seen with ephedra.

Guarana Guarana is the dried paste made from the crushed seeds of Paullinia cupana or P. sorbilis, a fast-growing shrub native to South America. The primary active component in the plant is caffeine, with concentrations that range from 3% to 5% compared with 1% to 2% for coffee beans. Currently the most common forms of guarana include syrups, extracts, and distillates used as flavoring agents and as a source of caffeine for the soft-drink industry. More recently it has been added to weight-loss formulations in combination with ephedra. Oral lethal doses of caffeine in dogs and cats range from 110 to 200 mg/kg of body weight and 80 to 150 mg/kg of body weight, respectively (Carson, 2001; also see Ephedra earlier in the

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SECTION  II  Toxicologic Diseases

TABLE 29-1  Additional Herbs of Toxicologic Concern Scientific Name

Common Names

Active Constituents

Target Organs

Acorus calamus

Acorus, calamus, sweet flag, sweet root, sweet cane, sweet cinnamon

β-Asarone (procarcinogen)

Liver: potent hepatocarcinogen

Aesculus hippocastanum

Horse chestnut, buckeye

Esculin, nicotine, quercetin, rutin, saponins, shikimic acid

Gastrointestinal, nervous

Arnica montana and A. latifolia

Arnica, wolf’s bane, leopard’s bane

Sesquiterpene lactones

Skin: dermatitis

Atropa belladonna

Belladonna, deadly nightshade

Atropine

Nervous: anticholinergic syndrome

Conium maculatum

Poison hemlock

Coniine, other similar alkaloids

Nervous: nicotine-like toxicosis

Convallaria majalis

Lily of the valley, mayflower, conval lily

Cardiac glycosides

Cardiovascular

Cytisus scoparius

Scotch broom, broom, broom tops

l-Sparteine

Nervous: nicotinic-like toxicosis

Datura stramonium

Jimsonweed, thorn apple

Atropine, scopolamine, hyoscyamine

Nervous: anticholinergic syndrome

Dipteryx odorata

Tonka, tonka bean

Coumarin

Hematologic: anticoagulant

Euonymus europaeus; E. atropurpureus

European spindle tree; wahoo, eastern burning bush

Cardiac glycosides

Cardiovascular

Eupatorium perfoliatum; E. purpureum

Boneset, thoroughwort; joe pye weed, gravel root, queen-of-the-meadow

Pyrrolizidine alkaloids

Liver

Heliotropium europaeum

Heliotrope

Pyrrolizidine alkaloids

Liver

Hyoscyamus niger

Henbane, fetid nightshade, poison tobacco, insane root, stinky nightshade

Hyoscyamine, hyoscine

Nervous: anticholinergic syndrome

Ipomoea purga

Jalap

Convolvulin

Gastrointestinal

Mandragora officinarum

Mandrake

Scopolamine, hyoscyamine

Nervous: anticholinergic syndrome

Podophyllum peltatum

Mayapple, mandrake

Podophyllin

Gastrointestinal: gastroenteritis

Sanguinaria canadensis

Bloodroot, red puccoon, red root

Berberine

Gastrointestinal

Solanum dulcamara, other Solanum spp.

Woody, bittersweet, climbing nightshade

Numerous glycoalkaloids including solanine and chaconine

Gastrointestinal, nervous, cardiovascular

Tussilago farfara

Coltsfoot

PA alkaloid, senkirkine

Liver

Vinca major and V. minor

Common periwinkle, periwinkle

Vincamine

Immune system

chapter for a discussion of a case series involving dogs ingesting a product containing guarana and ephedra; Ooms, Khan, and Means, 2001).

Kratom Kratom usually refers to the leaves of Mitragyna speciosa, a plant indigenous to Southeast Asia. Kratom, or Krypton, has been used traditionally for pain, depression, and anxiety. There is some recent use for treating symptoms associated with opiate withdrawal. The leaves contain several active components including mitragynine and 7-hydroxymitragynine (Horie et al, 2005). While structurally similar to yohimbine, mitragynine acts as a mu opioid receptor partial agonist. The relatively minor

component, indole alkaloid 7-hydroxymitragynine, is reported to be more potent than morphine. Kratom is a controlled substance in some countries, but not the United States (Babu et al, 2008). There are case reports in the literature describing adverse effects in humans but as yet little clinical information for animals (Kapp et al, 2011).

Noni Juice Noni juice is derived from Morinda citrifolia, sometimes called “starvation fruit” due to a taste unappealing to humans. Traditionally, noni juice (also called Ba Ji’Tian, Indian Mulberry, or Wild Pine) has been used for a variety of conditions ranging from asthma to smallpox,

CHAPTER  29  Herbal Hazards

TABLE 29-2  Salicylate-Containing Plants Common Name

Latin Name

Salicylate Content

White willow

Salix alba

Variable

Sweet birch

Betula lenta

Variable

White birch

Betula pendula

Variable

Meadowsweet

Filipendula ulmaria

Variable

depression, anorexia, diarrhea, bloody stool, melena, and metabolic acidosis. A dose of 100 to 300 mg/kg orally once daily for 1 to 4 weeks is associated with gastric ulceration; more prolonged dosing is potentially fatal (Osweiler, 1996).

Preparations for Diabetes Mellitus

TABLE 29-3  Salicylate-Containing Oils Name

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Salicylate Content

Wintergreen oil (Gaultheria procumbens)

98%

Hung Far Oil or Red Flower Oil

67%

Pak Far Oil or White Flower Oil

40%

Tiger Balm Liniment

28%

Kwan Loon Medicinal Oil

15%

Data from Davis JE: Are one or two dangerous? Methyl salicylate exposure in toddlers, J Emerg Med 32(1):63-69, 2007.

premenstrual syndrome, and leprosy but is not well studied for any of those. The herbal has a high potassium content that may predispose to interactions with potassium-sparing diuretics and certain antihypertensive medications. Xeronine and proxeronine are components mentioned in advertising, but at this time they have not been chemically identified or studied medically. Although there are several reports of hepatic damage in humans, there are insufficient data at this time to assess safety and efficacy in animals (Yue et al, 2011; Millonig et al, 2005; Stadlbauer et al, 2008).

Salicylate-Containing Preparations Some of the available salicylate-containing plants and oils are listed in Tables 29-2 and 29-3, respectively. Current indications for plant salicylate use include fever, rheumatism, and inflammatory conditions. The oils are readily absorbed through the skin. Both therapeutic and adverse effects occur through inhibition of prostaglandin synthesis. In addition, salicylates inhibit oxidative phosphorylation and Krebs cycle enzymes. Although salicylates are toxic to both dogs and cats, cats metabolize salicylates more slowly than other species and are therefore more likely to be overdosed. In cats acetylsalicylic (AS) acid is toxic at 80 to 120 mg/kg given orally for 10 to 12 days. In dogs AS at 50 mg/kg given orally twice a day is associated with emesis; higher doses can cause

A number of herbal agents are currently promoted for mitigating diabetes mellitus in humans and animals. One of these, Gymnema sylvestre, has been reported to decrease the taste of sugar in the mouth. This effect is reportedly due to glycosides called gymnemic acids. There are case reports of hepatic damage in humans from this supplement (Shiyovich et al, 2010). Galega officinalis (goat’s rue) was used in the Middle Ages to alleviate polyuria/polydipsia, a common manifestation of diabetes mellitus (and other conditions). Isolation and characterization of the active principle of G. officinalis led to the development of the prescription hypoglycemic agent metformin (Graham et al, 2011). Galega sp. has been associated with pulmonary edema in sheep (Keeler et al, 1986). Stevia rebaudiana (sweet herb) is another putative treatment for diabetes mellitus. The diterpene glycosides, or steviol glycosides, provide the sweet taste associated with the plant (Kujur et al, 2010). Lagerstroemia speciosa (Banaba leaf, Giant Crape-myrtle, Queen’s Crape-myrtle), a deciduous tree found in India, Southeast Asia, and the Philippines, has a long history in ethnic medicine. There is evidence in both humans and animals to suggest a possible hypoglycemic effect (Ulbricht et al, 2007). Momordica charantia (bitter melon, bitter squash, bitter gourd) is a vegetable grown in Asia, Africa, and the Caribbean. This plant is used in complementary and alternative medicine for treatment of diabetes mellitus, although a systematic review of the literature indicates insufficient data to evaluate Momordica’s medical effects (Ooi et al, 2012). At the present time there is insufficient information to assess either the safety or the efficacy of these supplements in companion animals. It should be noted that there are reports of herbal antidiabetic products adul­ terated with prescription pharmaceuticals (Ching et al, 2011).

Essential Oils Essential oils are the volatile, organic constituents of fragrant plant matter and contribute to plant fragrance and taste. They are extracted from plant material by distillation or cold-pressing. A number of essential oils are not recommended for use (e.g., aromatherapy, dermal or oral use) because of their toxicity or potential for toxicity (Tisserand and Balacs, 1999). They are listed in Table 29-4. These oils have unknown or oral median lethal dose (LD50) values in animals of 1 g/kg or less. Most toxicity information has been derived using laboratory rodents or mice. Such data should only be used as a rough guide since they cannot always be extrapolated to other species. Essential Oil Safety: A Guide for Health Care Professionals is

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SECTION  II  Toxicologic Diseases

TABLE 29-4  Most Toxic Essential Oils Oil

Genus/Species

Oral LD50 (g/kg)

Toxic Component (%)

Boldo leaf

Peumus boldus

0.13

Ascaridole: 16

Wormseed

Chenopodium ambrosioides

0.25

Ascaridole: 60-80

Mustard

Brassica nigra

0.34

Allyl isothiocyanate: 99

Armoise

Artemisia herba-alba

0.37

Thujone: 35

Pennyroyal (Eur.)

Mentha pulegium

0.40

Pulegone: 55-95

Tansy

Tanacetum vulgare

0.73

Thujone: 66-81

Thuja

Thuja occidentalis

0.83

Thujone: 30-80

Calamus

Acorus calamus var angustatus

0.84

Asarone: 45-80

Wormwood

Artemisia absinthium

0.96

Thujone: 34-71

Bitter almond

Prunus amygdalus var amara

0.96

Prussic acid: 3

Artemisia arborescens

Not established

Iso-thujone: 30-45

Buchu

Agathosma betulina; A. crenulata

Not established

Pulegone: 50

Horseradish

Cochlearia armoracia

Not established

Allyl isocyanate: 50

Lanyana

Artemisia afra

Not established

Thujone: 4-66

Pennyroyal (N. Am.)

Hedeoma pulegioides

Not established

Pulegone: 60-80

Western red cedar

Thuja plicata

Not established?

Thujone: 85

Data from Tisserand R, Balacs T: Essential oil safety: a guide for health care professionals, Edinburgh, UK, 1999, Churchill Livingstone.

an excellent reference for in-depth discussions of general and specific essential oil toxicity. The following essential oils are of particular concern.

Camphor Camphor is an aromatic, volatile, terpene ketone derived from the wood of Cinnamomum camphora or synthesized from turpentine. Camphor oil is separated into four distinct fractions: white, brown, yellow, and blue camphor (Tisserand and Balacs, 1999). White camphor is the form used in aromatherapy and in over-the-counter (OTC) products (brown and yellow fractions contain the carcinogen safrole and are not normally available). OTC products vary in form and camphor content; external products contain 10% to 20% in semisolid forms or 1% to 10% in camphor spirits. It is used as a topical rubefacient and antipruritic agent. Camphor is rapidly absorbed from the skin and gastrointestinal tract, and toxic effects can occur within minutes of exposure. In humans signs of intoxication include emesis, abdominal distress, excitement, tremors, and seizures followed by central nervous system (CNS) depression characterized by apnea and coma. Fatalities have occurred in humans ingesting 1 to 2 g of camphor-containing products, although the adult human lethal dose has been reported to be 5 to 20 g (Tisserand and Balacs, 1999; Emery and Corban, 1999). A 1-tsp amount of camphorated oil (≈1 ml of camphor) was lethal to 16-month-old and 19-month-old children.

Citrus Oil Citrus oil and citrus oil constituents such as D-limonene and linalool have been shown to have insecticidal activity. Although D-limonene has been used safely as an insecticide on dogs and cats, some citrus oil formulations or use of pure citrus oil may pose a poisoning hazard (Powers et al, 1988). Fatal adverse reactions have been reported in cats following the use of an “organic” citrus oil dip (Hooser, Beasley, and Everitt, 1986). Hypersalivation, muscle tremors, ataxia, lateral recumbency, coma, and death were noted experimentally in three cats following use of the dip according to label directions.

Melaleuca Oil Melaleuca is derived from the leaves of the Australian tea tree (Melaleuca alternifolia); it is often referred to as tea tree oil. The oil contains terpenes, sesquiterpenes, and hydrocarbons. A variety of commercially available products contain the oil; shampoos and the pure oil have been sold for use on dogs, cats, ferrets, and horses. Tea tree oil toxicosis has been reported in dogs and cats (Villar et al, 1994; Bischoff and Guale, 1998). One case report describes the illness of three cats exposed dermally to pure melaleuca oil for flea control (Bischoff and Guale, 1998). Clinical signs in one or more of the cats included hypothermia, ataxia, dehydration, nervousness, trembling, and coma. There were moderate increases in serum

CHAPTER  29  Herbal Hazards alanine aminotransferase and aspartate aminotransferase concentrations. Two cats recovered within 48 hours following decontamination and supportive care. However, one cat died 3 days after exposure. The primary constituent of the oil, terpinen-4-ol, was detected in the urine of the cats. Another case involved the dermal application of 7 to 8 drops of oil along the backs of two dogs as a flea repellent (Kaluzienski, 2000). Within 12 hours one dog developed partial paralysis of the hind limbs, ataxia, and depression. The other dog only displayed depression. Decontamination (bathing) and symptomatic and supportive care resulted in rapid recovery within 24 hours.

Pennyroyal Oil A volatile oil, pennyroyal oil is derived from Mentha pulegium and Hedeoma pulegioides. Pennyroyal oil has a long history of use as a flea repellent. There is one case report of pennyroyal oil toxicosis in the veterinary literature in which a dog was dermally exposed to pennyroyal oil at approximately 2 g/kg (Sudekum et al, 1992). Within 1 hour of application, the dog became listless, and within 2 hours it began vomiting. Thirty hours after exposure the dog exhibited diarrhea, hemoptysis, and epistaxis. Soon thereafter it developed seizures and died. Histopathologic examination of liver tissue showed massive hepatocellular necrosis.

Product Adulteration There is a long history of Chinese patent medicines being adulterated with metals and conventional pharmaceuticals or containing natural toxins (Ko, 1998; Au et al, 2000; Ernst, 2002a; Dolan et al, 2003). Sedatives, stimulants, and NSAIDs are common pharmaceuticals added to patent medicines with no labeling to indicate their presence. Commonly found natural toxins in Chinese patent medicines include borneol (reduced camphor), aconite, toad secretions (Bufo spp., Ch’an Su), mylabris, scorpionderived toxins, borax, Acorus, and strychnine (Strychnos nux-vomica) (Ko, 1998). Chinese patent medicines often contain cinnabar (mercuric sulfide), realgar (arsenic sulfide), or litharge (lead oxide) as part of the traditional formula. Recently dietary supplements purchased largely from retail stores were tested for arsenic, cadmium, lead, and mercury (Dolan et al, 2003). Eighty-four of the 95 products tested contained botanicals as a major component of the formulation, while 11contained lead concentrations that would have exceeded recommended maximum levels in children and pregnant women had the products been used according to label directions. Serious adverse health effects have been documented in humans using adulterated Chinese herbal medicines (Ernst, 2002a). There are no published cases in the veterinary literature, although we are aware of one case in which a small dog ingested a number of herbal tea “balls” that were prescribed to its owner for arthritis. The dog presented to a veterinary clinic in acute renal failure several days after the ingestion. Analysis of the formulation revealed low-level heavy metal contamination (mercury and lead) and large concentrations of caffeine

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and the NSAID indomethacin. The acute renal failure was most likely the result of NSAID-induced renal damage.

Drug-Herb Interactions Drug-herb interactions refer to the possibility that an herbal constituent may alter the pharmacologic effects of a conventional drug given concurrently or vice versa. The result may be either enhanced or diminished drug or herb effects or the appearance of a new effect that is not anticipated from the use of the drug or herb alone. Possible interactions include those that alter the absorption, metabolism, distribution, and/or elimination of a drug or herbal constituent and result in an increase or decrease in the concentration of active agent at the site of action. For example, herbs that contain dietary fiber, mucilage, or tannins might alter the absorption of another drug or herbal constituent. Herbs containing constituents that induce liver enzymes might be expected to affect drug metabolism and/or elimination (Blumenthal, 2000). Induction of liver metabolizing enzymes can increase the toxicity of drugs and other chemicals via increased production of reactive metabolites. The production of more toxic reactive metabolites is termed bioactivation (Zhou et al, 2004). Alternatively enhanced detoxification of drugs and other chemicals can decrease their toxicity or their therapeutic efficacy. Long-term use of herbs and other dietary supplements can induce enzymes associated with procarcinogen activation, thus increasing the risk of some cancers (Ryu and Chung, 2003; Zhou et al, 2004). The displacement of one drug from protein-binding sites by another agent increases the concentration of unbound drug available to target tissues. Pharmacodynamic interactions or interactions at receptor sites can be agonistic or antagonistic.

Diagnosis of Herbal Intoxication Because of the nonspecific signs associated with most intoxications, the diagnosis of a causative agent is extremely difficult without a history of exposure or administration. Such information may not be forthcoming from clients since they may not equate use of an alternative therapy with conventional drug use and therefore may not reveal this information when queried about prior medication history. Also, clients may not volunteer such information because of embarrassment or belief that the veterinarian will not approve of the alternative therapy. Therefore it is important to specifically question clients regarding use of natural products, including herbs, supplements, and vitamins. An added complication is that, even with a history of exposure and a product package, the animal may have been exposed to adulterating or contaminating agents that are not listed on the package label. Clinical laboratory tests (or postmortem findings) are rarely specific for intoxication from natural products; however, they do assist in determining affected organ systems and thus help formulate a differential list. It may be possible to detect specific herbal constituents in biologic specimens. For example, pulegone was detected in tissues from a dog intoxicated by pennyroyal oil (Sudekum

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et al, 1992). Currently however, analyses for organic natural products in tissues are not widely available, although analytic methods may improve as herbal use continues to increase.

Treatment of Herbal Intoxication The adage “treat the patient and not the poison” is appropriate in most suspected poisonings caused by herbal preparations. Treatment consists of decontamination followed by general supportive care and is discussed elsewhere in this section (see Chapters 23 and 27). Indications and contraindications for decontamination procedures should be followed (Poppenga, 2004). Inducing emesis is contraindicated when there is high risk of aspiration (the patient is unconscious or there is neurologic depression) or the patient is having or is likely to have a seizure. Generally dermal preparations can be removed by washing with a mild soap or detergent. Care should be exercised that the personnel performing this do not themselves become contaminated. Gloves, aprons, and good ventilation are necessary. It is also important to avoid hypothermia in the patient. Supportive care is based on the clinical signs exhibited by the patient. Body temperature, status of the major organ systems, hydration, acid-base balance, urine output, neurologic status, and cardiovascular function require regular monitoring and evaluation. In rare cases an antidote might be available (e.g., digoxin-specific F(ab) fragments for cardiac glycosides). There are also specific considerations for several botanical agents. Intoxication with salicylates frequently results in acidosis. Urinary alkalinization using sodium bicarbonate may increase the elimination by trapping the ionized salicylate molecules in the urine. It is also important to protect the gastrointestinal tract against the ulcerogenic potential of the salicylates. Treatment may include a protectant such as sucralfate, a histamine H2-receptor antagonist (cimetidine, ranitidine, or most often famotidine), a proton pump inhibitor (omeprazole), and potentially misoprostol (a PGE1 analog). In cases of poisoning from caffeine/guarana, ephedra, Citrus aurantium, and other materials causing CNS stimulation, the animal should be monitored for hyperthermia, dehydration, acidosis, cardiac arrhythmias, and seizures. Along with decontamination, fluid therapy increases urinary excretion and helps to correct electrolyte imbalances. Frequent premature ventricular complexes should be treated with lidocaine (without epinephrine). Tachyarrhythmias may require the use of a β-blocker. It must be remembered that β-blockers may also mask the early signs of shock or of hypoglycemia.

References and Suggested Reading Abdel-Rahman A et al: The safety and regulation of natural products used as foods and food ingredients, Toxicol Sci 123(2): 333-348, 2011. American Botanical Council: http//cmsherbalgram.org/press/2011/ HerbalMarketReport2010.html. Last accessed November 11, 2011. Au AM et al: Screening methods for drugs and heavy metals in Chinese patent medicines, Bull Environ Contam Toxicol 65:112, 2000.

Babu KM, McCurdy CR, Boyer EW: Opioid receptors and legal highs: Salvia divinorum and kratom, Clin Toxicol 46(2):146-152, 2008. Bent S et al: The relative safety of ephedra compared to other herbal products, Ann Intern Med 138(6):468, 2003. Birdsall TC: 5-Hydroxytryptophan: a clinically effective serotonin precursor, Altern Med Rev 3:271, 1998. Bischoff K, Guale F: Australian tea tree (Melaleuca alternifolia) oil poisoning in three purebred cats, J Vet Diagn Invest 10:208, 1998. Blumenthal M: Interactions between herbs and conventional drugs: introductory considerations, Herbal Gram 49:52, 2000. Carson TL: Methylxanthines. In Peterson ME, Talcott PA, editors: Small animal toxicology, Philadelphia, 2001, Saunders, p 563. Ching CK et al: Adulteration of herbal anti-diabetic products with undeclared pharmaceuticals: a case series in Hong Kong, Br J Clin Pharmacol Oct 28: 1365-2125, 2011. Davis JE: Are one or two dangerous? Methyl salicylate exposure in toddlers, J Emerg Med 32(1):63-69, 2007. DerMarderosian A, editor: Review of natural products, St Louis, 2001, Facts and Comparisons. deSmet PAGM: Toxicological outlook on the quality assurance of herbal remedies. In De Smet PAGM et al, editors: Adverse effects of herbal drugs 1, Berlin, 1991, Springer-Verlag, p 1. Dolan SP et al: Analysis of dietary supplements for arsenic, cadmium, mercury, and lead using inductively coupled plasma mass spectrometry, J Agric Food Chem 51:1307, 2003. Emery DP, Corban JG: Camphor toxicity, J Paediatr Child Health 35:105, 1999. Ernst E: Adulteration of Chinese herbal medicines with synthetic drugs: a systematic review, J Intern Med 252:107, 2002a. Ernst E: Toxic heavy metals and undeclared drugs in Asian herbal medicines, Trends Pharmacol Sci 23(3):136, 2002b. Fleischman S, Haake DA, Lovett MA: Salmonella arizona infections associated with ingestion of rattlesnake capsules, Arch Intern Med 149:705, 1989. Fugh-Berman A, Ernst E: Herb-drug interactions: a review and assessment of report reliability, J Clin Pharmacol 52:587, 2001. Fugh-Berman A, Myers A: Citrus aurantium, an ingredient of dietary supplements marketed for weight loss: current status of clinical and basic research, Exp Biol Med 229:698, 2004. Gloro R et al: Fulminant hepatitis during self-medication with hydroalcoholic extract of green tea, Eur J Gastroeterol Hepatol 17:1135, 2005. Graham GG et al: Clinical pharmacokinetics of metformin, Clin Pharmacokinet 50(2):81-98, 2011. Grande GA, Dannewitz SR: Symptomatic sassafras oil ingestion, Vet Hum Toxicol 29:447, 1987. Gwaltney-Brant SM, Albretsen JC, Khan SA: 5-Hydroxytryptophan toxicosis in dogs: 21 cases (1989-1999), J Am Vet Med Assoc 216:1937, 2000. Haller CA et al: An evaluation of selected herbal reference texts and comparison to published reports of adverse herbal events, Adverse Drug React Toxicol Rev 21(3):143, 2002. Haller CA, Benowitz NL, Jacob P III: Hemodynamic effects of ephedra-free weight-loss supplements in humans, Am J Med 118(9):998, 2005. Harris ES et al: Heavy metal and pesticide content in commonly prescribed individual raw Chinese herbal medicines, Sci Total Environ 409(20):4297-4305, 2011. Hooser SB, Beasley VR, Everitt JI: Effects of an insecticidal dip containing D-limonene in the cat, J Am Vet Med Assoc 189:905, 1986. Horie S et al: Indole alkaloids of a Thai medicinal herb Mitragyna speciosa that has opioid agonistic effect in a guinea pig ileum, Planta Med 71(3):231-236, 2005.

CHAPTER  29  Herbal Hazards Hung OL, Lewin NA, Howland MA: Herbal preparations. In Goldfrank LR et al, editors: Goldfrank’s toxicologic emergencies, ed 6, Stamford, CT, 1998, Appelton and Lange, p 1221. Kaluzienski M: Partial paralysis and altered behavior in dogs treated with Melaleuca oil, J Toxicol Clin Toxicol 38:518, 2000. Kapp FG et al: Intra-hepatic cholestasis following abuse of powdered kratom (Mitragyna speciosa), J Med Toxicol 7(3):227-231, 2011. Keeler RF et al: Toxicosis from and possible adaptation to Galega officinalis in sheep and the relationship to Verbesina encelioides toxicosis, Vet Hum Toxicol 28(4):309-315, 1986. Ko RJ: Herbal products information. In Poisoning and toxicology compendium, Cleveland, 1998, Lexi-Comp, p 834. Kujur RS et al: Antidiabetic activity and phytochemical screening of crude extract of Stevia rebaudiana in alloxan-induced diabetic rats, Pharmacognosy Res 2(4):258-263, 2010. Lazarou J, Pomeranz BH, Corey PN: Incidence of adverse drug reactions in hospitalized patients: a meta-analysis of prospective studies, JAMA 279 (15):1200, 1998. Lin CC, Chan TYK, Deng JF: Clinical features and management of herb-induced aconitine poisoning, Ann Emerg Med 43:574, 2005. Millonig G, Stadmann S, Vogel W: Herbal hepatotoxicity: acute hepatitis caused by a noni preparation (morinda citrifolia), Eur J Gastroenterol Hepatol 17(4):445-447, 2005. Ooi CP, Yassin Z, Hamid TA: Momordica charantia for type 2 diabetes mellitus, Cochrane Database Syst Rev Aug 15, 2012. Ooms TG, Khan SA, Means C: Suspected caffeine and ephedrine toxicosis resulting from ingestion of an herbal supplement containing guarana and ma huang in dogs: 47 cases (19971999), J Am Vet Med Assoc 218:225, 2001. Osweiler GD: Over-the-counter drugs and illicit drugs of abuse. In The national veterinary medical series: toxicology, Philadelphia, 1996, Williams & Wilkins, p 303. Pirmohamed M et al: Adverse drug reactions as a cause of admission to hospital: prospective analysis of 18,820 patients, Br Med J 329:15, 2004. Poppenga R: Treatment. In Plumlee KH, editor: Clinical veterinary toxicology, St. Louis, 2004, Mosby, p 13. Powers KA et al: An evaluation of the acute toxicity of an insecticidal spray containing linalool, d-limonene, and piperonyl

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butoxide applied topically to domestic cats, Vet Hum Toxicol 30(3):206, 1988. Prakash AS et al: Pyrrolizidine alkaloids in human diet, Mutat Res 443:53, 1999. Ryu S, Chung W: Induction of the procarcinogen-activating CYP1A2 by a herbal dietary supplement in rats and humans, Food Cosmet Toxicol 41:861, 2003. Saper RB et al: Heavy metal content of ayurvedic herbal medicine products, JAMA 292(23):2868, 2004. Segelman AB et al: Sassafras and herb tea: potential health hazards, JAMA 236:477, 1976. Shiyovich A, Sztarker I, Nesher L: Toxic hepatitis induced by Gymnema sylvestre, a natural remedy for type 2 diabetes mellitus, Am J Med Sci 340(6):514-517, 2010. Stadlbauer V et al: Herbal does not at all mean innocuous: the sixth case of hepatotoxicity associated with Morinda citrifolia (noni), Am J Gastroenterol 103(9):2406-2407, 2008. Stedman C: Herbal hepatotoxicity, Semin Liver Dis 22(2):195-206, 2002. Sudekum M et al: Pennyroyal oil toxicosis in a dog, J Am Vet Med Assoc 200:817, 1992. Tisserand R, Balacs T: Essential oil safety: a guide for health care professionals, Edinburgh, UK, 1999, Churchill Livingstone. Ulbricht C et al: Banaba (Lagerstroemia speciosa L.): an evidencebased systematic review by the Natural Standard Research Collaboration, J Herbal Pharmacotherapy 7(1):99-113, 2007. Vanherweghem LJ: Misuse of herbal remedies: the case of an outbreak of terminal renal failure in Belgium (Chinese herbs nephropathy), J Altern Complement Med 4:9, 1998. Villar D et al: Toxicity of Melaleuca oil and related essential oils applied topically on dogs and cats, Vet Hum Toxicol 36:139, 1994. Yang S, Dennehy CE, Tsourournis C: Characterizing adverse events reported to the California poison control system on herbal remedies and dietary supplements: a pilot study, J Herb Pharmacother 2(3):1, 2003. Yue I et al: Acute hepatotoxicity after ingestion of Morinda citrifolia (noni juice) in a 14-year-old boy, J Pediatr Gastroenterol Nutr 52(2):222-224, 2011. Zhou S et al: Herbal bioactivation: the good, the bad and the ugly, Life Sci 74:935, 2004.

CHAPTER 

30 

Lawn and Garden Product Safety JOHN H. TEGZES, Pomona, California

T

oday’s lawns and gardens are rife with products for making grass greener, controlling weeds and pests, and conserving water. These products can be classified by their intended use and include fertilizers, herbicides, mulches, and pesticides. They are often available in large volumes, stored in the garage, and applied throughout the year, making exposure to pets an everyday occurrence. Access can include pets eating concentrated product from bags and containers in storage areas and after application to lawns and gardens. Recent trends in lawn and garden care have created new dangers to pets including the increasing availability of products such as cocoa mulch. This chapter reviews some of the common fertilizers, herbicides, and mulches that are widely available, along with the clinical management of dogs and cats after exposure. Information on pesticides can be found in other chapters in this section.

Fertilizers According to the Soil Science Society of America, fertilizers are defined as “any organic or inorganic material of natural or synthetic origin (other than liming materials) that is added to a soil to supply one or more plant nutrients essential to the growth of plants.” Fertilizers include products that are granular or liquid and that contain either single ingredients or blends of plant nutrients. Plant nutrients can include nitrogen, phosphorus pentoxide (P2O5), water-soluble potash (K2O), and secondary nutrients such as calcium, copper, iron, magnesium, and sulfur. Some fertilizers are acid-forming and decrease soil pH after application. Organic fertilizers include naturally occurring organic materials such as manure, guano, worm castings, and compost. Some commercial fertilizer products contain combinations of soil nutrients, herbicides, and insecticides. The nutrient components of most fertilizers are unlikely to result in severe toxicity in dogs and cats. However, it is important to be aware of all ingredients in a particular product if ingestion occurs because treatment recommendations differ depending on the ingredients and their concentration. Regardless of the actual ingredients, fertilizers may cause vomiting and diarrhea if large amounts are ingested, a result of either irritant effects or bacterial contamination. The main ingredients of nitrogen, phosphorus, and potash are of low toxicologic significance and do not pose the threat of severe toxicity. In a controlled study dogs that were exposed to urea-based fertilizer, herbicide, and 130

insecticide mixtures via a stomach tube did not display clinical signs (Yeary, 1984). The volumes of mixtures given were extreme (10 ml/kg) and higher than those that could be eaten off grass after application. Based on these findings the ingestion of grass or walking or laying on lawns treated with fertilizers, alone or in combination with herbicides or insecticides, by dogs should not result in toxicologic effects requiring treatment.

Herbicides There are more than 200 types of herbicides. Herbicides are used both in agriculture and on home gardens and yards to help eradicate weeds and unwanted plants. In general, herbicides are classified by their chemical class (Gupta, 2007). These chemical classes include phenoxy derivatives, urea and thiourea compounds, organic phosphorus/phosphonomethyl amino acids, triazines and triazoles, and others. Although most herbicides are generally not a high toxicologic risk for household pets, there are a few of which the small animal practitioner should be aware.

Organic Phosphorus/Phosphonomethyl Amino Acid Herbicides Glyphosate, a broad-spectrum herbicide, is widely used by the general public on residential lawns and gardens. It has herbicidal activity against a vast range of annual and perennial weeds and is generally regarded as practically nontoxic to mammals and aquatic and avian species (Malik, Barry, and Kishore, 1989). Therefore it is unlikely that ingestions, even if directly from the container, will result in illness. Some dogs, however, experience vomiting, hypersalivation, and diarrhea after ingestion of glyphosate directly from the container. This is usually attributed to the inactive surfactant found in liquid formulations (Smith and Oehme, 1992). Dogs with protracted vomiting and/or diarrhea can be treated with antiemetics, antidiarrheals, and intravenous fluids, replacing electrolytes as needed based on serum electrolyte concentrations. These clinical effects usually resolve rapidly, and the prognosis is very good.

Phenoxy Acid Derivative Herbicides The phenoxy acid derivatives are broad-spectrum herbicides used extensively for broad-leaf weed control. The chlorophenoxy herbicide 2,4-dichlorophenoxyacetic acid

CHAPTER  30  Lawn and Garden Product Safety (2,4-D) is commonly used around the home and in agriculture. Experimental data suggest that dogs are sensitive to toxicity, leading to gastrointestinal signs and myotonia when given doses of 175 or 220 mg/kg (Beasley, 1991). A case report involving an intact male weimaraner demonstrated clinical evidence of myotonia after an accidental (nonexperimental) exposure (Chen, Bagley, and Talcott, 2010). Toxicity after oral exposure leads initially to gastrointestinal signs of vomiting, diarrhea, and abdominal pain, although absence of these signs does not rule out exposure. Prolonged gastrointestinal signs may lead to fluid and electrolyte imbalances. Neurologic signs occur after high doses or chronic exposures and are characterized by myotonia. Sustained muscle contractions occur after stimulation because of a failure of the muscles to relax. Muscle stiffness, extensor rigidity, and a stiff-limbed gait are observed. Although reports of myotonia are rare following accidental ingestions of 2,4-D, treatment should still be undertaken, including decontamination with oral activated charcoal and supportive care, based on the clinical signs observed. Treatment with intravenous fluids helps to replace fluids and electrolytes lost due to gastrointestinal signs and may help to excrete the herbicide and its metabolites. Keeping the dog cage-rested while minimizing stimulation may help relieve signs of myotonia. An association between lymphoma in dogs and the use of herbicides has been postulated. A case-control study in 1991 found an association between the use of 2,4-D on yards and the development of canine malignant lymphoma, with an odds ratio of 1.3 (Hayes et al, 1991). Additionally, the report documented a twofold increased risk of canine lymphoma in homes that used 2,4-D for 4 or more years. In 2001 another case-control study found an association between dogs living in an industrial area and the development of canine lymphoma. This same study also found an association between the use of chemicals by owners, specifically paints or solvents, and canine lymphoma (Gavazza et al, 2001). Additionally, a third case-control study reported in 2004 demonstrated an increased risk of transitional cell carcinoma of the urinary bladder in Scottish terriers associated with the use of phenoxy herbicides (Glickman et al, 2004). However, epidemiologic or observational studies such as those cited cannot demonstrate actual cause and effect. Moreover, depending on the study design, additional risk factors may or may not be included in the analysis. Nevertheless the development of neoplasias associated with chronic environmental exposure to phenoxy herbicides is a topic that will continue to be debated and investigated. Although these chronic environmental-type exposures do not require emergency veterinary care, clinicians need to be aware of them and educate owners of potential risks. At the least dog owners should be cautioned to limit access to lawns soon after herbicide applications if such applications cannot be avoided. Similar to the debate about neoplasia in dogs, there has been speculation about an association between the use of herbicides, fertilizers, or plant pesticides and the development of hyperthyroidism in cats. One casecontrol study in 1988 found an association, but another case-control study in 2000 did not (Scarlett, Moise, and Rayl, 1988; Martin et al, 2000). Although a definitive

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connection requires further investigation, it may be prudent to inform owners that a risk may be present and have them limit cats from access to lawns soon after these applications.

Bipyridyl Derivative Herbicides Paraquat is a bipyridyl herbicide with nonselective contact action. Paraquat use is very restricted but a few formulations are available. Instances of exposure in pets have occurred as a result of malicious poisoning; a series of alleged canine poisonings occurred in an urban dog park in 2003, providing clinical data regarding such exposures (Cope et al, 2004). Paraquat poisoning frequently leads to gastrointestinal signs of vomiting and anorexia soon after exposure. As time goes by, azotemia and progressive respiratory failure develop (Cope et al, 2004). Paraquat accumulates in the lungs, where it causes oxidative injury to type I and type II alveolar cells. As degeneration and sloughing of pneumocytes occur, the animal develops respiratory difficulty with poor exchange of respiratory gases. Often thoracic radiographs are normal in these cases, making ultimate diagnosis difficult unless the owner is aware of the paraquat exposure. In some patients, noncardiogenic pulmonary edema may be seen radiographically. Optimal therapy is uncertain and oxygen can accelerate further oxidative injury to pneumocytes. The dog should be maintained in a quiet environment with minimal stimulation on room air. Oxygen administration should be avoided, if possible. Unfortunately, most cases of paraquat poisoning are fatal, and treatment is supportive. Any animal with suspected ingestion of paraquat should be decontaminated as soon as possible after exposure with activated charcoal. After decontamination, any gastrointestinal signs can be treated with antiemetics and according to the specific signs the animal is exhibiting. Intravenous fluid administration is indicated to help maintain urine output and to protect the kidneys from accumulation and injury by paraquat. Most importantly, the animal should be kept calm and protected from unnecessary stimulation. The prognosis for most cases is poor.

Triazine and Triazole Herbicides Atrazine is the major herbicide in this class. It has been studied extensively in laboratory animals, looking at both high-dose and low-dose chronic exposures and any association with disease. Generally, it is regarded as having low mammalian toxicity and is unlikely to cause illness in pets with normal household use (Gupta, 2007).

Mulches Mulches are protective covers placed over soil in gardens to help retain moisture, reduce erosion, provide nutrients, and suppress weeds. Organic residue mulches are probably the most commonly used in households and include shredded bark and tree clippings, wood chips, sawdust, and other plant materials. Some mulches come mixed with animal manure to provide nutrients to soil. Compost is another effective mulch that also provides

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soil nutrients. These types of plant-based mulches generally are not a significant toxicologic risk but may pose risks associated with gastrointestinal foreign bodies and bacterial contamination. Recently there has been increased use of cocoa mulch, which consists of shells of spent cacao beans used in chocolate production. Cocoa mulches are attractive to use around the home because of their dark brown color and chocolate aroma. However, some of these mulches can contain the methylxanthines theobromine and caffeine (Carson, 2006). Some dogs are attracted to cocoa mulch because of its smell, and ingestions in dogs are not uncommon. There is variability in the methylxanthine content in cocoa mulches, and not all ingestions result in significant toxicity. However, cocoa mulch ingestions should be treated as suspect methylxanthine toxicity. Clinical effects of toxicity can range from mild vomiting, restlessness, and diarrhea with low-dose ingestions to cardiac arrhythmias, muscular rigidity, hyperreflexia, ataxia, and terminal seizures with high-dose ingestions. Treatment includes decontamination with activated charcoal. Multiple doses of activated charcoal should be administered when prolonged or severe clinical signs are observed. Activated charcoal without a cathartic can be dosed at 1 to 2 g/kg PO every 3 to 6 hours for up to 3 days postexposure. Clinical signs should be treated based on the patient’s presentation. Prolonged vomiting can be treated with antiemetics. Tachyarrhythmias are usually responsive to β-blockers such as esmolol, propranolol, or atenolol. Seizures can be treated initially with diazepam and barbiturates and progressed to constant-rate infusions of anesthetic drugs such as propofol for refractory seizure activity.

Treating the Poisoned Patient Generally, the products reviewed in this chapter are of low toxicity; however, some dogs may be sensitive to certain products. It is prudent to follow these basic principles when treating a known or suspected toxicity. First, after the initial assessment of the patient, all dermal and oral exposures should be decontaminated by administering activated charcoal at 1 to 2 g/kg. If the product exposure was to the hair coat and/or skin, as much of the product as possible should be removed by either clipping the fur or brushing, followed by bathing with a gentle shampoo. Additionally, these patients should also receive oral activated charcoal because most animals self-groom and potentially will ingest the garden chemical that was in the hair coat. Although some clinical signs can be anticipated after exposure to certain toxins, it is important to treat the patient and not the poison. As such, treatment plans need to be based on the clinical signs and assessment of the patient. Many garden products are irritants to the gastrointestinal tract, and vomiting may occur spontaneously after ingestion. Persistent vomiting can be treated with antiemetics. Cardiac arrhythmias should be treated on a

case-by-case basis, paying attention to the overall hemodynamic stability of the patient. Most supraventricular tachyarrhythmias respond to β-blockers, most ventricular arrhythmias to lidocaine, and most bradyarrhythmias to atropine unless associated with shock (as in cats) or profound hypothermia. Neurologic and/or neuromuscular signs can include myotonia, rigidity and hyperreflexia, agitation and anxiety, tremors and seizures, and CNS depression. Depending on the clinical signs presented, some treatment options include the use of skeletal muscle relaxants such as methocarbamol. For agitation and seizures benzodiazepines or barbiturates are often useful. When these signs are severe or prolonged, constant rate infusions of drugs such as propofol are helpful. Fluid and electrolyte losses due to gastrointestinal signs can be replaced through the administration of intravenous fluids, while monitoring serum electrolytes helps to select the best type of fluid and additives.

References and Suggested Reading Beasley VR et al: 2,4-D toxicosis I: a pilot study of 2,4-dichlorophenoxyacetic acid and dicamba-induced myotonia in experimental dogs, Vet Human Toxicol 33:435-440, 1991. Carson TL: Methylxanthines. In Peterson ME, Talcott PA, editors: Small animal toxicology, ed 2, St Louis, 2006, Saunders, pp 845-852. Chen AV, Bagley RS, Talcott PA: Confirmed 2,4-dichlorophenoxyacetic acid toxicosis in a dog, J Am Anim Hosp Assoc 46:43-47, 2010. Cope RB et al: Fatal paraquat poisoning in seven Portland, Oregon dogs, Vet Hum Toxicol 46(5):258-264, 2004. Gavazza A et al: Association between canine malignant lymphoma, living in industrial areas, and use of chemicals by dog owners, J Vet Intern Med 15:190-195, 2001. Glickman LT et al: Herbicide exposure and the risk of transitional cell carcinoma of the urinary bladder in Scottish terriers, J Am Vet Med Assoc 224(8):1290-1297, 2004. Gupta PK: Toxicity of herbicides. In Gupta RC, editor: Veterinary toxicology, New York, 2007, Elsevier, pp 567-586. Hayes HM et al: Case-control study of canine malignant lymphoma: positive association with dog owner’s use of 2,4-dichlorophenoxyacetic acid herbicides, J Natl Cancer Inst 83:1226-1231, 1991. Malik J, Barry G, Kishore G: The herbicide glyphosate, Biofactors 2(1):17-25, 1989. Martin KM et al: Evaluation of dietary and environmental risk factors for hyperthyroidism in cats, J Am Vet Med Assoc 217(6):853-856, 2000. Scarlett JM, Moise NS, Rayl J: Feline hyperthyroidism: a descriptive and case-control study, Prev Vet Med 6:295-309, 1988. Smith EA, Oehme FW: The biological activity of glyphosate to plants and animals: a literature review, Vet Hum Toxicol 34(6):531-543, 1992. Soil Science Society of America Web site: Glossary of soil science terms. Available at: www.soils.org/publications/soils-glossary#. Accessed Oct 27, 2011. Yeary R: Oral intubation of dogs with combinations of fertilizer, herbicide, and insecticide chemicals commonly used on lawns, Am J Vet Res 45(2):288-290, 1984.

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31 

Rodenticide Toxicoses MICHAEL J. MURPHY, Stillwater, Minnesota

P

esticides account for about 25% of toxin exposures in pets. Insecticides (see Chapter 32) and rodenticides represent the majority of these pesticide exposures. The rodenticides most frequently encountered by dogs and cats are anticoagulant rodenticides, cholecalciferol, strychnine, zinc phosphide, and bromethalin. Cholecalciferol is discussed in Web Chapter 5. The prevalence of rodenticide exposure in pets may change in upcoming years because the U.S. Environmental Protection Agency issued a direct final rule in 2008, with a final implementation date of June 2011 regarding residential rodenticide use. Briefly, rodenticides for residential use should be distributed in bait stations, and the second-generation anticoagulant rodenticides may no longer be directly available to residential users. The key aspects of toxicosis associated with anticoagulant rodenticides, bromethalin, strychnine, and zinc phosphide follow.

Anticoagulant Rodenticides The anticoagulant rodenticides continue to be the pesticide most commonly inquired about by animal owners. These compounds (including warfarin, brodifacoum, bromadiolone, diphacenone, and chlorophacinone) represent a substantial proportion of actual toxicoses treated in veterinary and emergency clinics. All anticoagulant rodenticides act by inhibiting the recycling of vitamin K1 from vitamin K1 epoxide reductase. This inhibition leads to a reduction in the active forms of clotting factors II, VII, IX, and X in circulation, with factor VII and the extrinsic pathway affected initially. The reduction in the active forms of these factors leads to prolonged clotting times. Prolonged clotting time is most commonly measured by activated clotting time (ACT), one-stage prothrombin time (PT), activated partial thromboplastin time (APTT), or a combination of these tests in the clinic. Prolongation of these times to 15% to 25% above the upper end of the normal range is commonly interpreted as a coagulopathy. Toxic doses of anticoagulant rodenticides induce a coagulopathy. The coagulopathy is not always apparent on clinical presentation and typically is delayed for a number of days following ingestion. The so-called second-generation anticoagulant rodenticides have a much longer duration of action when compared to warfarin. The toxic dose and median lethal dose (LD50) for various anticoagulant rodenticides in dogs and cats is quite variable. Data for specific compounds can be found in consultation with veterinary toxicologists (see www.abvt.org). Anticoagulant rodenticide toxicosis should be con­ sidered in dogs or cats with dyspnea, exercise intolerance, coughing, or hemoptysis related to intrathoracic or

intrapulmonary hemorrhage. Intrapulmonary hemorrhage occurs commonly in anticoagulant rodenticide toxicosis. Large pleural effusions and marked intrapulmonary bleeding (seen as a coarse, alveolar lung pattern) may be evident on thoracic radiography. Prolonged bleeding from venipuncture sites may be observed. Hematomas, hematemesis, melena, hemoptysis, hematuria, and pallor of mucous membranes are other relatively common clinical signs observed in animals with anticoagulant rodenticide toxicosis. Bleeding may occur in unusual locations such as the pericardial space or into the spinal cord. Of course, anticoagulant rodenticides represent just one cause of coagulopathies in dogs and cats, and other bleeding disorders must be considered. Detection of the specific anticoagulant rodenticide in serum is the most definitive means of confirming exposure to an anticoagulant rodenticide in a live animal. Liver is the specimen of choice for a dead animal. This testing is now available in many veterinary diag­ nostic laboratories throughout the United States (see www.aavld.org). Anticoagulant rodenticide–induced coagulopathies are commonly distinguished from other causes of coagulopathy in the clinic by a relatively rapid response to vitamin K1 treatment. ACT, PT, and APTT are each dramatically shortened within 24 hours of initiating daily therapy with 2.5 to 5 mg/kg of vitamin K1 administered orally or subcutaneously (but not intravenously or intramuscularly) with a small-gauge needle. Anaphylaxis can occur with parenteral administration of K1 by any route. Failure to see an initial response may suggest that the coagulopathy is not caused by anticoagulant rodenticide exposure. Oral therapy is very effective; some clinicians divide the daily dose into two or three treatments and aim to enhance absorption of the vitamin by administration with a fatty meal, such as some canned dog foods. In certain cases of recent ingestion (within 2 to 4 hours of presentation), general measures for treatment of toxicosis should be considered, including induction of emesis and administration of activated charcoal (see Chapter 23). Clotting tests are often normal in these cases, so they should be monitored for at least 3 days. Vitamin K1 treatment should be administered if the clotting time is prolonged. A severe coagulopathy may call for more than simple vitamin K1 treatment, and the clinician must appreciate that effects of vitamin K1 are not immediate. Animals with a packed cell volume less than 15 or those demonstrating complications of anemia may need fresh whole blood immediately. Furthermore, vitamin K1 alone may be insufficient when results of coagulation tests show rapidly progressing prolongation in clotting times. In 133

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these cases, administration of fresh or frozen plasma may be needed to provide clotting factors. Blood product therapy may be required for 12 to 36 hours after initiating vitamin K1 therapy to allow time for the synthesis of new functional clotting factors. Thoracocentesis may be needed if there is significant dyspnea related to bleeding within the pleural space. Rest, mild sedation, and oxygen are appropriate for intrapulmonary hemorrhage unless respiratory failure has developed, in which case shortterm ventilation may be needed. The dose and duration indicated for vitamin K1 vary with the specific anticoagulant rodenticide responsible for the coagulopathy. Dosages of 1 to 2.5 mg/kg daily for 3 to 5 days were often effective in treating toxicoses caused by warfarin. Treatment of brodifacoum, diphacenone, and chlorophacinone often requires vitamin K1 at 2.5 to 5 mg/kg daily for 2 to 4 weeks. Tests of clotting function can be useful guides for the duration of therapy. The bioavailability of vitamin K1 is greatest when given orally; thus this route is preferred unless contraindicated because of vomiting. Vitamin K1 may be given subcu­ taneously but should not be given intramuscularly or intravenously because of the increased risk of massive hemorrhage or anaphylaxis, respectively. Vitamin K3 therapy is contraindicated because it is not effective and may induce oxidative damage to red cells. Clients should be educated to remove all anticoagulant rodenticide bait from the pet’s environment. Unfortunately, pets occasionally are reexposed to rodenticide bait following discharge from the clinic. The long-acting anticoagulant rodenticides may be present in the serum and liver of the pet for weeks following successful treatment and recovery. Accordingly some anticoagulant rodenticides may be detected by analytic chemistry techniques in animals with no demonstrable coagulopathy and consequently no toxicosis.

Bromethalin Bromethalin is the active ingredient in rodenticide baits marked under the trade names Assault (Agrisel) and Terminator (Syngenta). The prevalence of bromethalin exposure may increase with the phase-out of second-generation anticoagulant rodenticides for residential consumer use. This compound acts by uncoupling oxidative phosphorylation and leads acutely to hyperexcitability followed by depression in the chronic phase of toxicosis. Muscle tremors, seizures, hind limb hyperreflexia, and death may be observed within approximately 10 hours after exposure to 5 mg/kg. Clinical signs can be progressive, with depression, recumbency, and coma preceding death. Clinical signs of toxicosis may persist for up to 12 days after exposure to 2.5 mg/kg of bromethalin. With analysis of bait, stomach contents, or vomitus it is possible to confirm exposure to bromethalin in a veterinary patient. Analysis of tissues, including fat, may be used to confirm exposure at postmortem examination. Routine complete blood count, serum biochemistries, and urinalysis generally do not assist in the diagnosis of exposure to bromethalin. No specific antidote exists. Aggressive charcoal ther­ apy is aimed at reducing absorption and possible

enterohepatic circulation of bromethalin. Mannitol and glucocorticoids have been used to reduce cerebral fluid pressure, but they may not reliably reverse clinical signs.

Strychnine Strychnine distribution has been restricted in many areas of the United States. It has been replaced by zinc phosphide in many areas. Nevertheless, strychnine toxicosis is seen occasionally in clinical practice. Strychnine inhibits the postsynaptic buffering effects of glycine on sensory stimulation of motor neurons and interneurons. Consequently strychnine-poisoned animals appear apprehensive, tense, and stiff within minutes to hours of exposure. Rectal temperature may be increased from muscular hyperactivity. Clinical signs progress to tonic extensor rigidity, especially after sensory stimulation by light, sound, or touch. Animals often die in opisthotonos because of paralysis of respiratory muscles. Urine samples obtained from a live animal and stomach contents retrieved from a dead animal are the samples of choice for analytic confirmation of exposure to strychnine. Other toxins can result in musculoskeletal stimu­ lation, including mycotoxins, nicotine insecticides (see Chapter 32), and zinc phosphide (see next section). Tetanus and hypocalcemia are other considerations. Therapy is centered on sedating the patient to prevent seizures. This allows time for strychnine metabolism. Pentobarbital (2 to 15 mg/kg IV for dogs), administered to effect, is the most often used sedative/anticonvulsant. Methocarbamol (55 to 220 mg/kg IV or PO) may be administered for muscle relaxation. One half of the dose can be given as a bolus, with the rest administered slowly to effect. Daily dose should not exceed 330 mg/kg. Although diazepam normally is the initial drug of choice for seizing animals, efficacy for strychnine-induced seizures is variable. Activated charcoal may be administered to reduce further absorption as long as precipitation of seizures is avoided. Stimulation should be avoided, and a quiet, darkened hospital kennel may be beneficial. The patient should be given good nursing care, with attention to clinical and vital signs, as well as rectal temperature. Other treatments may include intravenous fluids and urinary acidification (ammonium chloride) to assist with urinary excretion.

Zinc Phosphide Zinc phosphide is used for rodent and mole control and marketed under an increasing number of trade names, including Bartlett Waxed Mouse-Bait, Burrow Oat Bait, Rodent Bait, Rodent Pellets, ZIP RTU Bait, ZP Rodent Bait, and ZP Tracking Powder. This compound has become more prevalent since it replaced strychnine in many areas of the United States. Animals exposed to zinc phosphide have a rapid course of clinical signs. These can progress through anorexia, lethargy, dyspnea, vomiting (occasionally with hematemesis), ataxia, agitation, muscle tremors, weakness, recumbency, and death. Signs develop within minutes to hours of ingestion of a toxic dose of zinc phosphide. Detection of zinc phosphide in the vomitus of a live animal or

CHAPTER  32  Insecticide Toxicoses stomach contents of a dead animal supports the animal’s exposure to it. Unfortunately, this compound is volatile; freezing contents in air-tight receptacles may enhance the likelihood of detection in an analytic laboratory. There is no specific antidote for zinc phosphide. Treatment is mainly supportive. Methods aimed at moving zinc phosphide from the stomach in known cases of ingestion, including emetics, can be used. Increasing gastric pH may be helpful by reducing phosgene liberation. Milk of magnesia has been used as a home remedy;

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in the hospital gastric lavage with 5% sodium bicarbonate (take care to prevent bloat) may be used. Diazepam or pentobarbital may be needed for excessive musculoskeletal activity or seizures. In addition to intravenous fluid therapy, liver-supportive agents may be considered.

References and Suggested Reading Murphy MJ: Rodenticides, Vet Clin North Am Small Anim Pract 32: 469, 2002.

32 

Insecticide Toxicoses PATRICIA ANN TALCOTT, Pullman, Washington

I

nsecticides used in the United States to which small animals have been exposed include the organophosphate and carbamate cholinesterase inhibitor insecticides, the pyrethrin and pyrethroid groups of insecticides, the triazapentadiene compound amitraz, botanical insecticides, and miscellaneous insecticides that do not fit in any of these aforementioned groups. Each of these groups is discussed in turn.

Organophosphate and Carbamate Insecticides Organophosphate and carbamate insecticide poisonings are still one of the most commonly encountered toxicoses in small animals because of their widespread use on animals, around the house, and in agriculture (Hansen, 1995a,; Talcott, 2000). These insecticides may be used on animals intentionally or accidentally. Many exposures are accidental, caused by either inappropriate use by the applicator or accidental access to the product by the pet because of inappropriate storage or disposal. Many insecticide products are intended to be applied to the premises or other property, but some are components of pet products including shampoos, flea and tick collars, and insecticide dips. These products are generally formulated with oily vehicles or solvents to increase contact time and enhance stability. Literally hundreds of formulations are marketed in the form of sprays, dips, shampoos, collars, foggers, or bombs. These marketed products are sometimes mixed with food items to intentionally or maliciously expose pets. Hundreds of cholinesterase inhibitor insecticides are marketed in the United States. See Box 32-1 for a list of

some of the more commonly used chemicals. The toxicity of these chemicals varies widely. Unfortunately, there are few well-established toxic or lethal doses for dogs or cats reported in the literature. Dermal or oral exposures are commonly encountered by dogs or cats. The inhalation route of exposure is more common in humans. Most of the organophosphate and carbamate insecticides are rapidly metabolized by hepatic enzymes; then both the parent compound and its metabolites are rapidly eliminated in the urine. However, a few lipophilic compounds have longer half-lives, giving them a greater potential to cause central nervous system effects. Both the organophosphate and carbamate insecticides inhibit acetylcholinesterase (AChE) and pseudocholinesterase enzymes to varying degrees. AChE is responsible for breaking down acetylcholine released at cholinergic sites. Thus animals poisoned with cholinesterase inhibitors often exhibit a mixture of clinical signs as a result of overstimulation of the nicotinic receptors of the somatic nervous system (skeletal muscle), sympathetic and parasympathetic preganglionic junctions, all parasympathetic postganglionic junctions (including a few sympathetic postganglionic junctions), and some neurons within the central nervous system. The onset of clinical signs can vary between a few minutes to several hours, depending on the dose, the route of exposure, and the specific chemical involved. Commonly reported muscarinic signs include excessive salivation, anorexia, emesis, diarrhea, excessive lacrimation, miosis or mydriasis, dyspnea, excessive urination, and bradycardia or tachycardia. The mnemonics SLUD (i.e., salivation, lacrimation, urination, defecation) and DUMBBELS (i.e., diarrhea, urination, miosis, bronchospasm, bradycardia, emesis, lacrimation, salivation) are

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BOX 32-1  Examples of Insecticides Cholinesterase Inhibitors Organophosphates • Chlorpyrifos • Coumaphos • Cythioate • Diazinon • Dichlorvos • Dimethoate • Disulfoton • Ethoprop • Famphur • Fenthion • Malathion • Mevinphos • Parathion • Phorate • Phosmet • Terbufos • Tetrachlorvinphos Carbamates • Aldicarb • Carbaryl • Carbofuran • Methiocarb • Methomyl • Oxamyl • Propoxur Pyrethrins, Pyrethroids • Allethrin • Bifenthrin • Bioallethrin • Cismethrin • Cyfluthrin • Cyhalothrin

often used in the classroom as a device to remember these clinical signs. Prominent nicotinic signs include ataxia, weakness, and muscle twitching. In acute high-dose oral exposures, seizures can occur within 10 to 20 minutes. It is important to note that not all signs are seen in every poisoning case. Death is generally the result of respiratory failure and tissue hypoxia caused by excessive respiratory secretions, bronchoconstriction, paralysis of the respiratory muscles, and direct depression of the respiratory center in the medulla. Cats appear to be particularly sensitive to chlorpyrifos; anorexia, muscle weakness, ataxia, and depression are the predominant features. Exposure to these more lipophilic compounds has been referred to as the intermediate syndrome; additional clinical features may include muscle tremors, abnormal mentation, and abnormal posturing with hyperesthesia. A clinical diagnosis of organophosphate or carbamate poisoning relies heavily on observing compatible clinical signs and a history of known exposure. Inhibition of whole blood, plasma, serum, retinal, or brain

• • • • • • • • • • • • • • •

Cypermethrin Deltamethrin Esfenvalerate Fenfluthrin Fenvalerate Flumethrin Fluvalinate Permethrin Phenothrin Pyrethrin Pyrethrum Resmethrin Sumithrin Tetramethrin Tralomethrin

Triazapentadiene Compounds • Amitraz Botanicals • d-Limonene • Linalool • Melaleuca oil • Pennyroyal oil • Rotenone Miscellaneous • Fipronil • Imidacloprid • Lufenuron • Methoprene • Methoxychlor • Nitenpyram • Pyriproxyfen • DEET • Avermectins

cholinesterase activity (at least 25% to 50% of normal) suggests an exposure to these compounds and toxicosis if the clinical signs are compatible. Cholinesterase testing can still be performed after the administration of atropine and may still be useful several days after pesticide exposure. Lack of inhibition cannot rule out exposure to carbamate compounds because of the reversibility of their binding to the cholinesterase enzyme. In addition, because of the acuteness in onset of signs and possible death and the lack of some compounds to readily traverse the blood-brain barrier, brain cholinesterase may be normal in the acutely poisoned patient. Lower red blood cell counts may also lower true AChE activity; this is one reason to check the packed cell volume before running the assay. Therefore cholinesterase testing should be regarded as a screening tool, and false negatives and positives may occur. Tissue analysis for the organophosphate or carbamate insecticide is primarily reserved for confirming an exposure following a postmortem examination. Stomach and intestinal contents and samples from the liver, kidney, fat, and skin (in cases of suspect dermal

CHAPTER  32  Insecticide Toxicoses exposures) should be collected, individually bagged and labeled, and kept frozen during shipment to a laboratory. Changes observed on a complete blood count, serum chemistry panel, and urinalysis are typically very nonspecific and highly variable. Pancreatitis accompanied by significant elevations in amylase and lipase has been reported following exposures to certain organophosphate insecticides. Treatment should be aimed at preventing further absorption through aggressive decontamination procedures and controlling the muscarinic and nicotinic clinical signs. Many dermal exposures lead to subsequent oral exposures, particularly in cats; thus multiple decontamination procedures may be needed. In the asymptomatic orally exposed patient, emetics such as 3% hydrogen peroxide or apomorphine are generally recommended. Three percent hydrogen peroxide is dosed at 1 ml/lb or 2.2 ml/ kg PO, with a total dose not exceeding 10 ml in the cat or 50 ml in the dog, regardless of body weight (however, this volume has been routinely exceeded in dogs, and I have observed few serious complications). It can be used shortly after feeding a small amount of food. If emesis is contraindicated, a gastric lavage can be performed after inducing light anesthesia, followed by the placement of a cuffed endotracheal tube to prevent aspiration. Induction of emesis and gastric lavage should always be followed with the use of activated charcoal and a cathartic. Administration of multiple activated charcoal doses may be warranted; care should be taken to reduce the subsequent cathartic doses and monitor the patient for the rare occurrence of hypernatremia or hypermagnesemia. A mild detergent bath and thorough rinsing are recommended in cases of dermal exposure. In the topically exposed patient, particularly in cats, exposure may be both dermal and oral because of excessive grooming. In these cases both dermal and oral decontamination procedures may be beneficial. Atropine sulfate is used to control the muscarinic signs (e.g., miosis, salivation, diarrhea, bradycardia, bronchoconstriction). The usual dosage range is 0.20 to 0.50 mg/ kg (one fourth IV, the remainder SC or IM; some individuals administer the entire dosage IV). The dosage selected should be just enough to provide adequate atropinization, and atropine may be repeated at half the initial dose if signs return. Hypersalivation is often the most useful clinical sign for monitoring atropine therapy. Oxygen therapy with or without artificial respiration may be required until the patient is breathing normally on its own. Seizures, muscle tremors, or agitation can be controlled with intravenous diazepam, methocarbamol, or phenobarbital. Pralidoxime chloride ([2-PAM]; 10 to 20 mg/kg IM or SC BID or TID) can help reduce muscle tremors resulting from nicotinic receptor stimulation by an organophosphate. A clinical effect should be observed within the first 3 to 4 days, and treatment should be continued as long as improvement is observed. 2-PAM has its best effect if administered within 24 hours of exposure; however, some benefits may occur, particularly in cases involving large toxin exposures, if given within 36 to 48 hours. Rapid intravenous injection may cause

137

tachycardia, muscle rigidity, transient neuromuscular blockage, and laryngospasm. The use of oximes in cases of carbamate poisonings is somewhat controversial (particularly since the carbamate binding is reversible); one should weigh the benefits and risks of its use in each case. It is impossible to tell based on clinical signs alone whether the exposure was caused by an organophosphate or a carbamate insecticide. Diphenhydramine use is also controversial in the treatment of organophosphate and carbamate poisonings; I do not recommend it. One suggested dose of diphenhydra­ mine in dogs is 2 to 4 mg/kg orally every 6 to 8 hours. However, there have been reports of excessive sedation or excitement and anorexia when used in dogs and cats. Good supportive and nursing care, including intravenous fluid therapy, adequate nutritional management, and maintenance of normal body temperature and electrolyte balance, should also be considered in the acutely poisoned patient. Chlorpyrifos poisoning in cats requires special attention; these cats often show signs of ataxia, anorexia, depression, and muscle tremors for several days or weeks after initial exposure.

Pyrethrins/Pyrethroids Pyrethrins are organic esters extracted with fat solvents from flower heads of the pyrethrum plant, Chrysanthemum cinerariifolium. Pyrethroids are their synthetic cohorts that vary in both structure and potency. Pyrethroids generally are more toxic to insects and mammals and persist longer in the environment than pyrethrins (Hansen, 1995b; Talcott, 2000). A number of commonly used pyrethrin and pyrethroid chemicals are listed in Box 32-1. Many of these pesticide formulations are registered for topical use on dogs and cats for flea and tick control. Other formulations are marketed for household use, and still others can be used in agriculture. These products can be purchased through many readily available outlets and packaged as sprays, dips, shampoos, and spot-on formulations. The percentages of active ingredient can range from less than 1% to as much as 65% or greater; therefore it is crucial to read the label thoroughly when using them. There are hundreds of pyrethrin- and pyrethroidcontaining formulations, sometimes combined in mixtures along with insect growth regulators, insect repellents, and various synergists. Piperonyl butoxide is a common additive to pyrethrin products. Although it possesses limited insecticidal activity, it acts as a synergist to extend the killing duration of the pyrethrin. The mode of synergistic activity is not conclusively known. Hypothesized mechanisms of the synergistic effect of piperonyl butoxide include (1) prolongation of the action of pyrethrins by preventing rapid oxidation; (2) formation of complexes with the pyrethrins that lead to higher insecticidal activity; and (3) delay of pyrethrin detoxification by the insect’s tissue enzymes. A number of pyrethroid products also contain insect repellents. N-octyl bicycloheptene dicarboximide, di-n-propyl isocinchomeronate, and butoxypolypropylene glycol are insect repellents often present in pyrethrin- and pyrethroid-containing products at concentrations ranging from 0.34% to 15%. Toxicity of these mixtures may be

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attributed solely to the pyrethrins and pyrethroids or be caused by the combined effects of the insecticides plus the additives, synergists, and solvents. Pyrethrins work by stimulating the insect’s central nervous system. This action results in muscular excitation, convulsions, and paralysis. When dissolved in thin oils, pyrethrins readily penetrate through the hard, chitinous covering of the insect, and their insecticidal action is rapid. Both pyrethrins and pyrethroids affect nervous tissue in mammals by reversibly prolonging sodium conductance, producing increased depolarizing afterpotentials that result in repetitive nerve firing. Their toxicity to mammals is low and, when used according to label instructions, should not induce deleterious effects in mammals. Toxicoses in mammals can be observed when these products are ingested or when there is overzealous heavy topical application, particularly in cats and small dogs. Many poisonings in clinical practice are the result of products labeled “for use in dogs only” being used on cats. There are also many anecdotal instances in which cats exhibited adverse effects following topical exposure to appropriately applied formulations. Clinical signs are normally observed within minutes to a few hours after exposure. Clinical signs usually include excessive salivation (as a result of oral sensory stimulation), muscle tremors, depression, ataxia, anorexia, and vomiting. Less commonly reported adverse effects include weakness, dyspnea, diarrhea, hyperthermia or hypothermia, hyperesthesia (ear flicking, paw shaking; repeated contractions of the superficial cutaneous muscles), and recumbency. Occasionally one can see a topical allergic reaction characterized by urticaria, pruritus, and alopecia at the site of application. Death is rarely reported but can occur, typically following severe, uncontrollable seizure activity. A clinical diagnosis of pyrethroid poisoning most heavily relies on obtaining a history of recent use and access to these products. The clinical signs closely mimic other poisonings (e.g., organophosphate and carbamate poisonings), and there are no specific clinicopathologic abnormalities routinely observed in affected animals. Laboratory methods for analyzing pyrethrin/pyrethroid residues are not routinely available but can be done to confirm exposure if necessary. Since clinical signs often mimic organophosphate or carbamate poisonings, assessing blood or brain cholinesterase is recommended to rule out these differentials. Cholinesterase activity is not inhibited in cases of pyrethrin/pyrethroid poisonings, whereas it may be in organophosphate or carbamate exposures and poisonings. There is no specific antidote for pyrethrin/pyrethroid poisonings. Consequently treatment should be aimed at decontaminating the animal to prevent further absorption and addressing the clinical presentation. Bathing the animal in warm soapy water followed by a thorough rinsing is recommended for topical exposures. Longhaired dogs and cats may require multiple bathingsdryings-brushings or clipping to remove residues from the hair. Oral ingestions can be treated with emetics, activated charcoal, and cathartics and more aggressively with light sedation and gastric lavage. Muscle tremors can usually

be controlled with diazepam (0.5 to 1 mg/kg IV or to effect) or methocarbamol (55 to 220 mg/kg IV); it should be administered half rapidly, not to exceed 2 ml/min, and the rest to effect. Continuous monitoring of body temperature for hypothermia or hyperthermia is essential. Providing adequate hydration and electrolyte status is also important in achieving a positive outcome. The oral cavity can be rinsed to help control hypersalivation. The prognosis for the majority of pyrethrin/pyrethroid poisonings is excellent, with most animals recovering within 24 to 72 hours.

Amitraz Amitraz is a formamidine pesticide that is present in some tick collars used on dogs. It is often present at a concentration of 9%. The collars are designed to kill ticks for 4 months. Toxicosis can occur in dogs that ingest a substantial portion of, or the entire, collar. The entire collar weighs 27.5 g, so each gram of collar contains approximately 90 mg of amitraz. However, the collar is a controlled-release device that releases amitraz in firstorder kinetics over an effective period of more than 90 days. Therefore release is much higher when the collar is new than after it has been used for 4 months. Mitaban liquid concentrate contains 19.9% amitraz. It is used topically for the control and treatment of generalized demodicosis. Several different treatment protocols have been suggested, depending on the location and severity of the disease and the age of the affected animal. Amitraz is not recommended in lactating or pregnant animals or in animals that weigh less than 5 kg. The lethal dose of amitraz is estimated to be about 100 mg/kg orally in dogs, although toxic doses as low as 10 to 20 mg/kg have been reported. Amitraz is well absorbed by the gastrointestinal tract. Clinical signs of toxicosis usually begin within 1 hour of ingestion, sometimes as early as 30 minutes. Amitraz is a monoamine oxidase inhibitor, an α2adrenergic agonist, and an inhibitor of prostaglandin synthesis. Ocular exposure to this compound can lead to mild irritation. The clinical signs can be severe but often transient and rarely fatal. Most clinical signs are associated with the α2-adrenergic properties of amitraz and include depression, sedation, ataxia, bradycardia, mydriasis, hypothermia, vomiting, polyuria, and gastrointestinal stasis or diarrhea. Other signs that have been reported include hyperthermia, gastric dilation, hypersalivation, dyspnea, anorexia, shock, tachycardia, urinary incontinence, disorientation, tremors, and coma (Duncan, 1993; Grossman, 1993; Hovda and McManus, 1993). Clinical laboratory data often reveal a hyperglycemia. Most signs, whether in mild exposures or excessive exposures followed by aggressive treatment, usually last no longer than 24 to 48 hours. Treatment is aimed at decontamination to prevent further absorption and reversal of the adrenergic agonist effects. In the asymptomatic patient emesis should be induced with 3% hydrogen peroxide or apomorphine. Administering a non-oily laxative such as activated charcoal with a cathartic is recommended as long as no diarrhea is present. An enema to evacuate the colon may be

CHAPTER  32  Insecticide Toxicoses administered 12 to 18 hours after ingestion if diarrhea has not occurred or the laxative does not produce the desired effect. Abdominal radiography is recommended if a length of collar is the suspected source of the amitraz or if the depression/sedation is severe and prolonged. Retrieval of the collar or pieces of collar can be performed by endoscopy, gastrotomy, or enterotomy. Xylazine should be avoided because of the possibility of exacerbating hypotension. All surgical procedures and anesthesia protocols should be considered carefully because of the potential to exacerbate preexisting problems of gastric dilation or bradycardia. The probability of requiring these more invasive decontamination procedures is rare. Since amitraz is not a cholinesterase inhibitor, atropine and 2-PAM are contraindicated in the treatment of amitraz poisoning. In moderately or severely affected patients who cannot be aroused, the α2-antagonists, yohimbine or atipamezole, may be administered (Hsu, Lu, and Hembrough, 1986; Hugnet et al, 1996). Yohimbine is dosed at 0.1 mg/kg IV and since the duration of action is short (half-life = 1.5 to 2 hours), it may need to be repeated until the dog’s clinical condition improves significantly. Atipamezole can be initiated at the conservative dose of 50 µg/kg IV. A typical dosage range for atipamezole, based on body surface area, is from 230 µg/kg to 100 µg/kg IV (for dogs ranging from 5 kg to 50 kg), or from 400 µg/kg to 140 µg/kg IM (for dogs ranging from 5 kg to 50 kg). This extralabel dosing can be further informed by consulting the Antisedan product insert for reversal of dexmedetomidine for that patient’s specific body surface area. Both compounds should reverse amitraz-induced changes within 20 to 30 minutes. Body temperature should be monitored following yohimbine use to avoid hyperthermia. Fluid therapy (see Chapters 1 and 2) is also warranted in the bradycardic, dehydrated patient.

Botanical Oil Extracts Various fragrant volatile oils that are currently marketed as having parasiticidal properties have been isolated from a number of plants. The most popular of these oils include d-limonene and linalool. These oils are sold as shampoos, sprays, and dips for flea and tick control on dogs and cats or for premise control. Some citrus oil extracts are also found in household cleaners. These oils are considered to be relatively nontoxic and are generally regarded as safe by the Food and Drug Administration. Both d-limonene and linalool are present in oils extracted from the skins of citrus fruits and are typically associated with poisonings in dogs and cats when used at excessive concentrations. Cats are more sensitive to developing clinical signs after exposures than dogs. With normal use these compounds may cause temporary irritation to the eyes, skin, nose, throat, or respiratory tract. Adverse reactions to these compounds can occur following inhalation, dermal, or oral exposure. Clinical effects are often observed within 15 to 30 minutes after exposure. Typical signs after oral exposure include salivation, vomiting, diarrhea, and central nervous system depression. Other signs reported with higher exposures include muscle tremors, hypothermia, hypotension, ataxia, and mydriasis.

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Ataxia, weakness, depression, and dermal irritation (e.g., scrotal, perianal) have been seen following topical applications. Seizures and death are rare and are presumed to be secondary to severe hypotension and hypothermia. There has been one report of erythema multiforme and disseminated intravascular coagulation in a dog following a dermal application of a d-limonene–containing dip (Rosenbaum and Kerlin, 1995). An acute necrotizing dermatitis and subsequent septicemia was reported in a 2-year-old cat following application of a d-limonene–containing insecticidal shampoo (Lee, Budgin, and Mauldin, 2002). Other signs reported included lethargy, inappetence, vocalization, and abnormal aggressive behavior. Treatment is aimed at decontamination, with supportive care based on the clinical signs. Repeated bathing with warm, soapy water followed by thorough rinsing are recommended following topical applications. Gastric lavage with activated charcoal and a cathartic is recommended following oral ingestions. Body temperature and blood pressure should be monitored to prevent hypotension and hypothermia. Diazepam has been used to control the muscle tremors, and fluid therapy is generally recommended to prevent dehydration. Most affected animals recover within 24 hours. Pennyroyal oil has long been used as a flea repellent and is sold as a shampoo, powder, or the pure oil itself. Pennyroyal is an herb consisting mainly of leaves from two different plants, Mentha pulegium and Hedeoma pulegioides. The oil is derived from the leaves and flowering tops of these plants. Pulegone constitutes approximately 85% of the pennyroyal oil and is metabolized to the toxic metabolite menthofuran by the liver. Toxicoses have been described in both animals and humans following dermal application and oral ingestion. Clinical signs are associated primarily with gastrointestinal upset, liver failure, and severe neurologic injury. Clinical signs include lethargy, vomiting, diarrhea, hemoptysis, epistaxis, dyspnea, miosis or mydriasis, seizures, and death (Anderson et al, 1996). Massive hepatic necrosis has been reported in the dog following topical application of the oil (Sudekum et al, 1992). Pennyroyal oil ingestion is treated by decontaminating the stomach by gastric lavage and activated charcoal. Emesis is generally not suggested because of the rapid absorption of pennyroyal oil, the risk for developing aspiration pneumonia, and the potential for rapid onset of central nervous system depression. Repeated bathing with a mild detergent followed by thorough rinsings is recommended following topical applications. N-­ acetylcysteine has been suggested in cases in which there is a high risk of inducing a toxicosis, starting with a loading dose of 140  mg/kg and following with 70  mg/ kg every 4 hours. N-acetylcysteine therapy should be beneficial within the first few hours of poisoning and should continue for at least 24 to 48 hours. The cytochrome P-450 inhibitor cimetidine has also been recommended in the treatment of this poisoning. Mice pretreated with cimetidine exhibited less liver disease associated with intraperitoneal pulegone administration than controls (Sztajnkrycer, 2003). Any additional therapy is supportive only and should be based on clinical signs; this may include the use of antiemetics and fluid therapy. Basic support for liver failure may

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include plasma transfusions, antibiotics, vitamin K1, S-adenosylmethionine, vitamin E, and gastric protectants (sucralfate). A complete blood count, serum chemistry and coagulation profile, and urinalysis should be performed to monitor organ function. Another essential oil, Melaleuca oil or tea tree oil, is obtained from the leaves of the Australian tea tree (Melaleuca alternifolia). Melaleuca oil derivatives can be found in products used topically for skin infections, as insect repellents, as antipruritics, or as household cleaners. Melaleuca oil is known to contain as much as 60% terpenes; thus the clinical signs in poisoned patients strongly resemble those described for the essential oils d-limonene and linalool. Toxicities with these products have been reported in cats, dogs, rats, and humans, after either oral ingestion or topical application. Most reports of poisoning in pets occur after misuse of high topical doses of the product. The lipophilic terpenes are readily and rapidly absorbed across the skin and mucosal lining of the gastrointestinal tract. Cats are thought to be more sensitive than dogs, and toxicities might be observed more frequently in this species because of their fastidious grooming habits. The onset of clinical signs may occur within minutes to 8 hours after topical application. The time interval is highly dependent on dose and the extent of oral exposure following grooming behavior. The most common adverse signs include ataxia, incoordination, weakness, tremors, depression, hypothermia, and behavior abnormalities (Villar et al, 1994). Elevation in liver enzymes (alanine aminotransferase, aspartate aminotransferase) has been reported in cats following topical exposure (Bischoff and Guale, 1998). Treatment is directed toward symptomatic and supportive care. Topical exposures warrant bathing with a mild detergent followed by a thorough rinsing. Longhaired pets may benefit from having their hair cut or trimmed. Activated charcoal and a cathartic can be administered in orally exposed pets. Monitoring basic life support measures and correcting any temperature, fluid, and electrolyte abnormalities may be indicated. Prognoses are generally favorable, and most affected animals recover over a 2- to 3-day interval.

Miscellaneous Insecticides (Methoprene, Lufenuron, Fipronil, Imidacloprid, Pyriproxyfen, Nitenpyram) Many of the insecticides described in this section are used topically. When an adverse effect related to topical/oral exposure to these products is suspected, it is essential to read the label ingredients carefully. Many of the insecticides listed in the following paragraphs can occur as a single ingredient or in combination with other insecticides, mainly pyrethrins and pyrethroids. In addition, several adverse reactions reported such as salivation or skin irritation following dermal or oral exposures may be caused by the carriers present in the formulation. Typically these signs are mild and self-limiting. Insect growth regulators are a relatively new category in the war against fleas and ticks. All act as analogs of juvenile growth hormones, thereby interrupting the

normal growth patterns of the insect. Methoprene preferentially kills fleas and ticks in the larval stage by binding to and activating juvenile hormone receptors. It thereby prevents larvae from developing into adult fleas. Methoprene can be absorbed from the gastrointestinal tract, through the intact skin, or by inhalation. However, it is considered to be virtually nontoxic when ingested or inhaled and only slightly toxic after dermal absorption. Methoprene is not considered an eye or skin irritant. Lufenuron, a benzoylphenyl urea, inhibits the synthesis, polymerization, and deposition of chitin in the eggs or exoskeleton of fleas. Lufenuron is highly lipophilic and readily accumulates in adipose tissue. Lufenuron has shown no synergistic or additive effects when combined with other insecticides. It has proven to be safe at recommended dosage regimens in puppies and kittens as young as 6 weeks of age, as well as in lactating dogs and cats and their offspring. Various studies in dogs and cats using up to 10 times the normal dosage have shown no serious health effects over an exposure period of 1 to 9 months. No adverse effects were seen in cats orally exposed to up to 17 times the recommended dosage. A mild decrease in food consumption was reported in puppies exposed from 8 weeks to 10 months of age to 18 to 30 times the recommended dosage. However, the majority of studies have shown no significant adverse effects on food consumption, body weight, hematology, clinical chemistries, and urinalyses following excessive exposures. Few effects on fertility and reproduction have been reported. Administration of lufenuron to breeding male and female dogs at 90 times the recommended dosage of 10 mg/kg resulted in a reduced pregnancy rate compared with controls. Pups born to treated females exhibited nasal discharge, pulmonary congestion, diarrhea, dehydration, and sluggishness. It appears that lufenuron concentrates in the milk at a 60 : 1 milk : blood concentration ratio (CibaGeigy Corporation). Lufenuron, 90 mg/kg, was administered to breeding cats before mating and through gestation and lactation. Kittens born to these cats exhibited no adverse effects on health, growth, and survival (Ciba-Geigy Corporation, 1996; Shipstone and Mason, 1995). Plumb lists vomiting, lethargy, depression, urticaria, diarrhea, dyspnea, anorexia, and reddened skin as rare adverse effects (Plumb, 2005). Fipronil is a phenylpyrazole flea and tick adulticide currently marketed as a spray and topical liquid that boasts a wide margin of safety. It can be used on dogs, cats, puppies, or kittens greater than 8 weeks old. No adverse effects were noted in studies in which dogs or cats were fed five times the maximum dose. Fipronil acts on the γ-aminobutyric acid–mediated chloride channels of invertebrates, thereby interrupting nervous transmission and leading to rapid death of the fleas and ticks. Mammals reportedly have receptors inside the chloride channel that are shaped differently than the invertebrate receptors, and fipronil is not thought to be able to bind these channels for a long period of time. Following dermal application, it is not considered systemically active and is thought to be sequestered in the pet’s sebaceous glands. Mild skin irritation may occur following topical applications of these products.

CHAPTER  32  Insecticide Toxicoses Imidacloprid is another topically used adulticide that reportedly binds specifically to postsynaptic nicotinic acetylcholine receptors of insects and both kills adult fleas and exhibits some larvicidal action. Toxicity testing of imidacloprid has shown no adverse effects when used at five times the maximum dosage in dogs and cats. A few reports of alopecia and erythema have been observed following dermal application. Theoretically poisoning could occur by the oral route if the dosage or concentration were excessive. The most common complaint following ingestion is excessive salivation that is selflimiting. There is no specific antidote, and all treatment should be based on observed clinical problems. Topically exposed pets should be bathed and rinsed; orally exposed patients should be decontaminated by either emesis or lavage, followed by the use of activated charcoal and a cathartic. Pyriproxyfen and nitenpyram are two of the relatively newer products that have entered the marketplace. Nitenpyram is a neonicotinoid derivative that binds and inhibits specific nicotinic acetylcholine receptors. It does not inhibit AChE activity. Pyriproxyfen is an insect growth regulator used topically to control insects. No significant adverse effects have been reported with either of these products.

References and Suggested Reading Anderson IB: Pennyroyal toxicity: measurement of toxic metabolite levels in two cases and review of the literature, Ann Intern Med 124:726, 1996. Bischoff K, Guale F: Australian tea tree (Melaleuca alternifolia) oil poisoning in three purebred cats, J Vet Diagn Invest 10:208, 1998. Blagburn BL et al: Efficacy dosage titration of lufenuron against developmental stages of fleas in cats, Am J Vet Res 55:98, 1994. Blagburn BL et al: Efficacy of lufenuron against developmental stages of fleas in dogs housed in simulated home environments, Am J Vet Res 56:464, 1995. Blodgett DJ: Organophosphate and carbamate insecticides. In Peterson ME, Talcott PA, editors: Small animal toxicology, St Louis, 2006, Elsevier, p 941. Campbell WR, Lynn RC: Tolerability of lufenuron (CGA-184699) in normal dogs and cats, J Vet Intern Med 3:2, 1992. Ciba-Geigy Corporation: Program (lufenuron) for control of existing flea infestations, Adv Pract Vet, 1, 1996. Ciba-Geigy Corporation: Summary of studies submitted as part of the new animal drug application, No 41-035, for lufenuron tablets, Ciba-Geigy Corp, Greensboro, NC, 800-637-0281. Ciba-Geigy Corporation: Program (lufenuron): a radical breakthrough in flea control, Ciba Animal Health, Ciba-Geigy Animal Health, Greensboro, NC 27419. Duncan KL: Treatment of amitraz toxicosis, J Am Vet Med Assoc 208(8):1115, 1993. Fikes JD: Organophosphorus and carbamate insecticides, Vet Clin North Am 20(2):353,1990. Fikes JD: Feline chlorpyrifos toxicosis. In Bonagura JD, Kirk RW, editors: Kirk’s current veterinary therapy XI (small animal practice), Philadelphia, 1992, Saunders, p 188.

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Grossman MR: Amitraz toxicosis associated with ingestion of an acaricide collar in a dog, J Am Vet Med Assoc 203(1):55, 1993. Hansen SR: Management of adverse reactions to pyrethrin and pyrethroid insecticides. In Bonagura JD, Kirk RW, editors: Kirk’s current veterinary therapy XII (small animal practice), Philadelphia, 1995a, Saunders, p 242. Hansen SR: Management of organophosphate and carbamate insecticide toxicoses. In Bonagura JD, Kirk RW, editors: Kirk’s current veterinary therapy XII (small animal practice), Philadelphia, 1995b, Saunders, p 245. Hansen SR: Pyrethrins and pyrethroids. In Peterson ME, Talcott PA, editors: Small animal toxicology, St Louis, 2006, Elsevier, p 1002. Hansen SR, Buck WB: Treatment of adverse reactions in cats to flea control products containing pyrethrin/pyrethroid insecticides, Feline Pract 20(5):25, 1992. Hink WF et al: Evaluation of a single oral dose of lufenuron to control flea infestations in dogs, Am J Vet Res 55:822, 1995. Hooser SB: d-Limonene, linalool, and crude citrus oil extracts, Vet Clin North Am Small Anim Pract 20(2):383, 1990. Hovda LR, McManus AC: Yohimbine for treatment of amitraz poisoning in dogs, Vet Hum Toxicol 35(4):329, 1993. Hsu WH, Lu ZX, Hembrough FB: Effect of amitraz on heart rate and aortic blood pressure in conscious dogs: influence of atropine, prazosin, tolazoline, and yohimbine, Toxicol Appl Pharmacol 84:418, 1986. Hugnet C et al: Toxicity and kinetics of amitraz in dogs, Am J Vet Res 57(10):1506, 1996. Kanzler K, editor: Veterinary pharmaceuticals and biologicals, 1995/1996, ed 9, Lenexa, KS, Veterinary Medicine Publishing, p 841. Lee JA, Budgin JB, Mauldin EA: Acute narcotizing dermatitis and septicemia after application of a d-limonene–based insecticidal shampoo in a cat, J Am Vet Med Assoc 221(2):258, 2002. Miller TA: Personal communication, Virbac, Inc, 3200 Meacham Blvd, Fort Worth, TX 76137. Plumb DC: Plumb’s veterinary drug handbook, ed 5, Ames, IA, 2005, Blackwell Publishing. Rosenbaum MR, Kerlin RL: Erythema multiforme major and disseminated intravascular coagulation in a dog following application of a d-limonene–based insecticidal dip, J Am Vet Med Assoc 207(10):1315, 1995. Shipstone MA, Mason KV: Review article: The use of insect development inhibitors as an oral medication for the control of the fleas Ctenocephalides felis, C. canis in the dog and cat, Vet Dermatol 6:131, 1995. Sudekum M et al: Pennyroyal oil toxicosis in a dog, J Am Vet Med Assoc 200(6):817, 1992. Sztajnkrycer MD: Mitigation of pennyroyal oil hepatotoxicity in the mouse, Acad Emerg Med 10(10):1024, 2003. Talcott P: Toxicity of flea and tick products. In Bonagura JD, editor: Kirk’s current veterinary therapy XIII (small animal practice), Philadelphia, 2000, Saunders, pp 231, 233. Valentine WM: Pyrethrin and pyrethroid insecticides, Vet Clin North Am 20(2):375, 1990. Villar D et al: Toxicity of melaleuca oil and related essential oils applied topically on dogs and cats, Vet Hum Toxicol 36(2):139, 1994. Whittem T: Pyrethrin and pyrethroid insecticide intoxication in cats, Compendium 17(4):489, 1995.

CHAPTER 

33 

Pesticides: New Vertebrate Toxic Agents for Pest Species RHIAN COPE, Lower Hutt, New Zealand

G

iven that most indigenous animal life in New Zealand evolved for millions of years in the absence of terrestrial mammalian predators, the continued preservation of most endemic species is heavily contingent on effective suppression of introduced vertebrate predators with the use of vertebrate toxic agents. In New Zealand the most common method for the control of feral cats and stoats is trapping, which is effective but labor intensive. Sodium fluoroacetate (1080) is also currently registered for feral cat control in the form of a fish/meat meal pellet for either bait stations or handlaying, although it is not approved for stoat control. Notably, 1080 operations directed against brush tailed possums (Trichosurus vulpecula), rabbits (Oryctolagus cuniculus), and other mammalian pest species often serendipitously result in secondary poisoning of feral cats and stoats. However, 1080 is controversial because of genuine concern regarding secondary poisoning in nontarget domestic species, as well as the general public’s concern over its use. Thus New Zealand has been placed in the position of seeking new toxicants and technologies for the control of vertebrate pest species. New Zealand has recently approved a new vertebrate toxic agent for the control of feral cats (Felis catus) and stoats (Mustela erminea): para-aminopropiophenone (PAPP). The use of encapsulated sodium nitrite for the control of feral pigs (Sus scrofa domesticus) is currently in the final stages of regulatory approval. A third toxin, tutin, is currently under development. These toxins (toxicants) are the subjects of this chapter.

Para-Aminopropiophenone (PAPP) PAPP was originally developed as a potential antidote for acute cyanide poisoning and for its radioprotective properties against X, gamma, and high-energy proton irradiation. PAPP is the most potent methemoglobin inducer of the para-aminoalkylphenones. It is capable of inducing clinically significant methemoglobinemia, oxidative hemolytic anemia, and Heinz body formation in a variety of vertebrate species including mustelids, cats, dogs, and rodents, as well as in various bird species. In the United States, trials using PAPP for control of coyotes (Canis latrans) were conducted for the U.S. Fish and Wildlife Service. The coyote trials revealed problems with both formulation and regurgitation by dosed animals. Development of PAPP was not a priority after 1080 was registered for use in the Livestock Protection Collar. New Zealand PAPP formulations all contain an 142

antiemetic. This addition decreases the risk that vomiting of the bait will reduce the effectiveness of these formulations in targeted species. Unfortunately, the inclusion of an antiemetic potentially increases the hazard of PAPP baits ingested by nontarget species. PAPP is readily metabolized, is not bioaccumulative, and does not accumulate in the environment. The risk of secondary toxicity to nontarget species is regarded as low. However, nontarget burrowing seabirds are considered to be at risk of inadvertent poisoning because of the current design of the bait stations.

Lethal Doses PAPP has some selective toxicity for felids, mustelids, and canids. The lethal doses are: cats, 20 to 34 mg/kg; stoats, 37.1 to 94.8 mg/kg; ferrets (Mustela furo), 13 to 25 mg/kg; and dogs (Canis familiaris), 21.4 to 42.9 mg/kg. Birds and rodents are somewhat less susceptible, although there is some variability in the response of different bird species.

Methods of Use as a Vertebrate Toxic Agent Veterinarians should understand how these agents are deployed and how most exposures occur. PAPP is available as a 410 g/kg paste mixed with meat to produce meat boli that contain about 22 mg PAPP/g. The boli are placed in bait stations. PAPP is designed to be a single-feed vertebrate toxic agent. However, prefeeding with mince for 2 weeks prior to laying the PAPP baits is recommended. Prepared mince baits should be used within 24 hours of preparation and remain toxic for several days. A device in which a concentrated PAPP preparation is sprayed onto the ventrum of the animal and subsequently ingested via grooming is currently under development. This device is capable of dosing more than 100 animals without having to be reset or recharged.

Disposition PAPP is rapidly and nearly completely absorbed after oral exposure. It is a protoxicant that undergoes metabolic activation in vivo. In rodents, the putative methemoglobinproducing metabolite is 4-(N-hydroxy) aminopropiophenone (PHAPP). However, there are species differences in metabolism. In rats PAPP is metabolized predominantly by N-acetylation. In dogs metabolism is predominantly by ring and aliphatic hydroxylation, with lower rates of N-hydroxylation occurring in male dogs; consequently

CHAPTER  33  Pesticides: New Vertebrate Toxic Agents for Pest Species bitches produce more methemoglobin for a given dose of PAPP than male dogs. In primates both N-acetylation and oxidation occur. Elimination kinetics after oral dosing follows a two-compartment model. The elimination of PAPP metabolites appears to be dependent on glucuronidation, implying that species with low glucuronidation capacity, such as cats, may have greater difficulty eliminating the compound.

Mode of Action PAPP and its putative active metabolite PHAPP produce acute oxidative damage to the erythron, with resultant methemoglobinemia, Heinz body formation, and oxidative hemolysis. This results in decreased blood oxygen carrying capacity and tissue hypoxia. Frank methemoglobinemia is compounded by a concurrent left shift of the hemoglobin : oxygen dissociation curve, which further exacerbates tissue hypoxia. Peak methemoglobinemia occurs between 1 and 3 hours postingestion.

Clinical Signs Clinical signs are consistent with rapid-onset, acute methemoglobinemia and oxidative hemolytic anemia. Cyanotic and/or muddy/brown mucous membranes combined with depression, exercise intolerance, elevated respiratory and heart rates, incoordination, tremor, hemorrhage from body orifices, and hemoglobinuria are likely clinical signs. Traditional pulse oximetry measurements are inaccurate and unreliable in patients with high methemoglobin fractions because methemoglobin absorbs light at wavelengths that also absorb deoxyhemoglobin and oxyhemoglobin. Thus methemoglobin interferes with the colorimetric testing that is used to obtain the percentage of oxyhemoglobin to deoxyhemoglobin. Traditional pulse oximetry of patients with low-level methemoglobinemia often reveals falsely low values for oxygen saturation and falsely high values in those with high-level methemoglobinemia. Pulse co-oximetry should be used if possible.

Laboratory and Necropsy Findings Clinical pathology findings are typical of oxidative insult to the erythron: methemoglobinemia, sulfhemoglobinemia, elevated Heinz bodies, hemolysis (spherocytes, keratocytes or “bite” cells, “blister” cells, and irregularly contracted erythrocytes), hemoglobinemia, and hemoglobinuria. Surviving animals are likely to have elevated serum bilirubin. Gross and microscopic anatomic pathology findings are indicative of acute methemoglobinemia, acute oxidative hemolytic anemia, and general tissue hypoxia.

Treatment Decontamination of the gastrointestinal tract is unlikely to be effective given the form of the baits, the rapid absorption of PAPP, and the likely interval between exposure and treatment. Supplemental oxygen is recommended. Methylene blue is the first-line antidote but

143

should be used with caution if at all in cats (many consider this therapy contraindicated in this species). Methylene blue accelerates the enzymatic reduction of methemoglobin by NADPH-methemoglobin reductase to leukomethylene blue that, in turn, reduces methemoglobin. The initial dose is 1 to 2 mg/kg IV slowly over 5 minutes. Its effects should be seen in approximately 20 minutes to 1 hour. Patients may require repeated dosing, but high doses of methylene blue may actually induce a paradoxical methemoglobinemia, particularly in species that are prone to oxidative damage to erythrocytes (notably cats). Treatment failures may occur in patients with ongoing exposure, patients exposed to sulfhemoglobinemia, and individuals who have deficient NADPHmethemoglobin reductase enzymatic pathways. Ascorbic acid is an alternative treatment for methemoglobinemia. Ascorbic acid produces the nonenzymatic reduction of methemoglobin. It is relatively slow acting compared with methylene blue. Treatment protocol is 30 mg/kg PO every 6 hours for six or seven doses. The clinical effectiveness of N-acetylcysteine in PAPP poisoning has not been evaluated. It has been demonstrated to be of negligible benefit in human methemoglobinemias. However, it may be of some benefit in species with poor glucuronidation capacity (i.e., cats) because it may facilitate phase II sulfation by increasing the level of 3′-phosphoadenosine 5′-phosphosulfate in hepatocytes and thus the detoxification and excretion of the active PAPP metabolite. The concurrent use of N-acetylcysteine and methylene blue in cats should be avoided (particularly in male cats) because it causes severe depletion of blood glutathione levels and increases the elimination half-life of methemoglobin in this species. N-Acetylcysteine can be administered as a constant rate IV infusion (suggested dosage: 150 mg/kg IV over 1 hour, followed by 50 mg/kg over 4 hours, then 100 mg/kg over 16 hours). When administered orally the suggested loading dose is 140 mg/kg, followed in 4 hours by a maintenance dose of 70 mg/kg PO given every 4 hours). The drug has also been administered by inhalation and by the intratracheal route but it can be irritating. Dosing is commonly recommended to be continued for 72 hours; however, tailoring the duration of therapy to the patient’s clinical situation is often desirable. Both oral and intravenous N-acetylcysteine treatments are usually well tolerated. In humans oral administration has commonly caused nausea and vomiting, and intravenous use has been associated with the development of anaphylactoid reactions. Generally these reactions are mild and self-limiting, but life-threatening anaphylactoid reactions and deaths have been reported. An alternative to N-acetylcysteine is S-adenosylmethionine (SAMe). SAMe may reduce methemoglobin formation in cats. Whole blood transfusion or packed red cell transfusion is recommended provided that antidotal treatment has been instigated.

Prognosis The prognosis for inadvertently poisoned domestic spe­ cies is unknown at this time. It is likely to be guarded in

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cats and dependent on the interval between exposure and treatment.

Encapsulated Sodium Nitrite Encapsulated sodium nitrite baits are currently in the final stages of regulatory approval in New Zealand for the control of brush tailed possums and feral pigs. The encapsulation of the sodium nitrite masks the bitter salty taste, thus improving palatability and consumption by the target species. The baits contain 100 g/kg sodium nitrite and are hand-laid within bait stations. The bait stations are specifically designed to target feral pigs and to minimize nontarget species exposure.

Disposition and Mode of Action Nitrites are generally rapidly absorbed from the gastrointestinal tract. Peak methemoglobin formation is typically within 1 to 2 hours following oral exposure. Nitrite is also rapidly excreted, largely by renal filtration, with an elimination half-life of about 30 minutes. Nitrites act directly on the erythron to produce oxidative damage, methemoglobinemia, and nitritemethemoglobinemia, as described above. Nitrites are also potent smooth muscle relaxants, which results in vasodilation, diminished vascular return, and hypotension. The net overall result of these effects is tissue hypoxia. Nitrite methemoglobin also reacts with endogenously generated hydrogen peroxide to form reactive intermediates, further exacerbating damage to the erythron. The clinical signs, laboratory test results, and necropsy findings, as well as the treatment and prognosis, are identical to those described above for PAPP.

Tutin Tutin is a potent convulsant sesquiterpene lactone toxin derived from the New Zealand tutu plant (Coriaria arborea) and other native Coriaria spp. In New Zealand tutin exposure has historically caused heavy losses among grazing livestock and is associated with outbreaks of toxic honey poisoning when bees feed on the honeydew exudate from the passion vine hopper (Scolypopa australis) that, in turn, has been feeding on the sap of tutu bushes. Within vine hoppers, tutin is metabolized to a second toxin, hyenanchin (8-hydroxytutin; or mellitoxin). Currently tutin is undergoing development as a potential vertebrate toxic agent in New Zealand.

Disposition and Mode of Action Little is known about the disposition of tutin. It appears to be rapidly absorbed from the gastrointestinal tract. Tutin inhibits the action of neuronal glycine receptors at low concentrations and potentiates their activity at higher concentrations.

The resultant clinical signs in humans include vomiting, delirium, giddiness, increased excitability, stupor, coma, and violent epileptiform convulsions. In ruminants, clinical signs develop within 24 to 48 hours of ingestion and consist of drooling, nausea, excitement, convulsions, coma, and death. Cattle may become aggressive and bloated and may regurgitate. In sheep a “dummy” syndrome has been described in which poisoned animals stand still, are reluctant to move, and appear blind. Death usually occurs rapidly after exposure and often animals are just found dead. The laboratory and necropsy findings of tutin toxicosis are nonspecific.

Treatment and Prognosis Treatment of animals exposed to tutin is primarily symptomatic and supportive, with the goal of controlling the excitability and convulsions. Treatment with barbiturates is most commonly attempted. The prognosis for tutin poisoning following plant ingestion in livestock is generally very guarded and relates to the level of consumption. Reports of successful treatment are rare. Although data are currently lacking on the proposed tutin-based vertebrate toxic agent(s), the likely higher concentration of the active agent in these formulations suggests a poor prognosis unless there is immediate treatment.

References and Suggested Reading Bright JE, Marrs TC: A comparison of the methemoglobin-­ inducing activity of moderate oral doses of 4-dimethylaminophenol and p-aminopropiophenone, Toxicol Lett 13:81-86, 1982. Bright JE, Marrs TC: The induction of methaemoglobin by p-aminophenones, Toxicol Lett 18:157-161, 1982. Bright JE, Marrs TC: Kinetics of methaemoglobin production. (2). Kinetics of the cyanide antidote p-aminopropiophenone during oral administration, Hum Toxicol 5:303-307, 1986. Bright JE et al: Sex differences in the production of methaemoglobinaemia by 4-aminopropiophenone, Xenobiotica 7:79-83, 1987. Eason CT et al: Development of a new humane toxin for predator control in New Zealand, Integr Zool 5:31-36, 2010. Fisher P, O’Connor CE, Morriss G: Oral toxicity of p-aminopropiophenone to brushtail possums (Trichosurus vulpecula), Dama wallabies (Macropus eugenii), and mallards (Anas platyrhynchos), J Wildl Dis 44:655-663, 2008. Parton K, Bruere AN, Chambers JP: Tutu (Coriaria spp.). In Parton K, Bruere AN, Chambers JP, editors: Veterinary clinical toxicology, ed 3, Palmerston North, 2006, VetLearn, pp 343-345. Savarie PJ et al: Comparative acute oral toxicity of paraaminopropiophenone (PAPP) in mammals and birds, Bull Environ Contam Toxicol 30:122-126, 1983. Scawin JW, Swanston DW, Marrs TC: The acute oral and intravenous toxicity of p-aminopropiophenone (PAPP) to laboratory rodents, Toxicol Lett 23:359-365, 1984.

CHAPTER 

34 

Parasiticide Toxicoses: Avermectins WILSON K. RUMBEIHA, Ames, Iowa

A

vermectins are a group of parasiticidal drugs derived from soil Streptomyces microorganisms. Biochemically they belong to a group of com­ pounds known as macrocyclic lactones and are related to milbemycins. These drugs are widely used for their parasiticidal properties. Representative drugs (and prod­ ucts) include ivermectin (Heartgard; Iverhart), selamectin (Revolution), doramectin (Dectomax), eprinomectin (Eprinex), moxidectin (Proheart; Advantage Multi), milbe­ mycin (Interceptor), and abamectin. In general these drugs have a substantial margin of safety in dogs and cats and are very active against a wide range of parasites, including nematodes and arthropods. Practically they are highly effective at very low doses such as micrograms per kilogram of body weight. These drugs are not active against trematodes or cestodes. As such, they may be combined with other drugs that are active against trema­ todes and cestodes in some formulations. They are avail­ able for oral, topical, and parenteral formulations for use in different domesticated species and humans.

Toxicity of Avermectins and Milbemycins Because of their wide safety margin, avermectins and milbemycins are used safely in the majority of dogs and cats. However, some specific breeds of dogs are more sensitive to this group of drugs (i.e., collies, Australian shepherds, Shetland sheepdogs, Old English sheepdogs, German shepherds, long-haired whippets, and silken windhounds). Recent findings have determined that these breeds express a mutation in the multidrug resis­ tance (MDR-1) gene. This gene regulates the synthesis of P-glycoprotein, a 170-kDa transmembrane protein responsible for extruding drugs and other xenobiotics from the brain across the blood-brain barrier. A mutation in the MDR-1 gene causes synthesis of a truncated P-glycoprotein molecule that is unable to perform this regulatory role. The result is that breeds of dogs with this mutation cannot efficiently extrude xenobiotics such as avermectins and milbemycins from the brain.. Studies have demonstrated higher concentrations of ivermectin in brain tissues of dogs with the mutated MDR-1 gene than naïve control dogs that have normal-functioning P-glycoprotein. Collies as a breed have the highest prevalence of the MDR-1 mutation. Research from the United States, Europe, and Japan indicates that 75% of all collies carry this genetic mutation and explains why avermectin

toxicosis is more commonly observed in this breed. This statistic includes dogs that are either heterozygous carri­ ers or homozygous for the mutant allele, making the animal sensitive. Note that collies not carrying this muta­ tion (i.e., homozygous for the normal allele) have the same sensitivity to avermectin and milbemycin toxicity as other normal breeds of dogs. It is worth noting that some mixed breeds of dogs carry a single recessive gene mutation, making them heterozy­ gous carriers. These dogs have sensitivity to avermectins, which is between that of double recessive–sensitive mutants and naïve dogs with normal alleles.

Toxic Dose and Sources of Exposure The monthly oral dose of ivermectin for prevention of heartworms in dogs and cats is 0.006 to 0.024 mg/kg (6 to 24 µg/kg of body weight), respectively. The median lethal dose (LD50) of ivermectin in beagles is 80 mg/kg body weight. Most dogs with a normal MDR-1 gene toler­ ate oral dosages as high as 2.5 mg/kg body weight before they start to exhibit clinical signs of poisoning to this drug. However, dogs with a double recessive MDR-1 gene can only tolerate up to 0.1 mg/kg (100 µg/kg of body weight) of ivermectin. Sensitive collies tolerated doses of 28 to 35.5 µg/kg of body weight over a period of 1 year when administered oral chewable formulations of iver­ mectin. The highest observed nontoxic dose in cats is 1.3 mg/kg of body weight. However, toxicity in cats has been reported after as low as 0.3 mg/kg of body weight subcutaneously. Toxicosis to moxidectin was observed in a collie that received a dose 30 times higher than the recommended dose of 0.003 mg/kg of body weight. Toxi­ cosis to milbemycin has been observed in collies at doses that are 10 times higher than the recommended thera­ peutic dose of 0.5 mg/kg orally. In one study collie sen­ sitivity to milbemycin oxime at 10 mg/kg of body weight was judged to be clinically equivalent to that of ivermec­ tin at 120 µg/kg of body weight. Selamectin is potentially toxic to sensitive collies at oral doses greater than 15 mg/ kg of body weight. For the other avermectins, the minimum toxic doses in sensitive breeds of dogs are not well established. Typically toxicosis to avermectins and milbemycins is observed in the more sensitive breeds of dogs when dosage errors occur at more than 5 to 10 times higher than recommended doses, depending on a specific drug; when dogs are accidentally given formulations for large 145

146

SECTION  II  Toxicologic Diseases

animals; or when they eat a large number of drug tablets. Puppies and kittens are also very sensitive to both aver­ mectins and abermectins and care should be taken to avoid iatrogenic intoxication.

Following acute exposure, clinical signs are seen within a few hours. However, they may also become evident after several days of topical exposure. Typically clinical signs of avermectin and milbemycin toxicity are associated with depression of the central nervous system. Affected animals develop ataxia, weakness, and recumbency; if the dose is severe, respiratory failure and coma are evident. Some dogs exhibit signs of blindness, mydriasis, and muscle tremors; in some cases seizures have been reported. These clinical signs result from avermectins acting as ago­ nists of the γ-aminobutyric acid (GABA) in the central nervous system. Other non-GABA–related effects include mydriasis, hypothermia, vomiting, salivation, and shallow breathing. Avermectin toxicosis is a protracted disease that may last days or weeks. Treatment should be directed with these time intervals in mind.

exposed topically should be washed with mild dishwash­ ing detergents and plenty of water. In cases of acute oral exposure, patients should be induced to vomit if exposure is within 1 to 2 hours. Apomorphine is recommended in dogs, and xylazine in cats as emetic drugs (see Chapter 23). Following emesis, activated charcoal can be given to bind the unexpelled drug. Avermectins are excreted largely unchanged through the feces. Activated charcoal also may be beneficial in binding these compounds that are normally excreted unmetabolized through bile and feces. Treatments with physostigmine, neostigmine, or picrotoxin have resulted in either temporary relief or mixed results. Thus supportive care that includes fluid therapy, respi­ ratory support, parenteral alimentation, and maintenance of normal body temperature is vital to a successful treat­ ment outcome. Treatment of avermectin toxicosis is likely to be protracted since these drugs have prolonged halflives in dogs of at least 2 days for ivermectin, 11 days for selamectin, and 19 days for moxidectin. The effective half-life is likely longer in MDR-1 double recessive dogs, which are more likely to accumulate higher brain tissue concentrations.

Diagnosis and Therapy of Toxicosis

References and Suggested Reading

Diagnosis of avermectin toxicosis consists of a history consistent with exposure to large quantities of one or more of these drugs, clinical signs consistent with aver­ mectin intoxication, and chemical analysis of serum or blood plasma in live animals. In dead animals, adipose tissue, brain, and liver have been used for chemical analy­ sis to confirm exposure to avermectins. However, there are no well-established concentrations of avermectins in these matrices that can be regarded as “diagnostic marker concentrations.” Brain concentrations in excess of 100 ppb are supportive of ivermectin intoxication. History of excessive exposure and clinical signs consistent with aver­ mectin toxicosis remain the two most important diagnos­ tic criteria in live animals to date. In the United States there is a molecular genetics test for the presence of a mutant gene (available at the time of writing at Washing­ ton State University Veterinary Clinical Pharmacology Laboratory). This test, which uses cheek brush samples, is helpful in determining whether an individual dog is sensitive to avermectins and other drugs whose toxicoki­ netics are regulated by the MDR-1 gene. Therapy of avermectin toxicosis is symptomatic with no specific antidote. As such, prevention of absorp­ tion resulting from topical or oral exposure is key to successful therapy in cases of acute exposure. Animals

Griffin J et al: Selamectin is a potent substrate and inhibitor of human canine P-glycoprotein, J Vet Pharmacol Ther 28:257, 2005. Kawabata A et al: Canine MDR-1 gene mutation in Japan, J Vet Med Sci 67(11):1103, 2005. Mealy KL: Ivermectin: macrolide antiparasitic agents. In Peterson ME, Talcott PA, editors: Small animal toxicology, Philadelphia, 2006, Saunders, p 785. Mealy KL: Therapeutic implications of the MDR-1 gene, J Vet Pharmacol Ther 27:257, 2004. Mealy KL, Bentjen SA, Waiting DK: Frequency of mutant MDR-1 allele associated with ivermectin sensitivity in a sample popu­ lation of collies from northwestern United States, Am J Vet Res 63(4):479, 2002. Nelson OL et al: Ivermectin toxicity in an Australian Shepherd dog with the MDR-1 mutation associated with ivermectin sensitivity in collies, J Vet Intern Med 17(3):354, 2003. Paul AJ et al: Evaluating the safety of administering high doses of chewable ivermectin tablets to collies, Vet Med 86(6):623, 1991. Pawde AM et al: Ivermectin toxicity in dogs, Indian Ass Vet Res 1(2):51, 1992. Shoop WL, Mrozik H, Fisher MH: Structure and activity of aver­ mectins and milbemycins in animal health, Vet Parasitol 59:139, 1995. Tranquilli WJ, Paul AJ, Todd KS: Assessment of toxicosis induced by high-dose administration of milbemycin oxime in collies, Am J Vet Res 52 (7):1170, 1991.

Clinical Signs of Toxicosis

CHAPTER 

35 

Human Foods with Pet Toxicoses: Alcohol to Xylitol ERIC K. DUNAYER, Grand Cayman, Cayman Islands

M

any foods commonly and safely eaten by people can have toxic effects in dogs and cats. Dogs, with their indiscriminate, food-driven behavior, are more likely than cats to ingest these foods. Often, the toxicant is an ingredient that neither the pet owner nor the veterinarian knows to be toxic.

Alcohol (Ethanol) Ethanol, the type of alcohol found in beer, wine, and distilled spirits, is frequently ingested by dogs and occasionally ingested by cats. Dogs and cats may more readily consume alcoholic beverages if they contain sweet fruit juices or milk. Other products, such as mouthwashes and waterless hand sanitizers, may also contain ethanol. Because the growing yeast in rising bread produces ethanol and carbon dioxide, ingestion of raw bread dough can lead to both ethanol toxicosis and gastric distention. Ethanol content greatly varies with the type of beverage: generally, it is 4% to 7% in beer, about 12% in wine, and from 40% to about 100% in distilled spirits. The reported proof of an alcoholic beverage is twice the percentage of ethanol (e.g., “80 proof” signifies 40% ethanol). In dogs, the minimum lethal ingested dose for ethanol is about 5500 mg/kg, but significant signs of toxicosis can develop with smaller exposures. Following ethanol ingestion, onset of signs is rapid; initial signs appear within 15 to 30 minutes. Ataxia is usually observed first. Following ataxia, signs can rapidly progress to vomiting, central nervous system (CNS) de­­ pression, hypothermia, hypoglycemia, and coma. Ethanol is metabolized via alcohol dehydrogenase and aldehyde dehydrogenase. Both enzymes cause the release of numerous hydrogen ions, so significant metabolic acidosis can develop. Death is usually associated with CNS and respiratory depression, metabolic acidosis, and/or aspiration pneumonia. Treatment is symptomatic and supportive. Emesis can be attempted but should not be used if signs have already appeared. Activated charcoal adsorbs small molecules, such as ethanol molecules, poorly and is not considered useful. Additionally, because of the high incidence of vomiting, its use can increase the risk of aspiration pneumonia. Intravenous fluids containing added dextrose and B vitamins should be started to correct any dehydration and hypoglycemia. Blood gases should be monitored, and significant acidosis should be corrected with sodium

bicarbonate. If respiration is severely depressed, assisted ventilation through a cuffed endotracheal tube should be initiated (see Chapter 11). Yohimbine at 0.1 to 0.2 mg/kg IV has been reported to reverse some of the CNS depression. However, the effect is short-lived; the yohimbine may need to be repeated frequently. Dialysis (either hemodialysis or peritoneal dialysis) has been shown to rapidly clear ethanol and may be considered in the case of potentially lethal ingestions. Prognosis is good with small ingestions but can be guarded, especially in patients who are comatose or severely acidotic. When a dog ingests yeasted bread dough, the warmth and low oxygen tension of the stomach environment augment the yeast’s production of ethanol and carbon dioxide. In addition to ethanol toxicosis, expanding dough mass can lead to gastric distention with poor venous return and dyspnea secondary to diaphragmatic impingement. Therapy addresses both problems. In asymptomatic dogs, emesis can be attempted, but it often has little effect due to the weight and consistency of the dough mass. Gastric lavage with cold water can be used to chill or kill the yeast and reduce ethanol production. In severe cases, gastrotomy may be necessary to remove the dough mass.

Allium Plants Such as Onions and Garlic Onions, garlic, scallions, and leeks belong to the genus Allium. The disulfides and thiosulfates in Allium spp. are metabolized to compounds that can cause oxidative damage to erythrocytes, with the resultant production of Heinz bodies and methemoglobinemia. Cats are particularly sensitive to the toxic effects of Allium spp. because feline hemoglobin contains many exposed sulfhydryl groups and because methemoglobin reductase is relatively inactive in cats. Allium spp. are toxic whether fresh, dried, or cooked and may be ingredients in other foods. In dogs the minimum toxic dose of ingested onions is considered to be more than 0.5% body weight (>5 g/kg); garlic is more toxic than onions. Like cats, certain breeds of dogs such as the Japanese breeds (e.g., Akita, Shiba Inu) or those with hereditary red-blood-cell (RBC) enzyme deficiencies may be more sensitive to Allium spp. toxicosis. Because the damage to the RBCs is cumulative, the dose can be ingested over a period of days to weeks. Hours or days after ingestion, Heinz bodies appear, followed by hemolysis. The patient may show weakness (secondary to 147

148

SECTION  II  Toxicologic Diseases

anemia), pale mucous membranes, and hemoglobinuria (often reported by the owner as bloody urine). With methemoglobinemia the mucous membranes, the blood, and possibly the urine become brownish due to methemoglobinuria from hemolyzed RBC. The patient may show variable degrees of dyspnea. With recent ingestions, emesis may be useful; administration of activated charcoal should also be considered in significant ingestions. The dog or cat should be monitored for several days for the appearance of hemolysis or declining hematocrit. In severely anemic dogs or cats, RBC transfusions may be needed as support until increased hematopoieses replaces the lost RBCs. Patients with severe methemoglobinemia may need oxygen supplementation and blood transfusion. In cats, methylene blue is contraindicated as a treatment for methemoglobinemia. With control of signs, prognosis is generally good.

Hops Hops, the female cones harvested from Humulus spp., are used in the brewing of beer and also are present in some herbal preparations. Canine exposure generally occurs when dogs ingest spent hops that have been discarded after being used for home production of beer. Canine ingestion of herbal products has also been associated with signs of toxicity. The toxic principle and doses are unknown. Following ingestion, onset of signs is rapid; death can occur within 6 hours. The dogs develop malignant hyperthermia; body temperatures commonly exceed 42.2° C (108° F). Vomiting, tachypnea, and tachycardia are also common. Prior to onset of signs, induction of emesis should be attempted. In symptomatic dogs, gastric lavage may be effective. Activated charcoal can be given; enemas may accelerate gastrointestinal passage. Intravenous fluids and thermoregulation should be instituted. Dantrolene, a peripheral muscle relaxant, has been used to treat malignant hyperthermia. Doses of either 2 to 3 mg/kg IV or 3.5 mg/kg PO q8-12h (canine dose) should be started immediately. Anecdotal reports have indicated that cyproheptadine at 1.1 mg/kg PO or rectally PRN may help control hyperthermia until dantrolene can be obtained. Prognosis is guarded, especially once hyperthermia has developed.

Macadamia Nuts Macadamia nuts are harvested from Macadamia integrifolia or M. tetraphylla trees. They are consumed as nuts (sometimes chocolate-covered) or included in baked goods such as cookies. The toxic principle has not been identified. Dogs that ingest more than 2 g/kg of macadamia nuts may develop weakness and muscle tremors. Also, because the nuts are high in fat, pancreatitis is a possible sequela. Other nuts, such as almonds and walnuts, are not considered toxic in dogs. After a dog ingests macadamia nuts, signs of toxicity usually develop within 12 hours. Vomiting is common. Weakness (especially in the hind limbs), tremors, and

TABLE 35-1  Approximate Methylxanthine Content of   Various Products

Product Coffee beans Coffee, brewed Tea, dry

Caffeine (mg/oz for solids, mg/fl oz for fluids)

Theobromine (mg/oz)

310-620

0

13-25

0

850-1130

0

Tea, brewed

5-15

0

White chocolate

0.85

0.25

Milk chocolate

6

58

Dark chocolate

20

130

Semisweet chocolate

22

138

Baker’s chocolate

47

393

Cocoa powder

70

737

Note: For chocolates with a high percentage of cocoa (e.g., 70%), multiply the cocoa percentage by 400 mg/oz to obtain the methylxanthine content.

hyperthermia are frequently seen. Signs are generally mild and, in most cases, can be managed at home. In cases of heavy ingestion of macadamia nuts, emesis and activated charcoal should be considered. Severe tremors can be controlled with methocarbamol (55 to 220 mg/kg slow IV PRN). Intravenous fluids may be useful in controlling hyperthermia. Prognosis is generally good.

Methylxanthines (Especially in Chocolate) Methylxanthines—primarily caffeine and theobromine— are found in many foods, including coffee, tea, and chocolate. Methylxanthine content greatly varies by product (Table 35-1). Chocolate comes in many forms, such as baker’s chocolate, chocolate candy, and chocolate baked goods (e.g., cakes, cookies, brownies). Dogs are very attracted to chocolate foods that are high in sugar and fat. The Animal Poison Control Center of the American Society for Prevention of Cruelty to Animals (ASPCA) receives numerous reports of chocolate ingestion by dogs. The methylxanthine dose of chocolate should be calculated by combining the amounts of caffeine and theobromine in the product. However, in the case of chocolate baked goods or mixed-filled chocolates, estimating ingested doses of methylxanthine can be difficult. In dogs, gastrointestinal upset can result from ingestion of even very small doses of methylxanthine but is most likely if the dose exceeds 20 mg/kg. Doses greater than 40 to 50 mg/kg can cause cardiac signs such as supraventricular or ventricular tachycardia; doses over 60 mg/kg can cause CNS signs such as tremors and seizures. The minimum lethal dose is 100 mg/kg. After a dog ingests methylxanthine-containing agents, polydipsia is often the earliest sign. The dog may develop vomiting and diarrhea. Agitation can be seen at any dose.

CHAPTER  35  Human Foods with Pet Toxicoses: Alcohol to Xylitol If a dog ingests a large amount of chocolate, onset of cardiac and CNS signs may be delayed because ingesting a large amount of food can delay absorption. Treatment of chocolate ingestion should include emesis and activated charcoal. Emesis can be induced up to 12 hours following ingestion because chocolate can remain in the stomach for a long time. Activated charcoal should be administered every 6 to 8 hours for as long as the dog is symptomatic. Theobromine has a long half-life in dogs due to enterohepatic recirculation, which can be interrupted by repeated doses of activated charcoal. Diuresis should be started to support cardiac output and to increase renal elimination. Resting tachycardias of greater than 160 to 180 bpm should be controlled with β-blockers such as propranolol (0.01 to 0.02 mg/kg q6h IV). Acepromazine (0.025 to 0.05 mg/kg IV PRN) can be used to control agitation, and diazepam (5 to 10 mg IV) can be used to manage seizures. Because methylxanthines can be absorbed though the urinary bladder wall, frequent walks or urinary catheters should be used to keep the bladder empty. Prognosis is good except in severe cases, especially when the owner delays seeking veterinary care.

Tremorgenic Mycotoxins in Penicillium Molds Molds of the Penicillium spp. can produce the tremorgenic mycotoxins roquefortine or penitrem A. These molds can grow on spoiled foods such as dairy products, walnuts, spaghetti, and grains. They can also be found in compost heaps. Dogs can be exposed to the toxins if they get into trash that includes discarded food. The toxins’ precise mechanism of action is unknown. Onset of action can be rapid (within minutes to hours). In general, the more rapid the onset of signs, the more guarded the prognosis. Signs include vomiting and diarrhea, tachycardia, agitation, ataxia, muscle tremors, and seizures. Excessive muscle activity can cause lactic acidosis, rhabdomyolysis with leakage of myoglobin, myoglobinuric nephrosis, and severe hyperthermia with the development of disseminated intravascular coagulation (DIC). In asymptomatic patients, emesis can be attempted. Gastric lavage may be useful if signs have already developed. Activated charcoal can limit toxin absorption, but care must be taken to avoid aspiration. Intravenous fluids should be started to provide cardiovascular support, treat hyperthermia, and protect the kidneys from myoglobinuric nephrosis. Acid-base abnormalities should be treated if significant. Tremors are best controlled by methocarbamol (55 to 220 mg/kg slow IV PRN). Seizures should be controlled with diazepam or barbiturates as needed. Prognosis is good unless the signs cannot be controlled or secondary complications such as DIC or acute renal failure develop.

Vitis Fruits (Grapes and Raisins) In dogs, fruits of the Vitis spp. have been associated with development of acute renal failure secondary to acute proximal tubular necrosis. Anecdotal reports indicate that

149

this association also may be identified in cats and ferrets. Toxicity has been noted in homegrown, store-bought, and organic Vitis spp. Grapes and raisins whose ingestion has resulted in confirmed toxicoses have been tested for the presence of pesticides, heavy metals, and nephrotoxic mycotoxins, but no causative agent of grape/raisin toxicosis has been identified. Ingestion of more than 0.7 oz/kg of grapes or more than 0.11 oz/kg of raisins has been associated with signs of toxicosis, but lower doses also can be toxic. Some toxicologists think that cooked raisins, such as those found in raisin bread, are not toxic, but this hypothesis has not been confirmed. Many dogs do not develop signs of toxicosis after ingestion of grapes or raisins. This finding may indicate that the toxin is not always present or there may be undetermined factors in the dogs themselves that predispose to toxicity. Following ingestion, vomiting is seen within 24 hours; among dogs that later develop renal failure, 100% vomit after exposure. Anorexia, lethargy, and weakness may also develop. Clinical pathology changes include increased creatinine, blood urea nitrogen (BUN), and phosphorus starting around 24 hours after ingestion; hypercalcemia may also occur. Urinary granular casts and glucosuria, both indicative of renal tubular damage, may be seen about 18 hours after ingestion. Oliguria and anuria may develop 48 to 72 hours after the ingestion. Initial treatment should include emesis and multiple doses of activated charcoal. Enemas may expedite the movement of plant material through the gastrointestinal tract. Fluid diuresis at twice maintenance should be started as soon as possible and maintained for 48 hours. Baseline BUN, creatinine, phosphorus, and calcium should be obtained and monitored every 12 to 24 hours. If renal values are normal after 48 hours, fluids can be tapered off and the patient discharged. If acute renal failure develops, urine output should be monitored. Because grapes and raisins cause tubular epithelial necrosis but do not damage the basement membrane, there is the potential for repair of renal tubular injury, but it may be weeks or longer before normal renal function is restored. Dialysis can be used to support the patient until renal function recovers. Prognosis is good if the toxicosis is treated early (< 18 hours) but guarded once renal signs develop.

Xylitol (a Common Sweetener) Xylitol is a sugar alcohol commonly used as a sweetener in chewing gums, mints, puddings, and baked goods. It can be purchased as a granulated powder for use in home baking or as a sweetener of foods such as beverages and cereals. Xylitol also is used as a sweetener in chewable vitamins, liquid medications, and oral-care products such as toothpastes and mouthwashes. At present, confirmed reports of xylitol toxicity are limited to dogs. (There have been unconfirmed reports of xylitol toxicity in ferrets.) After a dog ingests xylitol, the pancreas releases a large amount of insulin, and there is rapid onset of hypoglycemia. The minimum toxic dose is about 75 to 100 mg/ kg. However, determining ingested dose can be difficult; many products do not specify xylitol content. In many

150

SECTION  II  Toxicologic Diseases

dogs, ingestion of xylitol has been associated with a transient increase in alanine aminotransferase (ALT); usually this increase is a few hundred U/L or less. Some dogs that have ingested more than 500 mg/kg of xylitol have developed severe, potentially fatal hepatic necrosis. However, it is unclear whether this reaction is dose-related or idiosyncratic. Following ingestion of xylitol, signs can appear within 15 to 30 minutes. With respect to gum that contains xylitol, absorption of xylitol is variable so onset of signs can be delayed up to 12 hours. After a dog ingests xylitol, vomiting is frequently the first sign, followed by weakness, ataxia, collapse, and seizures. At presentation, dogs with xylitol toxicosis usually are profoundly hypoglycemic; however, sometimes they present collapsed but hyperglycemic, likely due to glucose rebound (Somogyilike effect) from glycogen mobilization. Hypokalemia and hypophosphatemia associated with intracellular movement of the compounds are also common. Dogs that develop hepatic necrosis from xylitol ingestion may not initially show signs of hypoglycemia and may not become symptomatic for 24 to 72 hours. These dogs often present with acute collapse secondary to hemorrhagic shock from internal bleeding. On presentation, they have severely elevated ALTs (often ranging from 1000 to more than 10,000 U/L), hyperbilirubinemia, mild-to-moderate elevation of alkaline phosphatase (ALP), and coagulopathy and/or DIC (prolonged prothrombin time [PT]/activated partial thromboplastin time [aPTT], thrombocytopenia, decreased fibrinogen, and/or increased D-dimers/fibrin degradation products [FDPs]). Additional findings include hypoglycemia secondary to the hepatic failure and either hypophosphatemia or hyperphosphatemia; the latter is associated with a poorer prognosis. Emesis may be useful, depending on the type of xylitol product ingested. Gum can remain in the stomach for hours. Therefore, in the case of gum ingestion, delayed emesis may be considered. However, hypoglycemia, if present, should be corrected prior to emesis. Activated charcoal has not been effective in adsorbing xylitol and is not recommended. Blood glucose should be monitored hourly for the first 12 hours following exposure. If

hypoglycemia develops, an intravenous bolus of dextrose (0.5 to 1 g/kg of 25%) should be given and followed with a constant rate infusion (CRI) of 5% dextrose in a balanced electrolyte solution. With large ingestions of xylitol, a dextrose solution infusion can be started preemptively. Hypokalemia, if severe (< 2.5 mmol/L), can be treated by intravenous supplementation. Currently there is no consensus regarding the steps that should be taken to prevent severe hepatic necrosis because the cause has not been definitively determined. According to one theory, xylitol metabolism in the liver depletes ATP and leads to necrosis; therefore, in dogs that have ingested potentially hepatotoxic doses of xylitol, starting a dextrose infusion may increase the liver’s ATP via glycolysis. According to a second theory, hepatic necrosis results from oxidative damage to the hepatocytes; thus, starting hepatic protectants such as N-acetylcysteine, S-adenosylmethionine (SAMe), or vitamins C and E may reduce oxidative damage. Neither treatment regimen has been proven effective. If hepatic necrosis develops, treatment is supportive and symptomatic. Plasma transfusions can be used to provide clotting factors and control hemorrhage. Intravenous fluids with dextrose supplementation should be started. The prognosis for dogs with simple hypoglycemia or mild ALT elevation is generally good. Dogs who develop fulminant hepatic necrosis have a guarded to poor prognosis; their mortality rate is high.

References and Suggested Reading Dunayer EK: New findings on the effects of xylitol ingestion in dogs, Vet Med 101(12):791, 2006. Duncan KL et al: Malignant hyperthermia-like reaction secondary to ingestion of hops in five dogs, J Am Vet Med Assoc 210(1):51, 1997. Gwaltney-Brant S: Chocolate intoxication, Vet Med 96(2):108, 2001. Hansen SR et al: Weakness, tremors, and depression associated with macadamia nuts in dogs, Vet Hum Toxicol 42(1):18, 2000. Means C: Bread dough toxicosis in dogs, J Vet Emerg Crit Care Soc 13(1):39, 2003. Simmons DM: Onion breath, Vet Tech 22(8):425, 2001.

CHAPTER 

36 

Automotive Toxins KARYN BISCHOFF, Ithaca, New York

V

arious compounds used in vehicle maintenance and stored around the home have known toxic properties. An incomplete list of such chemicals includes ethylene glycol (EG), propylene glycol (PG), diethylene glycol (DEG), petroleum products, and methanol. EG is the most common component of antifreeze and unfortunately is the most common automotive product associated with poisoning in small animals. PG has been substituted for EG in antifreeze brands that are advertised as “safe” or “nontoxic,” and although PG is not without adverse effects, it is much less toxic than EG.

Ethylene Glycol EG, or 1,2-dihydroxyethane, is a colorless, sweet-tasting liquid with a density of 1.113, a high boiling point (197.2° C [326° F]), a low freezing point (−12.3° C [9.86° F]), and is miscible with water and alcohol. Less common sources of EG include deicer, hydraulic brake and transmission fluids, additives in motor oils, paints, inks, wood stains and polishes, photographic solutions, and industrial solvents. EG is one of the most common causes of fatal poisoning in small animals, perhaps because it is readily available in most households, is toxic in low doses, and is palatable. Toxicosis is most common in the late autumn or early spring, when radiators have been drained and open containers may be available to pets. Dogs occasionally chew through closed containers. Denatonium benzoate, a bittering agent, has been added to antifreeze to make it less palatable. The states of Arizona, California, Georgia, Illinois, Maine, Maryland, Massachusetts, New Jersey, New Mexico, Oregon, Tennessee, Utah, Vermont, Virginia, Washington, and West Virginia require addition of bittering agents to commercial antifreeze at the time of this writing.

Toxicity and Toxicokinetics The minimum lethal dose for EG in dogs is about 6.6 ml/ kg. Cats are more sensitive, with a minimum lethal dose around 1.4 ml/kg. Dogs are more frequently affected than cats, although cats are likely to become intoxicated through grooming activity after dermal contamination. Intact animals are more frequently affected. EG is absorbed rapidly from the gastrointestinal tract, particularly on an empty stomach. Peak plasma concentrations occur within 3 hours of ingestion. Metabolism begins within hours of ingestion and occurs predominantly in the liver, with minor renal and gastric meta­ bolism. The metabolic pathway of EG is illustrated in

Figure 36-1. The metabolism of EG to glycoaldehyde and then glycolic acid to glyoxylic acid are both rate-limiting steps. Oxalic acid is the most important final metabolite of EG. The plasma half-life of EG is approximately 3 hours, and elimination is almost complete within 24 hours. EG and its metabolites are eliminated in the urine.

Mechanism of Action The severe clinical effects associated with EG ingestion are caused by metabolites. Acidosis is produced by such metabolic products as glycolic acid. Renal tubular damage is the most common cause of death in small animals poisoned with EG. Metabolites of EG are directly cytotoxic to renal tubular epithelium. Oxalic acid binds to calcium ions (Ca2+) in the renal tubules (and in other tissues) to form calcium oxalate crystals, leading to hypocalcemia, obstruction of tubules, and renal epithelial damage. Renal blood flow can be compromised from acidosis.

Clinical Signs EG toxicosis is described as having three sometimes overlapping stages, although early stages are often missed. The first stage, usually within 30 minutes of exposure, can last for 2 to 12 hours. Some animals vomit. Polyuria and polydipsia are described in dogs, and cats are frequently polyuric. Apparent “inebriation” presents as ataxia and hyporeflexia. Dogs often have a period of apparent recovery from this stage, but cats typically do not. The second stage usually occurs 8 to 24 hours after exposure and is related to metabolic acidosis. Clinical signs include central nervous system (CNS) depression, changes in heart rate, hypothermia, muscle fasciculations, and sometimes coma. Cats often lose coordination in the pelvic limbs. Animals that survive the first two stages enter the third stage, acute renal failure, which can begin from less than 1 to 3 days after EG ingestion. Animals progress through oliguria to anuria. Signs of uremia include oral ulcerations, salivation, vomiting, anorexia, and seizures. Palpation of cats often reveals large, painful kidneys. Serum chemistries reveal an increased osmolal gap about an hour after EG ingestion, which usually declines within the first 18 hours. The anion gap increases in a few hours and can remain elevated for 48 hours. Hypocalcemia is reported due to calcium oxalate crystal formation. Phosphorus can be elevated early, as a result of the phosphate additives in antifreeze, and again as a consequence of renal failure. Other findings associated with 151

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Ethylene glycol

Alcohol dehydrogenase

Glycoaldehyde

Glyoxal

Aldehyde dehydrogenase

Glycolic acid

Figure 36-1  Hepatic metabolism of ethylene glycol.

Lactate dehydrogenase

Glyoxalic acid

Formic acid

Glycine Oxalic acid

Others Hippuric acid

renal failure include elevated serum urea nitrogen and creatinine, hyperkalemia, isosthenuria with low urine pH, hematuria, proteinuria, glycosuria, and granular and cellular casts. Calcium oxalate crystals are evident in urine within 8 hours of exposure, but are not a specific finding considering that crystalluria is identified in many healthy animals.

Diagnosis Speed is of the essence in the diagnosis (and management) of EG toxicosis. The prognosis decreases precipitously the longer treatment is delayed. EG concentrations begin to decline within 6 hours of exposure and are often undetectable in blood or urine by the time the animal presents to the veterinarian, further complicating the diagnosis. Various analytic tests have been used to confirm EG exposure. Commercial test kits are available, but some of these kits cross-react with PG, glycerol, sorbitol, ethanol, and other compounds that can be present in pet foods and pharmaceuticals; thus samples for testing should be collected before initiating treatment. Current test kits are able to detect EG at concentrations above 0.6 mg/dl, but due to rapid EG metabolism false-negative results can occur in samples collected more than 12 hours after

ingestion. Gas chromatography (GC) is frequently used to assay blood, urine, or kidney tissue for EG at diagnostic laboratories, although results are delayed by sample shipping and processing and false-negative results are still possible if the EG has been completely metabolized. The findings of increased anionic and osmolal gaps along with the appropriate history and presentation are highly suggestive of EG toxicoses, but are not always seen. Calcium oxalate monohydrate crystals are commonly found in the urine. Fluorescent dye, which is sometimes added to antifreeze, is visible in the urine, in the vomitus, or around the oral cavity under Wood’s lamp. However, other components of urine and some plastic containers also fluoresce. The “halo effect,” an ultrasound finding related to increased echogenicity of the renal cortex and medulla and decreased echogenicity at the corticomedullary junction and central medulla, is supportive (although not pathognomonic) for the diagnosis of EG toxicosis. This change occurs near the onset of anuria. Postmortem findings are frequently used to confirm the diagnosis of EG toxicosis. Typical findings include gastric hemorrhage, pulmonary edema, and pale firm kidneys. Histologic changes include degeneration and necrosis of proximal convoluted tubular epithelium with intraluminal birefringent crystals. Chronicity is indicated

CHAPTER  36  Automotive Toxins by evidence of tubular regeneration, interstitial fibrosis, and glomerular atrophy and synechia. Oxalate crystals are sometimes found in other tissues, including the liver and CNS.

Management The prognosis for EG toxicosis depends on the time of presentation. Animals treated early (stage 1) have an excellent prognosis, but the prognosis is poor for animals that present in renal failure (stage 3). Due to the rapid absorption of EG, gastrointestinal decontamination is unlikely to be beneficial. Antidotes that act by inhibiting metabolism of EG by alcohol dehydrogenase include fomepizole and ethanol. Antidotal treatment should be started as early as possible for best effect but can still be attempted if the animal is presented to the clinician up to 32 hours postexposure. Fomepizole The preferred antidote is fomepizole (4-methylpyrazole). This product is used in dogs at an initial dose of 20 mg/ kg IV, then 15 mg/kg IV at 12 and 24 hours, and then 5 mg/kg IV at 36 hours. Cats have recovered after being treated with the much higher doses of fomepizole of 125 mg/kg IV initially, then 31.25 mg/kg every 12 hours for three more doses. The dosing regimen can be extended if the dog or cat ingested a large amount of EG. Fomepizole causes less CNS depression than ethanol. Concurrent use of fomepizole and ethanol produces severe CNS depression due to ethanol toxicosis and is therefore contraindicated. The prognosis is good if fomepizole therapy is started within 8 to 12 hours of EG ingestion for dogs or within 3 hours for cats. Ethanol can be used if fomepizole is not immediately available. Fomepizole dosage must be adjusted if hemodialysis or peritoneal dialysis is used to treat renal failure. Ethanol Ethanol has been used for many years to treat EG toxicoses; however, ethanol enhances CNS depression and can cause respiratory depression. Animals remain stuporous during treatment, requiring close monitoring and supportive care. Ethanol is usually given IV to maintain blood concentrations of 50 to 100 mg/dl. A 5.5-ml/kg dose of 20% ethanol is given every 4 hours for the first five treatments and then every 6 hours for the next four treatments in dogs. Alternatively, dogs can be given a bolus dose of 1.3 ml of 30% ethanol followed by a constant rate infusion of 0.42 ml/kg/hr for 48 hours. Cats are given 5 ml/kg of 20% ethanol IV every 6 hours for five treatments and then every 8 hours for four treatments. Monitoring Patients should be monitored for hydration, urine production (which can be assessed via bladder catheterization), acid-base status, serum urea nitrogen, creatinine, electrolytes, and body temperature at least daily and treated symptomatically. Fluid therapy corrects dehydration and electrolyte imbalances and promotes diuresis: saline is used to establish urine flow in anuric patients, a slow infusion of bicarbonate solution is required to

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correct metabolic acidosis, and calcium gluconate is added to correct for hypocalcemia. Fluid therapy in patients with anuria may aggravate or cause pulmonary edema, and respiratory rate and depth must be monitored regularly. Tubular regeneration requires weeks or months, and urine concentrating ability can be lost indefinitely.

Propylene Glycol PG, or 1,2-propanediol, has a density of 1.036 and is colorless, odorless, and almost flavorless. Like other antifreeze compounds, it has a high boiling point (189° C [372° F]) and a low freezing point (−60° C [140° F]) and is freely miscible with water and alcohol. PG is used commonly in recreational vehicles and as an alternative type of antifreeze to the more toxic EG. PG can be used as a deicer, a hydraulic fluid, an industrial solvent, a humectant, a plasticizer, and an ingredient in pharmaceuticals, cosmetics, and foods. PG is frequently kept in large barrels in veterinary clinics to treat ruminant ketosis. Although no longer used in cat food, PG is still classified as “Generally Recognized as Safe (GRAS)” by the U.S. Food and Drug Administration.

Toxicity, Toxicokinetics, and Mechanism of Action PG is less toxic than other glycols. The median lethal doses (LD50s) in laboratory animals are around 20 ml/kg. The LD50 in experimental dogs is 9 ml/kg. Dogs tolerate a diet containing up to 20% PG with minimal clinical effects; however, 5% to 6% PG in the diet causes increased Heinz body formation in kittens and cats. Cats given high doses of PG (approximately 40% of the diet) had mild neurologic signs, including ataxia and depression. Toxicosis has been reported in humans, horses, and cattle and experimentally produced in dogs, laboratory animals, goats, and chickens. The author has seen apparently malicious PG poisoning in a dog. PG is absorbed rapidly from the gastrointestinal tract and lungs. About a third of the PG dose is excreted unchanged in the urine; the rest is metabolized mostly in the liver and kidneys. Lactic acid is a major metabolite. PG is conjugated to glucuronide in some species, but this metabolic pathway is inadequate in cats. Metabolites usually appear in the blood within 4 hours of exposure. PG is excreted completely within a day in dogs. PG causes osmotic diuresis and a direct narcotic effect similar to ethanol, but at about one third the potency. The L-isomer of the lactic acid metabolite enters the citric acid cycle and is metabolized, but D-lactic acid is not readily metabolized and contributes to lactic acidosis. The mechanism of PG-mediated Heinz body formation in cats is not completely understood.

Clinical Signs and Diagnosis Clinical signs in cats given high doses of PG include polyuria, polydipsia, and mild-to-moderate ataxia. Cats exposed to low dietary concentrations of PG, although asymptomatic, have increased numbers of Heinz bodies, reticulocytes, and low erythrocyte counts. Animals

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ingesting high dietary PG concentrations have increased blood D-lactic acid. Osmotic diuresis occurs after oral or parenteral administration of a high dose of PG. Severe clinical signs of acute PG toxicosis are attributable to acidosis; hypotension, circulatory collapse, and respiratory arrest have been reported in cats. Pure PG is hyperosmolar and is likely to cause hemolysis if given intravenously. Postmortem lesions are nonspecific but can include a foul, garlic-like odor to gastrointestinal contents. Diagnosis is based on history and clinical signs. Serum, urine, tissues, or the suspected source of PG may be analyzed using GC.

Management The prognosis for cats with chronic dietary exposure to PG is excellent. Heinz bodies resolve once the source of PG is removed. The prognosis for acute toxicosis is fair to guarded, depending on the clinical status of the animal. Decontamination using gastric lavage and activated charcoal is unlikely to be of benefit unless initiated within an hour of exposure due to rapid absorption of PG. Dehydration, acidosis, and hypoglycemia are treated routinely as needed. Antioxidants such as vitamins E and C and N-acetylcysteine do not show much benefit.

centrilobular necrosis have been reported. Hemorrhage involving the pericardium, adrenal medulla, lungs, and pleura has been reported in humans, and multifocal hemorrhage was observed by the author in one dog. Diagnosis is based on a history of exposure, clinical signs, and lesions. Tissues or suspected source of DEG can be analyzed using GC, keeping in mind the rapidity of DEG elimination.

Management Animals presenting soon after exposure have a fairto-guarded prognosis, but once animals have evidence of renal failure, the prognosis is poor. Therapy includes symptomatic and antidotal treatments similar to those described earlier for EG toxicosis. The combination of dialysis and fomepizole treatment has been successfully used to treat human cases of DEG toxicosis. As with EG, the fomepizole dose must be adjusted when the patient is also undergoing dialysis.

Petroleum Compounds

DEG has a specific gravity of 1.118 and is a colorless, nearly odorless, palatable liquid. It is an industrial solvent used in brake fluid, hydraulic fluid, lubricants, and canned cooking fuels. High mortality is reported in epidemic human poisonings.

Petroleum compounds include a wide variety of products with variable physical and chemical characteristics. Such compounds include fuels such as propane, gasoline, kerosene, and diesel; solvents such as paint thinner and degreasers; lubricants such as motor oil; and carriers for pesticides, paints, and drugs. Animals can ingest spilled hydrocarbons or drink from open containers. Material spilled on the skin causes dermatitis and can be ingested when the animal grooms. Animals are occasionally given petroleum products intentionally.

Toxicity, Toxicokinetics, and Mechanism of Action

Toxicity, Toxicokinetics, and Mechanism of Action

The LD50 of DEG in laboratory animals ranges from 3.6 to 11.6 ml/kg, making it more toxic than PG but less so than EG. DEG is rapidly absorbed through the gastrointestinal tract or damaged skin. Peak plasma concentrations occur within an hour or two. Similar to other glycols, DEG is metabolized primarily in the liver by alcohol and aldehyde dehydrogenases. DEG and metabolites are excreted in the urine, with nearly complete excretion within 36 hours. DEG produces a direct narcotic effect and renal damage, but oxalate crystals are not produced.

Absorption occurs through the gastrointestinal tract, skin, and lungs. Low-molecular-weight compounds such as gasoline are better absorbed; high-molecular-weight compounds such as greases, mineral oils, and waxes are not well absorbed. Hydrocarbons are distributed to all major organs. Aliphatic hydrocarbons are oxidized in the liver to polar compounds that are more readily excreted. Respiratory excretion is important for volatile compounds, and highly volatile hydrocarbons can be excreted completely within 24 hours. Highly volatile compounds are likely to be aspirated, and low-viscosity compounds have greater penetration into airways. Aspirated hydrocarbons dissolve lipids in cell membranes and cause degeneration and necrosis of the respiratory epithelium; secondary bacterial infections are common. Direct irritation of the skin and eyes is caused by the solvent effects of volatile hydrocarbons on cell membranes. Absorbed compounds interact with neuronal cell membranes to cause CNS depression.

Diethylene Glycol

Clinical Signs and Diagnosis Clinical signs of DEG toxicosis are similar in most species. CNS depression and vomiting are reported early but resolve and are followed by renal failure within a day or more. Cardiac abnormalities have been reported in some species. Serum chemistry findings include elevated urea nitrogen, creatinine, and potassium, as well as evidence of lactic acidosis. Findings at necropsy usually include pale, swollen, mottled kidneys that bulge on cut surface. There is necrosis and degeneration of proximal convoluted tubular epithelium and tubular ectasia. Hepatic lipidosis and

Clinical Signs and Diagnosis Early clinical signs of ingestion include increased sali­ vation, head shaking, and pawing at the muzzle. Vomiting and colic are typically seen with more volatile

CHAPTER  36  Automotive Toxins compounds, and diarrhea with heavier compounds such as mineral oil. Aspiration is sometimes seen in the absence of apparent emesis. Signs of aspiration pneumonia include choking, coughing, gagging, dyspnea, and cyanosis. Signs of CNS involvement include ataxia, confusion, depression, narcosis, and coma. Tremors and convulsions have been reported in a few cases, as have cardiac arrhythmias and cardiovascular collapse. Animals that die after hydrocarbon ingestion frequently have gross lesions typical of aspiration pneumonia, with oily material visible in small airways. Secondary bacterial pneumonia is evident in animals that die later. Centrilobular hepatic necrosis, myocardial necrosis, and renal tubular necrosis have been reported in animals surviving more than 24 hours. Dermatitis, characterized by alopecia with or without erythema, has been reported in cats and other species with dermal exposure to petroleum hydrocarbons. Petroleum hydrocarbons float to the top of vomitus or stomach contents when mixed with warm water, and this is a rapid test for hydrocarbon exposure. If skimmed with a paper towel, these compounds evaporate quickly and have a characteristic odor that is often detectable on the breath or skin of the affected animal. Confirmation of exposure involves analysis of the gastrointestinal content or material on the skin, to be compared with suspected source material, via GC. Samples should be collected quickly and placed in glass containers or wrapped in foil, to avoid contact with plastic, and frozen until analysis can be performed.

Management Early management involves identification of the compound involved. When possible, the owner should bring the container or label of the suspected source of exposure. Gastrointestinal detoxification must be pursued with great care. Emetics and instillation of oily cathartics are contraindicated because of the risk of aspiration. Gastric lavage of the sedated intubated animal and dosing with activated charcoal have been recommended. Monitoring of the exposed animal should include auscultation and thoracic radiography to assess pulmonary status. Aspiration pneumonia is treated symptomatically with cage or stall rest, supplemental oxygen, and β2agonists if needed for bronchospasm. Corticosteroids increase the risk of bacterial infection and should not be used, but prophylactic antibiotics should be considered. Cardiac function should be monitored, and arrhythmia treated as needed. The prognosis for animals that have ingested lowvolatility compounds such as mineral oil or motor oil is good, assuming these products did not contain other toxicants such as pesticides or heavy metals. Management in this case involves cage rest and observation. Animals with no evidence of aspiration pneumonia 12 to 24 hours

155

after ingestion have a good prognosis. Uncomplicated aspiration pneumonia is usually resolved after 2 weeks, but the prognosis is poor if animals have extensive pulmonary lesions or present comatose. If there is dermal contamination, especially with a viscous product like tar, vegetable oil is applied to the affected surface of the stabilized animal. This is followed by a mild detergent bath. Clipping of long or matted hair is useful, and animals should be kept warm.

Methanol Methanol is used in automotive window washer fluids, gasoline antifreezes, canned cooking fuels, and various solvents. It is highly toxic to humans and other primates, causing formic acidosis, CNS disturbances, and retinal damage, with severe toxicosis resulting in death. Methanol is much less toxic to dogs and cats because they are able to efficiently metabolize formic acid using a folatedependent enzyme system. Methanol is, in fact, less toxic in small animals than ethanol. Clinical signs of methanol toxicosis in dogs and cats are similar to those of inebriation with ethanol. Treatment is based on monitoring and symptomatic and supportive care. Treatment of veterinary patients other than primates with ethanol or fomepizole to inhibit alcohol dehydrogenase will intensify clinical signs and is discouraged.

References and Suggested Reading Bischoff K: Diethylene glycol. In Peterson ME, Talcott PA, editors: Small animal toxicology, ed 2, St Louis, 2006a, Elsevier Saunders, p 693. Bischoff K: Methanol. In Peterson ME, Talcott PA, editors: Small animal toxicology, ed 2, St Louis, 2006b, Elsevier Saunders, p 840. Bischoff K: Propylene glycol. In Peterson ME, Talcott PA, editors: Small animal toxicology, ed 2, St Louis, 2006c, Elsevier Saunders, p 996. Dalefield R: Propylene glycol. In Plumlee KH, editor: Clinical veterinary toxicology, St Louis, 2004a, Mosby, p 168. Dalefield R: Ethylene glycol. In Plumlee K, editor: Clinical veterinary toxicology, St Louis, 2004b, Mosby, p 150. Hill AS: Antioxidant prevention of Heinz body formation and oxidative injury in cats, Am J Vet Res 62:370, 2001. Raisebeck MF, Dailey RN: Petroleum hydrocarbons. In Peterson ME, Talcott PA, editors: Small animal toxicology, ed 2, St Louis, 2006, Elsevier Saunders, p 986. Tart KM, Powell LL: 4-Methylpyrazole as a treatment in naturally occurring ethylene glycol intoxication in cats, J Vet Emerg Crit Care 21: 268, 2011. Thrall MA: Ethylene glycol. In Peterson ME, Talcott PA, editors: Small animal toxicology, ed 2, St Louis, 2006, Elsevier Saunders, p 986. Thrall MA, Hamar DW: Alcohols and glycols. In Gupta RC, editor: Veterinary toxicology basic and clinical principles, ed 1, New York, 2007, Elsevier, p 605. Valentine WM: Short-chain alcohols, Vet Clin North Am Small Anim Pract 20:515, 1990.

CHAPTER 

37 

Lead Toxicosis in Small Animals SHARON M. GWALTNEY-BRANT, Mahomet, Illinois

L

ead contamination of residential environments has decreased through removal of lead from residential paints, gasoline, and other household items. Accordingly, the incidence of lead poisoning in small animals has decreased over the last 30 years, and lead now accounts for less than 1% of reported accidental poisonings in pets. Nevertheless, lead intoxication in pets does occur, and the vagueness of clinical signs that frequently accompany lead poisoning can create diagnostic challenges.

Pathogenesis of Lead Toxicosis Sources of Lead Lead may be found in a wide variety of products, including paints, linoleum, caulking and putty compounds, solders, wire shielding, old metal tubing, certain weights (e.g., fishing sinkers, curtain weights), roofing felt, golf balls, ammunition, computer equipment, wine cork covers, pottery glazing, lead-containing toys, and lead arsenate pesticides. In addition, contaminated soil and water can be potential sources of lead. Exposure to organolead from various leaded petroleum products has decreased considerably following legislation restricting the use of leaded gasoline and oil in the United States. The most common source of lead in cases of small animal poisoning is leaded paints from buildings erected before passage of the 1977 legislation requiring that residential paints contain no more than 0.06% (600 ppm) lead. In many cases older leaded paints have been painted over with unleaded paints, and it is estimated that 74% of privately owned homes built before 1980 still contain hazardous amounts of leaded paint. Renovation of these homes results in the generation of paint chips or dust that, if ingested by pets, can result in clinical lead intoxication. Cats may be at increased risk for toxicosis during these situations because of their grooming habits, which can result in significant ingestion of lead-containing particulates that collect in their fur.

Kinetics The degree to which ingested lead is absorbed depends on variables such as the physical form of lead, particle size, and matrix association. In addition, patient variables that influence the degree of lead absorption from the gastrointestinal (GI) tract include age, diet, and preexisting disease. The acidic environment of the stomach favors ionization of the lead, which is then absorbed from the 156

duodenum. Lead shot embedded in soft tissues such as skeletal muscle is not appreciably absorbed and is not an important source of lead toxicosis. Conversely, lead shot that enters areas capable of active inflammation (e.g., joint cavities) may become solubilized by the enzymatic activity of the inflammatory reaction and could subsequently be absorbed. Once absorbed, lead is carried primarily on the red blood cells, with less than 1% to 2% bound to albumin or free in the plasma. Unbound lead distributes widely through tissues, with the highest concentrations found in bone, teeth, liver, lung, kidney, brain, and spleen. Bone serves as a storage depot for lead, which substitutes for calcium in the bone matrix. During times of increased activity of bone remodeling such as fracture repair stored lead may be released from the bone, resulting in toxicosis. Lead crosses the blood-brain barrier and concentrates in the gray matter of the brain. This passage of lead into the brain occurs to a greater extent in young animals. Unbound lead crosses the placenta and is passed through the milk in lactating animals. Most ingested lead is excreted in the feces unabsorbed. Lead in the blood passes through the glomerulus and accumulates in the renal tubular epithelium. During the natural process of sloughing of tubular epithelial cells, the lead is slowly eliminated from the body. Chelation therapy can greatly increase the rate of urinary excretion of lead by allowing the chelated lead to be passed in the urine without entering the tubular epithelium. Lead has a multiphasic half-life because of its distribution into depot areas such as bone and brain. In dogs intravenously administered lead, it has triphasic elimination half-lives of 12 days, 184 days, and 4,591 days.

Mechanism of Action Lead has a wide variety of effects within the body, including interfering and competing with calcium ions, binding to cellular and enzymatic sulfhydryl groups, altering vitamin D metabolism, and inhibiting membraneassociated enzymes. Inactivation of the enzymes ferrochelatase and δ-aminolevulinic acid dehydratase causes impairment in heme synthesis, resulting in red blood cell abnormalities. Anemia can develop with chronic exposure to lead. GI signs in lead-intoxicated patients may be caused in part by alteration of smooth muscle contractility as a result of interference of lead on intracellular calcium-dependent mechanisms. Lead can disrupt the blood-brain barrier of immature animals by interfering

CHAPTER  37  Lead Toxicosis in Small Animals with normal endothelial cell function. Lead decreases cerebral blood flow and alters neuronal energy metabolism and neurotransmission within the central nervous system (CNS). Recently, the propensity of lead to induce oxidative damage through the production of reactive oxygen species has been the subject of much study. Leadinduced inhibition of endogenous antioxidant enzymes such as superoxide dismutase and catalase can lead to injury of cell macromolecules through a variety of oxidative pathways including lipid peroxidation of cellular membranes.

157

Radiography may be helpful in identifying lead opacities within the GI tract. Lead lines, linear opacities in the epiphyses of long bones used to aid in diagnosis of lead toxicosis in humans, are not commonly found in domestic animals.

Diagnosis

Toxic dosages of lead reported for dogs range from 191 to 1,000 mg/kg, depending on the form of lead; 3 mg/kg/ day caused vomiting and behavioral changes in cats. However, these dosages have little clinical relevance in most cases of lead toxicosis in small animals because the amount of lead ingested is rarely determined. Young animals are at greater risk than mature animals because they absorb up to five times more lead following ingestion. Lead absorption is enhanced in animals deficient in calcium, zinc, iron, or vitamin D. Younger cats are thought to be at higher risk for development of leadinduced seizures.

The diagnosis of lead toxicosis can be difficult because the signs most commonly associated with this disease (anorexia, lethargy, vomiting) are nonspecific. Blood lead levels can be measured in a timely fashion and, when evaluated in light of compatible clinical signs, can be helpful in making a diagnosis. The widespread distribution of lead throughout the body can result in fluctuating blood levels, and the level of lead in the blood may not be indicative of the total body burden. Some animals may have fairly high blood lead levels without significant clinical signs, whereas other animals may have significant clinical signs with only moderately elevated blood lead levels. Most dogs and cats have background lead levels of 10 to 15 µg/dl (0.1 to 0.15 ppm); blood lead levels exceeding 30 to 35 µg/dl (0.3 to 0.35 ppm) along with appropriate clinical signs suggest lead toxicosis. Levels greater than 60 µg/dl are generally considered diagnostic for lead toxicosis.

Pathologic Findings

Treatment and Prognosis of Lead Toxicosis

Few gross lesions have been described in dogs and cats with lead toxicosis. Necropsy may reveal the presence of lead objects, especially in the GI tract. Histopathologic findings may include degenerative changes within the white matter of the brain and spongiosis of the cerebrum. In dogs degenerative changes in the kidney and liver may be seen, occasionally associated with intranuclear inclusion bodies.

Management of lead toxicosis entails control of immediate clinical signs, removal of the immediate source of lead intoxication, chelation therapy, supportive care, and removal of other potential sources of lead from the environment. Seizures should be managed with anticonvulsants such as diazepam or barbiturates (see Chapter 230). Similarly, vomiting and diarrhea should be managed, and any fluid and electrolyte abnormalities should be corrected as needed (see Chapter 1).

Lead Toxicity

Clinical Signs and Diagnosis The primary signs seen with lead intoxication in dogs and cats are related to GI upset. Anorexia, vomiting, diarrhea, weight loss, lethargy, and abdominal discomfort have been reported. In cats the most common signs are lethargy and anorexia. Neurologic signs may also occur but are less common than GI signs. Neurologic effects can include behavior changes, ataxia, tremors, seizures, and agitation. Less commonly polyuria, polydipsia, blindness, aggression, dementia, pica, vestibular signs, coma, and megaesophagus (cats) have been reported.

Laboratory and Radiographic Findings In acute lead intoxication very few changes are expected in terms of clinical pathology. Anemia, basophilic stippling, and elevations in nucleated red blood cells (NRBCs) have been reported as indicative of lead toxicosis; however, these abnormalities are not consistently found and are not pathognomonic for lead toxicosis. Basophilic stippling and NRBCs (>40 NRBCs per 100 white blood cells) are more likely to occur in dogs than in cats with lead toxicosis.

Decontamination GI decontamination must occur before chelation therapy because most chelators, with the exception of succimer, actually enhance the absorption of lead from the GI tract. Sulfate-containing cathartics (magnesium sulfate, sodium sulfate) may be administered to aid in emptying the GI tract and to precipitate the lead as lead sulfate, which is poorly absorbed. Large lead-containing objects (e.g., lead sinkers, lead weights) may require removal via endoscopy or gastrotomy/enterotomy if too large to pass using bulking cathartics. When cats are suspected of exposure through grooming, thorough bathing should be performed.

Chelation Therapy Chelation therapy is intended to bind lead into a soluble complex that will be excreted via the urine. Because of the nephrotoxic nature of most chelators, as well as the lead chelate, it is imperative that renal function be assessed before and during chelation and that adequate hydration be maintained during chelation. Chelation of

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SECTION  II  Toxicologic Diseases

asymptomatic animals that have elevated blood lead levels is not recommended because the chelator may increase blood lead levels and precipitate clinical signs. In cases of asymptomatic animals with elevated blood lead levels, decontamination and removal from the source of lead will allow the animal to eliminate the lead at its own pace. Available chelators for lead include calcium disodium ethylenediaminetetraacetic acid (Ca-EDTA), British anti-Lewisite (BAL), penicillamine, and succimer (meso-2,3-dimercaptosuccinic acid). Calcium EDTA Ca-EDTA, the first chelator agent used for lead toxicosis, has an established track record in veterinary and human medicine. Sodium EDTA should not be used for chelation because it will bind serum calcium and cause hypocalcemia. Ca-EDTA is administered parenterally and may cause pain at the injection site. The dosage for dogs is 25 mg/ kg q6h for 2 to 5 days (not to exceed 2 g per dog per day), with each dose divided every 8 hours, diluted to a final concentration of 10 mg of Ca-EDTA per milliliter of 5% dextrose and administered subcutaneously at different sites. Expect clinical improvement within 24 to 48 hours. If further treatment is required after the first 5 days of therapy, a 5-day hiatus is recommended between treatments. Patients should be kept well hydrated during Ca-EDTA therapy. Side effects of Ca-EDTA therapy include lethargy, vomiting, diarrhea, and renal injury. Oral zinc supplementation may minimize the GI side effects. British Anti-Lewisite (Dimercaprol) BAL is occasionally used in combination with Ca-EDTA, especially when significant CNS signs are present. BAL increases both urinary and biliary excretion of lead. The dosage of BAL is 2 to 5 mg/kg intramuscularly every 4 hours for 2 days, then every 8 hours for 1 day, and then every 12 hours until recovery. BAL is contraindicated in animals with hepatic dysfunction, is nephrotoxic, and causes pain on injection. Other potential side effects include vomiting, hypertension, sulfur odor of breath, and seizures. Penicillamine Penicillamine is an oral medication that eliminates the need for painful injections of BAL and Ca-EDTA. It binds essential nutrients such as zinc, iron, and copper, and its chelates may be nephrotoxic. Reported dosage for dogs is 10 to 15 mg/kg q12h PO. Feline dosage is 125 mg per cat orally every 12 hours for 5 days. Adverse effects reported with penicillamine include vomiting, fever, lymphadenopathy, and blood dyscrasias. Long-term administration may result in deficiencies of some essential nutrients such as zinc and copper. Succimer An analog to BAL, succimer has several advantages over BAL, Ca-EDTA, and penicillamine. Succimer can be administered orally or, in vomiting animals, rectally. The dose is 10 mg/kg orally or rectally every 8 hours for 10 days. Succimer is much less likely to cause nephrotoxicity than the other three chelators, and it does not bind essential minerals such as copper, zinc, calcium, and iron.

Succimer does not enhance absorption of lead from the GI tract as do the other chelators, and it has been shown to decrease GI lead absorption in studies with rats. Succimer also has a lower incidence of GI side effects. It does impart a mercaptan odor to the breath, similar to BAL, which some clients may find objectionable.

Additional Therapy Following chelation therapy, blood lead levels may show a rebound within 2 to 3 weeks as a result of redistribution of lead from bone and tissue stores. Provided that this rebound is not associated with significant clinical signs, further chelation is not indicated. However, it is prudent to have the animal’s environment evaluated to be sure the rebound is not caused by reexposure to lead. Supportive care involves providing adequate nutritional support since many animals with chronic lead toxicosis may be in a negative nutritional state because of chronic anorexia and vomiting. Hydration should be maintained, and force- or hand-feeding provided as needed. The use of antioxidants such as pyridoxine (vitamin B6), thiamine (vitamin B1), ascorbate (vitamin C), tocopherol (vitamin E), and N-acetylcysteine have been advocated by some to help minimize the oxidant effects of lead within the body, but controlled studies are lacking as to the efficacy of any of these treatment modalities. The animal’s environment should be examined to identify and remove any additional sources of lead so that the animal does not become reexposed when reintroduced to its environment.

Prognosis Provided that prompt and appropriate care is pursued, including removing the source of lead from the animal’s environment, the prognosis for animals showing mild-tomoderate signs is favorable. Animals showing severe CNS signs or with repeated exposure to lead may merit a more guarded prognosis.

Public Health The relative susceptibility of household pets to lead toxicoses makes them good sentinel animals for the potential for human exposure to lead. Veterinarians treating lead-intoxicated pets should ensure that pet owners are aware of the risk to family members, especially young children, from lead in the environment. Pet owners should be directed to their own health care professionals or public health officials for more information. Infor­ mation on the risks of lead to human health can be found on the Environmental Protection Agency’s website (www.epa.gov).

References and Suggested Reading Casteel SW: Lead. In Peterson ME, Talcott PA, editors: Small animal toxicology, ed 2, St Louis, 2006, Elsevier Saunders, p 795. Gwaltney-Brant SM: Lead. In Plumlee KH, editor: Clinical veterinary toxicology, St Louis, 2004, Mosby, p 204.

CHAPTER  38  Aflatoxicosis in Dogs Gwaltney-Brant SM, Rumbeiha WK: Newer antidotal therapies, Vet Clin Small Anim 32:323, 2002. Knight TE, Kent M, Junk JE: Succimer for treatment of lead toxicosis in two cats, J Am Vet Med Assoc 218:1946, 2001. Knight TE, Kumar MSA: Lead toxicosis in cats—a review, J Feline Med Surg 5:249, 2003.

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Thompson LJ: Lead. In Gupta RC, editor: Veterinary toxicology: basic and clinical principles, St Louis, 2007, Elsevier Academic Press, pp. 438-441.

38 

Aflatoxicosis in Dogs KARYN BISCHOFF, Ithaca, New York TAM GARLAND, College Station, Texas

A

flatoxicosis in dogs was first described as hepatitis X in 1952. The disease was experimentally reproduced in 1955 using contaminated feed and again in 1966 using purified aflatoxin B1. Moldy corn poisoning of swine and turkey X disease were reported in the 1940s. Turkey X disease was linked to aflatoxin in 1961. Aflatoxins are a group of related compounds produced as secondary metabolites of various fungi, including Aspergillus parasiticus, A. flavus, A. nomius, and some Penicillium spp. Aflatoxins are not produced by all strains of these fungi. The most common aflatoxins in grains are named, in part, for their fluorescent color: aflatoxins B1 and B2 fluoresce blue and aflatoxins G1 and G2 fluoresce green. Aflatoxin B1 is the most common and most potent of the aflatoxins. High-energy and high-protein agricultural crops are most often affected. Corn, peanuts, and cottonseed are frequently implicated; however, rice, wheat, oats, sweet potatoes, potatoes, barley, millet, sesame, sorghum, cacao beans, almonds, soy, coconut, safflower, sunflower, palm kernel, cassava, cowpeas, peas, and various spices have been affected. Ingestion of homemade pet foods, moldy garbage, and improperly stored dog foods also has been implicated in aflatoxicosis. Mold can grow on crops in the field or during storage. Mycotoxin synthesis depends on factors such as temperature, humidity, drought stress, insect damage, and handling techniques. Commercial grain is screened routinely for aflatoxins, but contamination of pet food has occasionally resulted from sampling errors. Uneven distribution of mold within a given lot of grain (by analogy, one moldy orange in a large bag of fruit or blue veins in a block of blue cheese) increases the risk of sampling error. A simple black light at 366 nm can be used to detect kojic acid, which fluoresces blue-green and is also produced by many aflatoxinproducing fungi, but its presence does not confirm the

presence of aflatoxins, and its absence does not guarantee that aflatoxin is not present. More sensitive analyses that test directly for aflatoxins use enzyme-linked immunosorbent assays, high-performance liquid chromatography (HPLC), and liquid chromatography/mass spectrometry. Many pet food companies currently sample each lot of grain before use and sample postproduction batches of pet food for testing to minimize the problem of sampling error.

Toxicity Dogs and cats are considered very sensitive to aflatoxin (Newbern and Butler, 1969). The oral median lethal dose (LD50) for aflatoxins in dogs ranges from 0.5 to 1.8 mg/ kg. It is difficult to determine the total dose of aflatoxin in field cases when detailed information on the amount ingested and period of exposure is not usually available. Exposure to dog food containing as low as 60 ppb of aflatoxin for 60 or more days has been implicated in aflatoxicosis. The experimental oral LD50 for aflatoxin in cats is 0.55 mg/kg. There is anecdotal evidence of aflatoxicosis in cats known to have consumed contaminated dog food for approximately 3 months. The cats were lethargic and had vomiting and diarrhea. One of the affected cats died and had liver lesions compatible with aflatoxicosis. Factors such as dose, genetic predisposition, and concurrent disease influence the course of aflatoxin poisoning. Generally, younger animals, particularly males, seem to be more susceptible. Aflatoxin-related deaths in pups sucking a clinically healthy dam have been reported. Pregnant and whelping bitches also appear to be more susceptible. Early castration decreases mortality in males of some species. Low dietary protein enhances hepatocyte damage, whereas nutritional antioxidants, vitamin A, and carotene decrease it.

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Toxicokinetics Aflatoxins are highly lipophilic and are absorbed rapidly and almost completely in the duodenum. Aflatoxins entering the portal circulation are highly protein bound. The unbound fraction is distributed to the tissues, with the highest concentration occurring in the liver. The liver is the primary metabolic site for aflatoxins, although some metabolism occurs in the kidneys and small intestine. Phase I metabolism of aflatoxin B1 by cytochrome P-450 enzymes produces aflatoxin M1 and the reactive intermediate aflatoxin B1 8,9-epoxide. During phase II metabolism aflatoxin B1 8,9-epoxide is conjugated to glutathione in a reaction catalyzed by glutathione S-transferase. Metabolites of aflatoxin are excreted in both urine and bile. Dogs excrete primarily aflatoxin M1 in the urine. More than 90% of urinary excretion of metabolites occurs within 12 hours of dosing in dogs, and aflatoxin metabolites are no longer detectable by 48 hours. Conjugated aflatoxin is excreted predominantly in the bile. Approximately 1% of an oral dose of aflatoxin is excreted as aflatoxin M1 in the milk in dairy cattle.

Mechanism of Action Phase I metabolism of aflatoxin B1 produces the highly reactive electrophile aflatoxin B1 8,9-epoxide, which binds readily to cellular molecules, including nucleic acids, proteins, and subcellular organelles. Formation of deoxyribonucleic acid (DNA) adducts modifies the DNA template, altering the binding of DNA polymerase and thus affecting replication. Effects on ribosomal translocase inhibit protein production. These changes lead to necrosis of hepatocytes and other metabolically active cells such as renal tubular epithelium. Coagulopathy results from decreased prothrombin and fibrinogen production. Excretion of aflatoxin adducts is slow compared with the parent compound and other metabolites. Aflatoxins are classified by the International Agency for Research on Cancer as class I human carcinogens. Hepatocellular carcinoma has been associated with chronic aflatoxin exposure and concurrent infection with hepatitis B virus. Aflatoxins are also known carcinogens in ferrets, ducks, trout, swine, sheep, and rats, but are not known to be carcinogenic in dogs or cats. Aflatoxin-induced neoplasia is rare in domestic animals in general, probably due to the limited life spans of most domestic species.

Clinical Signs Although aflatoxicosis may be caused by prolonged exposure to contaminated food, the presentation in small animals is usually acute. Toxicosis has been reported in dogs after ingesting contaminated food for as long as 90 to 120 days before onset of clinical signs. The course of clinical aflatoxicosis is usually a few days but can be protracted for up to 2 weeks. Dogs can and do survive when the concentration is low or exposure is limited. Experimentally poisoned cats died of aflatoxicosis within a few days of onset of clinical signs, but in the anecdotal cases described above some affected cats survived.

The most commonly reported early clinical signs of aflatoxicosis in dogs include feed refusal or anorexia, weakness and obtundation, vomiting, and diarrhea. A few die unexpectedly without showing clinical signs. As the toxicosis progresses, dogs become icteric and can have bilirubinuria. Hepatic encephalopathy has been reported. Many dogs die from disseminated intravascular coagulation, evidence of which includes melena or frank blood in the feces, hematemesis, petechial hemorrhages, and epistaxis. Hemorrhage into the calvarium has been associated with seizures.

Diagnosis Differential diagnoses for dogs in pet food–related cases of aflatoxicosis can include leptospirosis, parvovirus, anticoagulant rodenticide toxicosis, and a variety of hepatotoxic agents, including acetaminophen, cyanobacterial toxins, mushroom toxins, and cycad palms, as well as phosphine and iron. Diagnosis of aflatoxicosis is often based on history, clinical signs, clinical pathology findings, and postmortem changes. Laboratory testing of dog food or other implicated material is helpful in confirming the diagnosis, but often all the contaminated food has been consumed by the time the animal becomes clinically affected. It is important to retain bar codes and lot numbers from containers of pet food when contamination is suspected because this information is critical for case tracking and in product recalls. Some laboratories test for aflatoxin M1 in the urine, although urinary metabolites are no longer detectable 48 hours postexposure in dogs. Some laboratories have had success analyzing serum or liver for aflatoxin, but due to the low concentrations ingested and rapid metabolism and excretion, this too is of limited diagnostic use if negative.

Clinical Chemistry Complete blood count, serum chemistry including bile acids, and urinalysis are recommended to support the diagnosis of aflatoxin poisoning and rule out other causes of liver failure. Total bilirubin is increased in aflatoxicosis. Alanine aminotransferase, alkaline phosphatase, and aspartate aminotransferase are frequently elevated, but the elevations do not correlate well with the magnitude of hepatic damage. Liver function tests have been used to support the diagnosis of aflatoxicosis, including decreased serum albumin, protein C, antithrombin II, and cholesterol, and increased prothrombin time.

Postmortem Findings Diagnosis of aflatoxicosis is often made on necropsy. Common gross pathology findings include icterus; hepatomegaly, which could be mild; abdominal or pleural effusions; gastrointestinal hemorrhage; and multifocal petechia and ecchymosis. The primary histologic changes of canine aflatoxicosis are associated with the liver, although necrosis of the proximal convoluted renal tubules has been reported. Liver lesions associated with acute aflatoxicosis include

CHAPTER  38  Aflatoxicosis in Dogs centrilobular necrosis, canalicular cholestasis, mild inflammation, and fatty degeneration of hepatocytes, which may contain one to many lipid vacuoles. Similarly, dogs with subacute toxicosis have hepatocytic fatty degeneration, canalicular cholestasis, and multifocal-to– locally extensive hepatic necrosis, often associated with neutrophilic inflammation and hepatocyte regeneration. However, as aflatoxicosis progresses, bridging portal fibrosis and bile duct proliferation become more prominent, and the central vein can be obscured by dilated sinusoids. Chronic aflatoxicosis is characterized by less fatty degeneration of hepatocytes and marked fibrosis and regeneration, disrupting the hepatic architecture. Lesions reported in cats are somewhat different. Experimentally affected cats had hepatomegaly with multifocal petechia. Hepatocytes contained mostly glycogen with minimal lipid. Bile duct hyperplasia was noted in cats that survived clinical aflatoxicosis for more than 72 hours.

Prognosis and Management The prognosis for small animals with clinical aflatoxicosis is guarded, with a mortality rate of approximately two out of three affected dogs. Animals with severe clinical signs usually respond poorly to treatment. Early intervention, especially in preclinical exposed animals, greatly improves the chance of survival. Removal of contaminated food is key to survival. The food should be replaced with a high-quality protein diet. As with most other conditions, patient assessment and stabilization are the first steps in management. Oral activated charcoal is appropriate to limit absorption in cases of recent high-dose exposure, as can occur when moldy garbage is ingested. Supportive care includes correcting hydration and electrolyte imbalances with intravenous fluids. B-vitamins and dextrose can be added to fluids. Vitamin K1 therapy reportedly decreased clinical coagulopathy within 72 hours. Plasma transfusions have been used to improve clotting profiles in severely affected dogs. Gastroprotectants such as sucralfate and famotidine, and sometimes parenteral nutrition, are necessary in animals with severe gastroenteric signs. Vitamin E, a fat-soluble antioxidant, and liver protectants such as silymarin have been used clinically and experimentally. Silymarin is a mix of flavonolignans, such as silybin, from milk thistle (Silybum marianum). Silymarin decreased the hepatotoxic effects of dietary aflatoxin B1 in experimental chickens. One proposed mechanism of action for silybin is decreasing the metabolism of aflatoxin B1 to the epoxide form. S-adenosylmethionine (SAMe) has also been used

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clinically as a hepatoprotectant in the treatment of aflatoxicosis. Sulfhydryl groups on SAMe are believed to bind aflatoxin B1 8,9-epoxide. Although milk thistle and SAMe are considered liver supportive, combined therapy in patients with prolonged exposure to dietary aflatoxin could prevent aflatoxin adducts from being excreted. N-acetylcysteine, given parenterally, has been used in severely intoxicated dogs. It is known to increase cytosolic and mitochondrial glutathione and may act directly as a free-radical scavenger. Experimentally N-acetylcysteine has been shown to enhance elimination of aflatoxin B1 and prevent liver damage in poultry. The antischistosomal drug oltipraz has been used to treat aflatoxicosis in humans and experimental animals. Oltipraz inhibits phase I enzymes, CYP1A2 in particular, that metabolize aflatoxin B1 to the epoxide form. It also induces phase II enzymes, including glutathione S-transferase, to facilitate conjugation of aflatoxin B1 8,9epoxide. This drug protects against hepatocarcinogenesis in rats. Oltipraz has not been used in veterinary medicine to the authors’ knowledge.

References and Suggested Reading Bastianello SS et al: Pathological finding in a natural outbreak of aflatoxicosis in dogs, Onderstepoort J Vet Res 64:635, 1987. Bingham AK et al: Identification and reduction of urinary aflatoxin metabolites in dogs, Food Chem Toxicol 42:1851, 2004. Bruchim Y et al: Accidental fatal aflatoxicosis due to contaminated commercial diet in 50 dogs, Res Vet Sci 93(1):279-287, 2012. Garland T, Reagor J: Chronic canine aflatoxin and management of an epidemic. In Panter KE, Wierenga TL, Pfister JA, editors: Poisonous plants: global research and solutions, Wallingford, Oxon, UK, 2007, CABI Publishing. Meerdink GL: Mycotoxins. In Plumlee KH, editor: Clinical veterinary toxicology, St Louis, 2004, Mosby, p 231. Newbern PM, Butler WH: Acute and chronic effects of aflatoxin on the liver of domestic and laboratory animals: a review, Cancer Res 29:236, 1969. Stenske KA et al: Aflatoxicosis in dogs and dealing with suspected contaminated commercial foods, J Am Vet Med Assoc 228:1686, 2006. Tedesco D et al: Efficacy of silymarin-phospholipid complex in reducing the toxicity of aflatoxin B 1 in broiler chickens, Poult Sci 83:1839, 2004. Valdivia AG et al: Efficacy of N-acetylcysteine to reduce the effects of aflatoxin B 1 intoxication in broiler chickens, Poult Sci 80:727, 2001. Wang JS et al: Protective alterations in phase 1 and 2 metabolism of aflatoxin B 1 by oltipraz in residents of Qidong, People’s Republic of China, J Natl Cancer Inst 91:347, 1999.

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WEB CHAPTER 

5 

Nephrotoxicants WILSON K. RUMBEIHA, Ames, Iowa MICHAEL J. MURPHY, Stillwater, Minnesota

T

he kidney is a frequent target for toxic chemicals (Web Box 5-1). Pet food or pet treat recalls associated with renal damage have prompted further consideration of nephrotoxicity in dogs and cats. This chapter provides an overview of the more common nephrotoxicants and includes diagnostic considerations for nephrotoxicosis and a possible diagnostic approach for veterinary patients at the clinic or at the time of postmortem evaluation.

Pathophysiologic Considerations Renal failure is common, but only a small percent of cases of renal insufficiency are caused by chemical toxicants. The kidney constitutes only 1% of body weight in most mammals but receives about 25% of normal cardiac output. This high cardiac output exposes the kidney to many substances foreign to the body, including food additives, drugs, and other foreign chemicals (i.e., xenobiotics). These chemicals often reach relatively high concentrations in the renal ultrafiltrate. Kidneys also possess unique transporters that concentrate toxicants in this organ. In many instances a high concentration of xenobiotics is associated with nephrotoxicity, but other factors may also play a role. The kidneys also conduct substantial metabolism of endogenous and exogenous chemicals. Bioactivation of some chemicals can lead to nephrotoxicity, although metabolism of most chemicals leads to detoxification. Animals may be predisposed to nephrotoxicity. Young and geriatric animals generally are believed to be more susceptible to the nephrotoxic effects of xenobiotics. Young animals may not have fully developed detoxifying enzyme systems, and these systems may be diminished in geriatric animals. Malnutrition, dehydration, shock, preexisting renal conditions, and concurrent exposure to multiple nephrotoxins are some of the factors that may influence the potential for nephrotoxicity. Causes of acute renal failure in dogs and cats generally can be classified as hemodynamic-related, infectious, or toxic. Toxicant-induced acute renal failure is most commonly encountered in small animals. Younger animals are the most frequently involved. In dogs the most common causes of nephrotoxicosis are ethylene glycol (EG), nonsteroidal antiinflammatory drugs (NSAIDs), cholecalciferol (CCF), and aminoglycoside antibiotics. In cats the most common causes of nephrotoxicity are EG, CCF, and Easter lilies. An expanded list of known nephrotoxins is presented in Web Box 5-1. Only the most common causes of nephrotoxicosis are discussed here,

with additional comments directed toward the issue of pet food–related toxicosis.

Establishing a Diagnosis of Nephrotoxicosis The causes of acute renal failure in dogs and cats are so extensive (see Web Box 5-1) that refinement of the etiologic diagnosis usually relies on the history, clinical signs, physical examination, and results of toxicology laboratory testing. The goal in toxicology cases is establishing a cause. Often the facts necessary for such a conclusion are not evident, and morphologic, presumptive, or clinical diagnoses are made. Two tenets of toxicology are exposure and dose response. Pets must first be exposed to a toxicant for it to cause a toxicosis. Further, they must be exposed to a potentially toxic dose and have the adverse effect previously demonstrated for that toxicant before a clinician can reach a conclusive diagnosis of a toxicosis. In veterinary patients the history and specific laboratory tests are normally used to determine whether an animal has been exposed to a nephrotoxin. The history is often the less reliable of the two methods. For example, does the owner know if his or her pet was exposed to a potentially toxic dose of a drug (NSAIDs, aminoglycosides) with demonstrated nephrotoxicity? Specifically one might inquire if EG, aminoglycosides, or Lilium spp. of plants are present in or around the home. If so, the next step is to confirm or rule out exposure by specific toxicology laboratory testing when available in order to arrive at an etiologic diagnosis. Tests should identify the parent compound and/or its metabolites. Quick screening tests are often used to make treatment decisions, but analytic laboratory tests may be required to confirm an etiologic diagnosis. The availability of such confirmatory tests may be investigated by contacting an accredited veterinary diagnostic laboratory (see www.aavld.org or www.abvt.org). Serum or urine is usually the specimen of choice in live animals. For example, although calcium oxalate crystals in urine might be present in toxicoses in a dog or cat with renal failure, this finding is nonspecific; therefore serum and/or urine glycolic acid or EG concentrations would better support a diagnosis of EG exposure. Similarly, serum concentrations of 25-hydroxycholecalciferol are used to indicate exposure to CCF; serum or urine concentrations of NSAIDs and aminoglycosides may be used for the same purpose. The clinical signs, physical examination findings, and routine laboratory tests may be instructive. Clinical signs of renal toxicosis often include gastrointestinal upset, e29

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WEB BOX 5-1  Known Nephrotoxins and Other Causes in the Differential Diagnosis of Acute and Chronic Renal Failure in Dogs and Cats Household Products and Pesticides • Cholecalciferol (see text) • Sodium fluoride, superphosphate fertilizer • Rodenticides (e.g., phosphorus, thallium) • Herbicides (e.g., Paraquat, diquat) Industrial Compounds • Ethylene glycol (see text) • Diethylene glycol • Chlorinated hydrocarbons (e.g., carbon tetrachloride, chloroform, hexachlorobutadiene) • Melamine, cyanuric acid Heavy Metals • Mercury, cadmium, lead, arsenic, chromium Pharmaceuticals, Diagnostic Aids, and Anesthetics • Aminoglycoside antibiotics (see text) • Cephalosporins (e.g., cephaloridine, cefazolin, cephalothin) • Polymyxins • Sulfonamides (e.g., sulfapyridine, sulfathiazole,   sulfadiazine) • Amphotericin B • Nonsteroidal antiinflammatory drugs (see text) • Lithium • Phosphorus-containing urinary acidifiers • Cyclosporine • Antineoplastics (e.g., methotrexate, cisplatin) • Methoxyflurane • Chelating agents (e.g., D-penicillamine, ethylenediaminetetraacetic acid [EDTA])

central nervous system depression, cardiopulmonary involvement, anuria, oliguria, and polydypsia, as observed with EG toxicosis. For example, signs of NSAID toxicosis often may include gastrointestinal bleeding and ulceration, acidosis, and mild elevations of hepatic enzymes. Clinical signs of CCF toxicosis include dark bloody feces, oliguria, or polyuria. Ultrasound may show renal cortical damage. Involvement of other organ systems may provide additional diagnostic leads as to the toxicant involved. Laboratory testing often is required to establish the adverse effects of toxicity. Obviously increased serum urea nitrogen and creatinine concentrations, along with urinalysis, are used clinically to indicate renal injury. Urine specific gravity, cellular casts, and presence of crystals can aid in the diagnosis of acute nephrotoxicity. Calcium abnormalities are common with EG and with CCF toxicosis. Values within the normal range for all these tests would be interpreted as arguing against a diagnosis of nephrotoxicity. Such findings may not exclude exposure to a subtoxic dose of a nephrotoxic chemical. When a patient dies or is euthanatized, necropsy and histopathology findings can in some instances support an argument of exposure to a toxicant. For example, the finding of EG solution, CCF rodenticide bait,

• • • •

Radiologic contrast media Gold salts Diuretics (e.g., thiazides, furosemide) Vitamin D3 analog (e.g., psoriasis medications)

Natural Toxins • Easter lily (Lilium longiflorum [see text]) • Mycotoxins (e.g., ochratoxin A, citrinin) • Snake venom • Mushrooms (e.g., amatoxins, orellanine) Ischemic Renal Injury • Severe volume depletion • Hemolytic compounds (e.g., zinc toxicosis, acetaminophen toxicosis in cats) • Thromboembolism of renal arteries in cats Infectious Conditions • Acute nephritis (e.g., leptospirosis) or pyelonephritis • Chronic tubulointerstitial nephritis Primary Renal Diseases • Chronic renal disease (idiopathic) • Amyloidosis • Familial renal disease Obstructive Uropathy • Melamine-cyanurate crystals Ruptured Urinary Conduit

medications, or lily plant parts supports exposure to the respective toxicants. The observation of birefringent crystals histologically is very suggestive of EG exposure, but even in this case the findings are not specific. For example, such crystals can occur following exposure to soluble oxalates (Oxalis spp. plants). Similarly renal mineralization is compatible with, but not specific for, CCF exposure. Renal mineralization can be present in hypercalcemia of malignancy, for example. Thus the diagnosis of nephrotoxicity must rely on evidence of exposure to a sufficient quantity of a toxic chemical, clinical or analytic laboratory findings that confirm or strongly suggest toxicosis, and clinical or necropsy findings of compatible illness. These same principles should be applied to the diagnosis of emerging toxicities, such as melamine-cyanuric acid intoxication, associated with pet foods, and the recently recognized Fanconi syndrome in dogs that have consumed dog treats.

Ethylene Glycol and Diethylene Glycol EG is a sweet-tasting liquid that is widely used as a solvent in several commercial products such as antifreeze, paints,

WEB CHAPTER  5  Nephrotoxicants and polishes. Antifreeze is the most common source of EG exposure in pets. Commercial antifreeze contains about 50% to 95% EG. EG toxicosis is reported all year round but is more prevalent in late fall and early spring. Toxicosis most commonly occurs within hours of ingestion. EG is rapidly absorbed from the gastrointestinal tract, with peak plasma concentrations occurring about 2 to 3 hours after ingestion. The plasma half-life of EG in small animals is about 3 hours; thus about eight elimination half-lives occur in a day. Diethylene glycol (DEG) is also a widely used organic solvent in commercial products. Antifreeze is the most common source of EG exposure in pets. EG is metabolized predominantly in the liver. It is metabolized from EG to glycoaldehyde by alcohol dehydrogenase. Glycoaldehyde is metabolized to glyoxalate by aldehyde dehydrogenase. Glyoxalate is finally converted to oxalate, glycine, and formate. The conversion of EG to glycoaldehyde and of glycoaldehyde to glycolate requires nicotinamide adenine dinucleotide (NAD) as a cofactor. Lactate dehydrogenase and glycolic acid oxidase catalyze the conversion of glycolate to glyoxylate. The conversions of EG to glycoaldehyde and of glycolate to glyoxalate are the rate-limiting steps in the metabolism of EG. EG itself is mildly toxic, but its metabolic products, especially glycoaldehyde, glyoxalate, and oxalate, are potentially lethal; thus treatment is aimed at preventing this metabolism from taking place or at least containing it.

Toxicity and Signs Cats are more sensitive to EG toxicity than dogs. The minimum lethal dose of undiluted EG is 1.4  ml/kg in cats and 4.4  ml/kg in dogs. The clinical presentation of EG toxicosis in dogs and cats is often divided into three phases. The first phase generally occurs 0.5 to 8 hours after ingestion of a toxic dose. The predominant clinical signs in phase 1 are vomiting, depression, and ataxia (an almost “drunken” appearance). These signs are attributed to EG and its metabolite, glycoaldehyde. The latter reaches a peak plasma concentration 6 to 12 hours after EG ingestion. The second phase is generally 8 to 24 hours after ingestion. The predominant clinical signs in phase 2 are depression, anorexia, tachycardia, and pulmonary congestion. If the animal survives these two phases, the third phase begins about 25 to 72 hours after ingestion. The predominant signs during the third phase include vomiting, anuria or oliguria, and uremia, reflecting acute renal failure. Neurologic signs, including seizures, may be observed in some severe cases of intoxication. Laboratory tests are altered during these phases (see Chapter 36). An increased anion gap, hyperosmolality, elevated blood urea nitrogen (BUN) and creatinine, hypocalcemia, isosthenuria, and calcium oxalate monohydrate crystalluria are the biochemical hallmarks of EG toxicosis in small animals. Glycolic and lactic acids are the main causes of acidosis in EG toxicosis. Lactic acid formation is favored by an increase in the ratio of nicotinamide adenine dinucleotide hydrogen (NADH) to NAD, which drives the lactate dehydrogenase reaction.

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Acidosis can be detected as early as 3 to 4 hours after EG ingestion. Acute renal failure is the consequence of the direct toxic effects of EG metabolism on renal epithelial cells and of the tubular obstructive effects of calcium oxalate crystals. Hyperechoic renal cortices may be evident on ultrasound examination of the kidneys. Urinary bladder size may be small, indicating reduced urine formation.

Treatment of Ethylene Glycol Toxicosis Treatment of EG toxicosis is most successful if initiated within 12 hours of ingestion (see Chapters 23 and 36 for details of therapy). Gastric decontamination should be initiated by inducing emesis, followed by administration of activated charcoal, provided the patient is presented within 2 to 3 hours of ingestion. Previously intravenous ethanol was the treatment of choice for EG toxicosis, but with approval of 4-methylpyrazole (4-MP) for EG toxicosis in dogs the situation has changed. Now 4-MP is the drug of choice in both dogs and cats. Cats are responsive to 4-MP at a dosage that is 3 times higher than that for dogs. In dogs the first dose is given as a 5% solution at 20 ml/kg intravenously. The second dose is given at 15 mg/kg 12 to 24 hours after the first dose. The third dose, if necessary, is given at 5 mg/kg 36 hours after the first one. Hemodialysis is a referral option in some areas and may be beneficial if started up to 24 hours after EG ingestion. However, dialysis is most effective when initiated within 3 to 4 hours of exposure. Further studies are needed to determine if hemodialysis removes the more toxic metabolites of EG, the time frame over which this therapy is beneficial, and whether or not 4-MP can be used in conjunction with hemodialysis. Because most patients are presented for treatment late in the course of clinical disease, the mortality rate of EG toxicosis is higher than 70%. Treatment procedures for EG-induced nephrotoxicosis are summarized in Web Box 5-2 and Chapter 36. DEG is also rapidly absorbed from the gut, with peak plasma concentrations reached in 1 to 2 hours. It is metabolized in the liver to its sole metabolite, 2-hydroxyethoxyacetic acid. Oxalate is not a metabolite of pure DEG. DEG is excreted in urine as both parent compound and metabolite. Toxicosis of DEG is characterized by renal failure, acidosis, and cardiac irregularities. The diagnosis of DEG nephrotoxicosis is difficult and can be supported by its presence or that of its metabolite in blood or urine. Ethers of EG such as EG butyl ether, a component of glass cleaners, may also cause oxalateinduced renal failure.

Aminoglycoside Antibiotics Aminoglycoside antibiotics are the most frequent class of drugs associated with nephrotoxicosis in dogs and cats. Gentamicin, tobramycin, amikacin, kanamycin, and netilmicin are used for the treatment of gram-negative infections but have a narrow therapeutic index and should be used with caution in animals at high risk for

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WEB BOX 5-2  Summary of General and Supportive Treatment of Toxic-Induced Acute Renal Failure Keep the Patient Alive If Presented Less than 3 Hours After Ingestion • Emesis Apomorphine hydrochloride, 0.02-0.04 mg/kg IV or IM   (if available) Syrup of ipecac, 2-6 ml PO or 3% hydrogen peroxide, 5 ml/dog or cat • Activated charcoal Acta-Char, 1-4 g/kg or Charcodote, 6-12 ml/kg • Cathartics Mineral oil, 10-50 ml/dog, 10-25 ml/cat q12h PO or Sodium sulfate, 1 g/kg Supportive Treatment • Hyperkalemia and acidosis Sodium bicarbonate, 10 mg/kg q8-12h PO or BW (kg) × 0.3 × base deficit or (20–TCO2) in mEq; half of this dose is given slowly IV in 15-30 min

• Fluid therapy Ideal fluid is 0.9% normal saline, or 2.5% dextrose in 0.45% saline; to enhance urinary excretion of toxin, correct electrolyte imbalances, manage moderate acidosis, dilute waste products normally excreted by the kidneys • Diuretics to enhance toxin and metabolic waste products excretion Furosemide (avoid in gentamicin nephrotoxicity),   2-4 mg/kg as needed IV, IM, SC Mannitol, 1 g/kg of 5%-25% solution IV (avoid in pulmonary edema) • Antiemetics or H2 blockers to correct uremia-induced vomiting Metoclopramide, 0.2-0.5 mg/kg IV, IM, q6-8h or Cimetidine, 2.5-5 mg/kg IV q8-12h • Give proper nutrition: glucose supplementation, low-quantity but high-quality protein • Peritoneal dialysis or hemodialysis if azotemia is progressive despite fluid therapy Run Toxicology Tests to Identify and Remove Specific Underlying Causes • Withdraw offending drug; eliminate sources (e.g., feed); give chelation therapy in cases such as exposure to heavy metals

BW, Body weight; IM, intramuscularly; IV, intravenously; PO, orally; SC, subcutaneously.

nephrotoxicity, especially those suffering from dehydration or receiving diuretic (furosemide) therapy. Aminoglycosides are not metabolized in vivo and, because of their low molecular weights and high water solubility, are excreted almost exclusively through the urine. In vivo these antibiotics easily ionize to cationic complexes that bind to anionic sites on the epithelial cells of the proximal tubules. Following binding, the drugs are internalized by pinocytosis. Renal cortical concentrations of aminoglycoside antibiotics may exceed plasma concentration by tenfold. In general, the toxicity of aminoglycoside antibiotics correlates positively with the number of ionizable groups on the drug. For example, neomycin with six ionizable groups is extremely nephrotoxic and is not used systemically. Gentamicin, tobramycin, amikacin, kanamycin, and netilmicin all have five ionizable groups and a high potential for renal toxicity when used systemically. Aminoglycoside antibiotics can cause acute tubular necrosis through a variety of mechanisms. Aminoglycoside-induced renal failure is most commonly iatrogenic in origin. Animals receiving aminoglycoside therapy should be monitored for renal injury with periodic urinalyses (specifically evaluation for protein and casts) and with serial determinations of serum urea nitrogen and creatinine. The mortality rate in monitored animals is low. Clinically affected animals may have polyuria, proteinuria, azotemia, and high urinary N-acetyl-BD-glucosaminidase activity. Nephrotoxicity often can be

prevented by increasing the dosage interval by a factor related to the serum creatinine concentration. For ex­­ ample, if the recommended dosing interval is 8 hours and the serum creatinine concentration is 3 mg/dl, the dosing interval should be extended by 3 × 8 hours = 24 hours. The treatment of aminoglycoside-induced nephrotoxicosis consists of withdrawing aminoglycoside therapy and then initiating other nonspecific symptomatic treatment measures (see Chapter 23).

Nonsteroidal Antiinflammatory Drugs NSAIDs have diverse chemical structures but similar pharmacologic effects. These drugs are broadly classified into two groups: the carboxylic acids and the enolic acids. Aspirin, indomethacin, tolmetin, sulindac, naproxen, ibuprofen, and flunixin meglumine belong to the carboxylic acid group. Phenylbutazone and piroxicam belong to the enolic acid group. Additional classification is based on inhibition of specific enzymes (e.g., COX-1 or COX-2 inhibition). Many NSAIDs are sold over the counter and are widely available in homes. Because of the wide availability of these medications, their accidental ingestion is encountered commonly in small animal practice. Acute toxicosis occurs more frequently in dogs than in cats. Iatrogenic NSAID toxicosis is encountered occasionally, is often chronic, and may be the result of the higher sensitivity of some animals than others to these drugs. Dehydration,

WEB CHAPTER  5  Nephrotoxicants poor renal perfusion (as in heart failure), and concurrent treatment with corticosteroids may increase the likelihood of toxicosis. In general, NSAIDs are well absorbed orally and predominantly metabolized in the liver. Some NSAIDs are metabolized via glucuronidation. Cats are especially sensitive to the toxicosis of NSAIDs because they have a reduced capacity for glucuronic acid conjugation. Nephrotoxicity is certainly not the only adverse effect of NSAIDs. In particular, hepatopathy and gastrointestinal erosion and ulceration pose serious risks to veterinary patients. Gastric and intestinal toxicity often creates signs of anorexia, vomiting, diarrhea, melena, and anemia. Furthermore, these drugs can enhance bleeding tendencies and, especially in cats, also predispose to methemoglobinemia. The nephrotoxic effects of these compounds are discussed in the following paragraphs. The nephrotoxic and antiinflammatory effects of NSAIDs pertain to the ability of these drugs to inhibit prostaglandin production. Most NSAIDs inhibit cyclo­ oxygenase, the enzyme responsible for conversion of arachidonic acid to endoperoxides. Endoperoxides are intermediates in prostaglandin synthesis. Ibuprofen, mefenamic acid, and indomethacin reversibly inhibit cyclooxygenase, whereas aspirin and phenylbutazone inhibit it irreversibly. Some NSAIDs may block prostaglandin receptors. Ingestion of large doses of NSAIDs may induce acute renal failure. Chronic exposure to toxic doses of NSAIDs may cause renal papillary necrosis. Dehydrated animals, animals in shock, and those with preexisting renal disease are most vulnerable to NSAID-induced nephrotoxicity. Diagnostic tests of value include a careful history, examination of the stool for melena, urinalysis, tests of renal function, serum biochemistries reflecting liver injury, and a complete blood count. The treatment of acute NSAID toxicosis should involve gastrointestinal decontamination with emetics and activated charcoal (see Chapter 27), intravenous fluid therapy to correct acidosis and maintain urine output, and other life-support measures as needed (see Web Box 5-2). The gastrointestinal tract should be treated for potential ulceration and protected from further injury with drugs such as famotidine, omeprazole, sucralfate, or misoprostol (see Chapter 123). In chronic toxicosis the offending drug should be withdrawn. The prognosis is generally good in acute renal injury but is guarded to poor in chronic exposure situations when renal papillary necrosis has occurred.

Cholecalciferol CCF (vitamin D3) is marketed as a rodenticide as well as a nutritional supplement and a treatment for psoriasis. Toxicosis from this compound is related to disruption of calcium homeostasis. CCF toxicosis should always be considered whenever acute renal failure is observed in pets. Rat baits containing CCF are sold over the counter as Quintox, Rampage, Rat-B-Gone, and other trade names. Poisoning in pets occurs after accidental or intentional bait ingestion. Ingestion (including licking) of human psoriasis medications that contain synthetic vitamin

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D, analogs such as calcipotriol and calcipotriene, can lead to vitamin D toxicosis. These creams are dispensed under trade names that include Dovonex, Taclonex, and Psorcutan. Although the median lethal dose (LD50) of CCF in dogs is widely reported to be 43 to 88 mg/kg, the experience in the author’s laboratory is that as little as 10 mg/kg given once orally can be lethal. Normal dogs that ingest as little as 4 to 6 mg/kg of CCF once may become sick. Clinically normal dogs that ingest single doses of 2 mg/ kg of CCF may develop serum calcium concentrations greater than 12.5 mg/dl. CCF is rapidly absorbed after ingestion and then transported to the liver. CCF is stored and then slowly metabolized to 25-hydroxy-vitamin D3 (25-OH-D3). Then 25-OH-D3 is metabolized to calcitriol (1,25-dihydroxyvitamin D3), the active metabolite of CCF in the kidney. Calcitriol stimulates calcium uptake from the gut. In conjunction with parathyroid hormone, calcitriol mobilizes calcium from bone tissue and conserves calcium by enhancing calcium resorption from distal tubules. It is known that high serum concentrations of 25-OH-D3 stimulate the 1,25-OH-D3 receptors and trigger similar physiologic events. The combined result of these effects is hypercalcemia and hyperphosphatemia, an important point in the differential diagnosis of hypercalcemia or recent onset. Calcification of soft tissues, especially the kidneys, occurs when the calcium and phosphorous product (in milligrams per deciliter) exceeds 60. Renal calcification starts 12 to 18 hours after ingestion, but peak elevation may not be observed until 48 to 72 hours after CCF exposure, coinciding with elevations in serum BUN and creatinine. Early signs of CCF toxicosis include anorexia, vomiting, melena, and depression. If there is no known history of ingesting bait or psoriasis cream, the clinical signs of toxicosis may be relatively nonspecific. Signs of hypercalcemia, including polydipsia, polyuria, and vomiting, may be evident. Isosthenuria is typical. Hypercalcemia and hyperphosphatemia should prompt consideration of vitamin D toxicosis, especially if renal function is still normal. However, other causes of hypercalcemia must be considered, including malignancies (lymphoma, perianal adenocarcinoma, parathyroid tumors), chronic renal failure, and hypoadrenocorticism.

Treatment of CCF Toxicosis Treatment of hypercalcemia related to CCF toxicosis can be challenging (see Chapter 31). The mortality rate is high because animals are often presented late in the course of disease after substantial renal injury has occurred. Nonspecific gastrointestinal tract decontamination procedures should be attempted if the animal is presented within 2 to 3 hours of known ingestion (see Chapter 23). Specific therapy is aimed at lowering blood calcium to 8 to 11 mg/dl with the use of salmon calcitonin or another drug. The recommended dosage of calcitonin is 4 to 6 units subcutaneously every 4 to 6 hours until the calcium stabilizes (at least 3 weeks). Pamidronate disodium given at 1.2 mg/kg by a slow saline infusion over 2 hours has been shown to be an effective alternative therapy

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to calcitonin. Two intravenous infusions of pamidronate given 8 days apart have been shown to reverse hypercalcemia of 16 mg/dl to normal for 28 days. Other biphosphonate drugs have been used successfully for treatment of vitamin D–related toxicosis and hypercalcemias of different etiologies but should only be used after consulting an internal medicine specialist or toxicologist. Nonspecific treatment (see Web Box 5-2) is frequently used in conjunction with specific calcium-lowering therapies including furosemide at 2.5 to 4.5 mg/kg every 8 to 16 hours, or prednisone at 2 to 6 mg/kg intravenously, intramuscularly, or orally every 24 hours or until blood calcium concentrations return to normal. Fluid therapy with 0.9% normal saline is recommended to enhance urine flow and calcium excretion and to correct dehydration.

Toxic Ornamental Plants Ingestion of leaves, flowers, or both of the Easter lily (Lilium longiflorum) may cause nephrotoxicity in cats. Lily toxicosis in cats was first reported in 1992 and has subsequently been reproduced experimentally. Shortly after eating leaves or flowers, cats develop signs of gastrointestinal upset and become depressed. Acute renal failure characterized by polyuria, dehydration, proteinuria, and glucosuria may be observed 48 to 96 hours after exposure. The toxic agent and mechanism of toxicity have not been established. The recommended nonspecific therapy includes gastrointestinal decontamination with the use of emetics, activated charcoal, sodium sulfate, and fluid therapy to correct dehydration. This treatment approach is most likely to be beneficial when performed within 6 hours of plant exposure.

Nephrotoxicity Associated with Pet Foods Nephrotoxicosis associated with consumption of pet food is quite rare. Yet several million pouches, cans, and bags

of pet food were recalled during the spring of 2007 following calls into regional offices of the Food and Drug Administration (FDA) after reports of possible pet food– related nephrotoxicity. Distal renal tubular degeneration and necrosis with crystal deposition were reported in most dogs and cats ingesting pet foods associated with this recall. At the conclusion of the episode, a number of cats and dogs died and about an equal number were clinically affected but recovered with treatment. This extensive recall included the United States and Canada. Diagnostic laboratories and the FDA identified the presence of melamine, ammelide, ammeline, and cyanuric acid in some recalled products. The presence of melamine and its analogs was unprecedented in the feed industry. Experimental studies in cats and pigs have revealed that crystal formation was a result of interaction between melamine and cyanuric acid to form unique characteristic plate-like crystals. These crystals caused tubular blockage and distal tubular epithelial necrosis. Treatment is generally supportive, and includes urinary alkalinization, fluid therapy, and general symptomatic treatment for renal failure.

Fanconi Syndrome in Dogs At the writing of this chapter there is an emergic disease in dogs ingesting some varieties of beef jerky and other dog treats. The cause of this Fanconi syndrome in dogs is currently unknown and the FDA is currently investigating new cases in collaboration with diagnostic laboratories that are part of the Veterinary Laboratory Research Network (VetLRN).

References and Suggested Reading Elliot DA, Cowgill LD: Acute renal failure. In Bonagura JD, editor: Kirk’s current veterinary therapy XIII (small animal practice), Philadelphia, 2000, Saunders, p 173-178.

WEB CHAPTER 

6 

Reporting Adverse Events to the Food and Drug Administration—Center for Veterinary Medicine SUSAN J. BRIGHT-PONTE, Rockville, Maryland LEE ANNE MYERS PALMER, Rockville, Maryland

T

he U.S. Food and Drug Administration (FDA) is a regulatory, science-based federal agency responsible for pro­tecting and promoting the public health through the monitoring and regulation of a variety of products necessary for the health and well-being of consumers. The FDA’s jurisdiction includes most food products (other than meat and poultry); animal feed and pet food; human and animal drugs; medical devices; vet­ erinary devices; therapeutic agents of biologic origin for humans (e.g., vaccines); radiation-emitting products for consumer, medical, and occupational use; cosmetics; and tobacco products.

FDA Center for Veterinary Medicine The FDA’s Center for Veterinary Medicine (CVM) is responsible for ensuring that animal drugs and medicated feeds are safe and effective for their intended uses and that food from treated animals is safe for human consumption. Before a new animal drug can be marketed legally in the United States, it must be approved by the FDA on the basis of quality, safety, and efficacy. When the drug is to be approved for use in food-producing animals, safety to the target animal species must be demonstrated, in addition to safety of food products derived from the treated animals that are intended for human consumption. Once approved products are on the market, CVM monitors the use of the products through surveillance and compliance programs. CVM is an internationally recognized public health organization responsible for the evaluation, approval, and surveillance of animal drugs, food additives, and feed ingredients. CVM works to increase the availability of safe and effective drug products that relieve animal pain and suffering, sustain their health, and improve animal productivity without compromising public health. CVM’s Office of Surveillance and Compliance (OS & C) has primary responsibility for several of CVM’s core functions, including compliance-related actions, postapproval monitoring, and animal feed safety. Within OS & C, the Division of Veterinary Product Safety (DVPS) is responsible for monitoring the safety and effectiveness of marketed animal drugs, devices, and pet food through

review and analysis of adverse experience reports. The information obtained from analysis of these reports helps CVM make decisions about product safety, potentially leading to regulatory actions, label revisions, or other changes necessary to ensure the safe and effective use of a product. Submitted adverse experience reports are maintained in databases used by OS & C to conduct postmarket surveillance and pharmacovigilance activities. Pharmacovigilance, as defined by the World Health Organization (WHO), is “the science and activities relating to the detection, assessment, understanding, and prevention of adverse effects or any other drug-related problems” (WHO, 2012). The goal of a veterinary pharmacovigilance program is to ensure the continued safety and effectiveness of animal drugs once they are being used in a wide and diverse population of animals. A primary objective of CVM’s pharmacovigilance program is to provide early recognition of signals about potentially serious and previously unknown safety problems associated with marketed animal drugs. Spontaneous reports of adverse experiences, medication errors, and product defects comprise the primary data source on which CVM’s postapproval surveillance and pharmacovigilance efforts depend.

Adverse Drug Experience Reporting System for Approved Animal Drugs Adverse Drug Experience: Definition An adverse drug experience (ADE) is currently defined in the Code of Federal Regulations (21 CFR 514.3) as “any adverse event associated with the use of a new animal drug, whether or not considered to be drug related, and whether or not the new animal drug was used in accordance with the approved labeling (i.e., used according to label directions or used in an extralabel manner, including but not limited to different route of administration, different species, different indications, or other than labeled dosage). Adverse drug experience includes, but is not limited to: (1) An adverse event occurring in animals in the course of the use of an animal drug product by a

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veterinarian or by a livestock producer or other animal owner or caretaker; (2) Failure of a new animal drug to produce its expected pharmacological or clinical effect (lack of expected effectiveness); (3) An adverse event occurring in humans from exposure during manufacture, testing, handling, or use of a new animal drug.”

ADEs may be further classified as to seriousness and expectedness. 21 CFR 514.3 currently defines a serious adverse drug experience as “an adverse event that is fatal, or life-threatening, or requires professional intervention, or causes an abortion, or stillbirth, or infertility, or congenital anomaly, or prolonged or permanent disability, or disfigurement.” In addition, an unexpected adverse drug experience is “an adverse event that is not listed in the current drug labeling for the new animal drug and includes any event that may be symptomatically and pathophysiologically related to an event listed on the labeling, but differs from the event because of greater severity or specificity. For example, under this definition hepatic necrosis would be unexpected if the labeling referred only to elevated hepatic enzymes or hepatitis.”

Adverse Drug Experience Reporting CVM directs veterinarians or animal owners who want to report an ADE in an animal or human to contact the product manufacturer. In the United States, ADE reporting by veterinarians and consumers is voluntary. However, manufacturers and distributors of FDA-approved animal drugs may be subject to the mandatory ADE reporting requirements in 21 CFR 514.80, as discussed later. All unsolicited reports from veterinarians or consumers received by the FDA via either the voluntary or the mandatory route are called spontaneous reports.

ADE Reporting for Veterinarians and Consumers Consumers and veterinarians can report ADEs directly to CVM by downloading and filling in FDA Form 1932a from CVM’s website (FDA, CVM (a), 2010). This form should be printed and sent to the FDA. Veterinarians and consumers can also report information directly to CVM by calling the CVM hotline at 1-888-FDA-VETS. In response to the inquiry, CVM provides an FDA Form 1932a that can be completed by the reporter and mailed to CVM. At this time there is no electronic submission process available for ADE reports from consumers or veterinarians. More information about voluntary reporting of adverse events by consumers and veterinarians is available on CVM’s website (FDA, CVM (b), 2011).

ADE Reporting Regulations for Drug Manufacturers The regulations that address the ADE reporting obligations for manufacturers and distributors of FDA-approved animal drugs are contained in 21 CFR 514.80, “Records and reports concerning experience with new animal drugs for which an approved application is in effect.”

The regulations impose reporting obligations on drug companies, including manufacturers and distributors, that meet the definition of an “applicant” or “nonapplicant” as defined in 21 CFR 514.3. An “applicant” is defined as “a person or entity who owns or holds on behalf of the owner the approval for an [New Animal Drug Application (NADA)] or an [Abbreviated New Animal Drug Application (ANADA)], and is responsible for compliance with applicable provisions of the act and regulations.” A “nonapplicant” is defined as “any person other than the applicant whose name appears on the label and who is engaged in manufacturing, packing, distribution, or labeling of the product” (21 CFR 514.2). Applicants, including manufacturers and distributors who hold a product’s approved NADA/ANADA, are required to submit all ADE reports to CVM on FDA Form 1932 within certain time frames, as discussed later. As of May, 2010, applicants have the option to submit ADE reports electronically to CVM through the Safety Reporting Portal (SRP) or by the gateway-to-gateway submission process. Nonapplicants, including manufacturers and distributors whose names appear on the product label but that do not hold the product’s approved NADA/ANADA, must forward information about ADEs to the applicant within 3 working days of receiving the information and must maintain records of all reports. If a nonapplicant elects to also report directly to the FDA, the nonapplicant should submit the report on FDA Form 1932 within 15 working days of receiving the information (21 CFR 514.80(b)(3) ). For more information on reporting of adverse drug experiences by drug companies, see CVM’s website (FDA, CVM(c), 2012). ADE reports are classified into essentially four categories: (1) three-day field alert reports, (2) fifteen-day alert initial reports, (3) follow-up reports, and (4) periodic reports. Three-day field alert reports contain information regarding product and manufacturing defects that may result in serious ADEs (21 CFR 514.80(b)(1) ). The applicant (or nonapplicant through the applicant) must submit the report on paper FDA Form 1932 to the appropriate FDA district office or local field office within 3 working days of first becoming aware that a defect may exist. The applicant that elects to submit a 3-day field alert report electronically through the SRP must also submit the report via telephone or other telecommunications means and in paper form to the FDA district office or local resident post. Reports of serious, unexpected ADEs are submitted as 15-day alert or “expedited” reports. These reports must be submitted on Form FDA 1932 to the FDA by the applicant within 15 working days of first receiving the information (21 CFR 514.80(b) (2) ). Follow-up reports are submitted on Form FDA 1932 by the applicant if significant new information is revealed during its investigation of adverse drug events that are the subject of 15-day alert reports (21 CFR 514.80(b)(3) ). Periodic reports contain ADE or product defect reports, based on the criteria in 21 CFR 514.80 (b)(4)(iv), and contain “expected” signs already on the label of the product, or are product defects not expected to result in serious adverse events. Periodic reports are submitted on Form FDA 2301 by the applicant at periodic intervals defined by regulation (21 CFR 514.80(b)(4) ).

WEB CHAPTER  6  Reporting Adverse Events to the Food and Drug Administration—Center for Veterinary Medicine

Approved versus Unapproved Drugs ADE submission is required by regulation only from companies marketing FDA-approved and conditionally approved animal drugs. Currently there are no regulatory requirements for submitting ADEs for unapproved animal drugs (animal drugs that have not gone through the FDA’s approval process) or for human drugs used in animals. Exceptions to this are those drugs on FDA’s Index of Legally Marketed Unapproved New Animal Drugs for Minor Species (the “Index”). These drugs are legally marketed for a specific use in certain minor species. Many approved animal drugs can be identified by the presence of a NADA number on the label, or a C-NADA number for conditionally approved animal drugs, although these identifiers on labeling are not currently required by regulation. Information about indexing, conditional approval, and designation of drugs intended for minor uses in major species or for use in minor species can be obtained from CVM’s Office of Minor Use and Minor Species (FDA, CVM (d), 2012). In addition, detailed information about the FDA’s animal drug approval process can be found on CVM’s website (FDA, CVM (e), 2011). Veterinarians and consumers may submit ADE reports involving unapproved drugs; these reports are included in CVM’s ADE database.

Medication Errors The National Coordinating Council for Medication Error Reporting and Prevention (NCCMERP) defines a medication error as “any preventable event that may cause or lead to inappropriate medication use or patient harm while the medication is in the control of the health care professional, patient, or consumer. Such events may be related to professional practice, health care products, procedures, and systems, including prescribing; order communication; product labeling, packaging, and nomenclature; compounding; dispensing; distribution; administration; education; monitoring; and use” (NCCMERP website, 2012).

Of these, prescribing errors have been documented to cause the most harm in human patients (Strom and Kimmel, 2006). CVM has received reports of preventable medication errors in animals that may cause unnecessary harm and injury. Medication errors can occur in several settings, including veterinary clinics and hospitals, universities, and human and veterinary pharmacies. Evaluation of ADE reports involving medication errors aids CVM in determining the frequency and severity of medication errors in animals. The information collected in these reports also helps CVM develop educational and outreach materials in an effort to prevent medication errors in animals. Unclear medical abbreviations are among the most common causes of medication errors. Not all practitioners interpret abbreviations uniformly, and therefore the intended meaning is not always conveyed. This can occur with both written and typed prescriptions. Pharmacists may be unfamiliar with some of the medical abbreviations commonly taught in veterinary school. For example, the abbreviation “SID” (once daily) used on

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animal drug prescriptions is not recognized by most pharmacies and may be interpreted as “BID” (twice daily) or even “QID” (four times daily), resulting in drug overdoses for animal patients (FDA, CVM (f), 2010). CVM has received several reports of medication errors of this type. Other commonly misinterpreted abbreviations include the use of “U” for units (“U” misread as zero) and the use of “µg” or “mcg” for microgram (mistaken for “mg”). Another common cause of medication errors is the use of trailing zeros and not using leading zeros when writing doses in medical records or on prescriptions. For example, a “5 mg” dose written with the trailing zero as “5.0 mg” can easily be misread as “50 mg.” Similarly, a “0.5 mg” dose written without the leading zero as “.5 mg” can be mistaken for “5 mg.” The FDA has worked to increase the safe use of drug products by minimizing user errors attributed to unclear nomenclature, labels, labeling, and packaging design of drug products. Both premarket and postmarket divisions within CVM review proposed trade names, labels, and packaging and dosing devices during the preapproval process to identify any potential problems. For example, dosing syringes may not be calibrated properly or readily legible, so CVM may recommend changes in the proposed design of these devices to help prevent medication errors after the product is marketed. Sometimes problems may not become evident until after the product has been marketed for some time. Adverse events associated with moxidectin-related overdoses in horses were found to be related to slippage of a syringe locking mechanism during administration of an approved moxidectin product. Several adverse event reports were received regarding this problem, and as a result CVM worked with the sponsor to produce an improved syringe lock (Hampshire et al, 2004).

Adverse Experience Reporting for Animal Devices, Pesticides, and Vaccines Reporting Adverse Experiences for Animal Devices The Federal Food, Drug, and Cosmetic Act [Section 201(h), (21 USC 321 (h) )] defines a medical device as “an instrument, apparatus, implement, machine, contrivance, implant, in vitro reagent, or other similar or related article, including a component part, or accessory which is: • intended for use in the diagnosis of disease or other conditions, or in the cure, mitigation, treatment, or prevention of disease, in man or other animals, or • intended to affect the structure or any function of the body of man or other animals, and which does not achieve any of its primary intended purposes through chemical action within or on the body of man or other animals and which is not dependent upon being metabolized for the achievement of any of its primary intended purposes.”

The FDA does not currently require premarket approval for devices intended for use in animals (e.g., suture material, certain types of bandage materials, intravenous catheters, anesthetic machines, imaging equipment). It is the responsibility of the manufacturer and/or distributor of

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these articles to ensure that they are safe, effective, and properly labeled. The FDA does have regulatory oversight over veterinary devices and can take appropriate regulatory action if a device is misbranded, mislabeled, or adulterated. Although not required by regulation, manufacturers and distributors of veterinary devices may submit reports of adverse events associated with marketed devices. Most adverse event reports that CVM receives for animal devices come directly from veterinarians or animal owners.

Reporting Adverse Experiences Associated with Pesticides The Environmental Protection Agency (EPA), rather than the FDA, regulates pesticides (e.g., some topical flea/tick products that are not systemically absorbed). Veterinarians can report pesticide-related adverse events online to the EPA and the National Pesticide Information Center (NPIC, 2012). Consumers can report adverse events associated with pesticides by calling 1-800-858-7378 or by email at [email protected].

Reporting Adverse Experiences Associated with Vaccines The FDA does not regulate vaccines or biologics intended for use in animals. Animal vaccine–related adverse events can be reported to the vaccine manufacturer or to the Center for Veterinary Biologics at the United States Department of Agriculture on their website (USDA APHIS, 2012).

Reporting Pet Food–Related Adverse Events or Product Problems Veterinarians and consumers are encouraged to report problems believed to be associated with pet foods or animal feed to the FDA. Additionally, manufacturers of these products provide contact information on their labels and may be notified if a problem is believed to be related to one of their products. Manufacturers are not required to submit adverse event reports they receive to the FDA, but they must report known product problems that have a reasonable probability of causing serious adverse health consequences to the Reportable Foods Registry (RFR) by using the SRP. More information about required food problem reporting by manufacturers can be found on CVM’s website (FDA, CVM (g), 2012). For veterinarians and consumers, there are two ways to report pet food–related adverse events or product problems to the FDA. They may be submitted online through the SRP (www.safetyreporting.hhs.gov). The SRP does not accept large animal feed reports at this time. Alternatively, a suspected pet food–related adverse event or product problem, or a large animal feed–related problem, may be reported by telephone to the FDA Consumer Complaint Coordinator for the reporter’s geographic region. Information about the FDA Consumer Complaint Coordinator can be found on CVM’s website (FDA, CVM (h), 2011). More details on how to report pet food

problems are also available on CVM’s website (FDA, CVM (i), 2010). To further enhance the surveillance and early detection of pet food problems, the Pet Event Tracking Network (PETNet) was launched in August, 2011. PETNet is a secure, web-based information exchange tool that will allow the FDA and other federal, as well as state, agencies to share information about pet food–related incidents to help with the early identification of emerging pet food problems. Members can evaluate the need for action within their jurisdiction based on information shared in PETNet. The concept for this system developed in the aftermath of the 2007 melamine pet food recall. One of the challenges encountered during that crisis was the inability to share information between states and the FDA in a timely manner. The PETNet system should enhance the ability of government officials to share information, aiding in the detection and response to emerging pet food issues.

Evaluation of ADE Reports by CVM CVM has received increasing numbers of ADE reports annually, with over 50,000 ADE reports received for all drug products in both 2010 and 2011 (Web Figure 6-1).

ADE Review Process CVM receives ADE reports in both paper and electronic format. The paper reports are manually entered by data entry contractors into an electronic database system, STARS (Submission Tracking and Reporting System). ADE reports submitted electronically from manufacturers are received via the electronic gateway-to-gateway system or through the SRP and deposited into the PV Works (Assured Information Systems) database. As described later, preapproval data are limited in terms of the number of animals in which the product is evaluated, so new safety concerns can emerge once recently approved drugs enter the marketplace and are used in thousands of animals. In consideration of the large volume and complexity of ADE data that are received, CVM uses a triage system and focuses on recently approved drugs to complete the safety profile of the product. These newer products are assigned to individual safety reviewers in the DVPS, so that one specific reviewer is responsible for closely monitoring a particular product throughout its first years on the market. In regards to these recently approved products, CVM focuses on the medical review and causality assessment of the individual case reports to identify safety signals of concern. Additionally, CVM is employing data mining techniques to enhance the prompt and efficient identification of safety signals. The ADE reports for older marketed products are entered into the database and monitored with lower priority unless a new safety issue arises, in which case they are elevated in priority to address the safety question of concern. As part of the review process, reported clinical signs are coded and/or verified and edited as appropriate. Clinical signs for reports in the STARS database are coded according to an internal CVM dictionary contained in the STARS database. These reports are migrated on a regular

WEB CHAPTER  6  Reporting Adverse Events to the Food and Drug Administration—Center for Veterinary Medicine

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60,000 50,000 40,000 30,000 20,000 10,000

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Web Figure 6-1  Number of adverse event reports received by CVM annually, 1991-2011.

basis to the PV Works database, so that all data can be accessed from a single database. To facilitate the data migration, STARS’ clinical signs have been mapped to corresponding terms in the Veterinary Medical Dictionary for Drug Regulatory Authorities (VeDDRA). Information about VeDDRA terms can be found on the European Medicine Agency’s website (EMA, 2012). CVM uses a form of causality assessment, administered according to a set of criteria, to weigh the possible relatedness between the adverse event and the product. Presently, as the reviewer workload allows, CVM uses the Modified Kramer algorithm to provide consistency in regards to causality scoring, and the assessment is applied to each clinical sign in a report. The algorithm takes into account the association in time between product administration and onset of the clinical sign, dechallenge and rechallenge with the product if this occurred, previous association of the product with the type of adverse event reported, dose relatedness, and presence or absence of an alternative etiologic candidate among other information, including whether or not there is enough information to assess the reaction. The FDA does not endorse any specific categorization of causality, and other causality assessment methods are used by foreign regulatory authorities and some pharmaceutical companies (FDA, 2005). For example, an alternative system, the ABON system (European Medicines Agency, 2004), gives an overall qualitative score to the entire adverse event report, rather than each clinical sign. Most causality assessment systems generally include categories of “possible,” “probable,” and “unlikely.” “Insufficient information” may also be a category used.

Signal Detection A safety signal is defined by WHO as “reported information on a possible causal relationship between an adverse event and a drug, the relationship being unknown or incompletely documented previously” (WHO, 2012). If a safety signal or trend is identified during the ADE review process, a medical review and causality assessment of the case reports generating the signal are completed. For more recently approved products, this process includes

performing a summary review that gives a list of clinical signs for a particular product in decreasing order of their reporting frequency. The clinical sign profile that is seen postapproval is compared with the labeled adverse reactions for the product, and the development of a Postapproval Experience (PAE) section may be proposed for addition to the drug labeling. Generally, a reviewer considers both the frequency and the severity of signs for PAE section development, but a specific frequency threshold is not used to determine inclusion in the PAE section. A list of potential signs for inclusion in a PAE section is developed for consideration. For products that already have a PAE section as part of their labeling, new signs may be added as the result of signal detection and case series analysis. The case series is essentially a summary of descriptive clinical information that can be used to help characterize the drug’s safety profile and identify potential risk factors associated with certain adverse events. This case series information is used to develop product label information that may enhance the safety and/or effectiveness of the product. Any signs being considered for addition to a PAE section are presented at a Monitored Adverse Reaction Committee (MARC) meeting. The MARC meeting is an interactive cross-divisional CVM pharmacovigilance forum held on a regularly scheduled basis. The group consists of veterinarians and other scientists from the CVM OS & C and the Office of New Animal Drug Evaluation (ONADE) (both postapproval and preapproval areas of the Center). During the MARC meeting, safety reviewers present the case series information they have developed and the supporting pharmacovigilance data regarding the safety signal(s) of interest. Furthermore, they participate in discussions to reach a consensus regarding the de­­ velopment of appropriate label revisions and Center risk management responses. In addition, pharmacology overviews of recently approved products are presented to the MARC meeting attendees by the ONADE scientific review staff so that safety reviewers can become more familiar with the safety and effectiveness profile of these products before ADE reports are received at CVM. With the large volume of data CVM receives annually, safety reviewers cannot always review the reports

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individually. We will rely more on descriptive statistics to identify safety issues of concern. Data mining strategies, which involve the use of computer algorithms to analyze data in large, complex databases, are being employed at CVM to identify safety signals. These automated signal detection methods do not replace hands-on clinical review and assessment of the case reports that contributed to the signal. Signals generated by our statistical software include measures of disproportionality, such as the proportional reporting ratio (PRR) and the reporting odds ratio (ROR) (Bate and Evans, 2009). The use of data mining software to facilitate signal detection at CVM is evolving and increased use is anticipated to enhance efficiency of review as more ADE reports are received each year.

Importance of ADE Reporting Drugs are approved after the FDA determines in the preapproval phase that a product’s benefits outweigh the risks associated with its labeled use for the intended population. Although CVM has a rigorous preapproval process for animal drugs, well-conducted, randomized, controlled clinical trials may not be of sufficient size to identify every safety problem. Once a product is marketed, there is a substantial increase in the number of patients exposed to the drug, including animals with coexisting medical conditions and those being treated with concomitant medications and biologic agents such as vaccines. There are potential food interactions as well. Clinical trials are unlikely to reliably detect uncommon, serious adverse events that occur with long latency or in subpopulations (e.g., breed, reproductive status) not included in preapproval studies. Additional information about medical product safety and effectiveness is obtained after a product is marketed and used under actual field conditions in large diverse populations of animals. This information completes the safety profile of a product, helps to ensure that drug product labeling is adequate and accurate, and ultimately assists practitioners in making informed decisions to minimize risks while maximizing benefits of the drugs. Practicing veterinarians play a critical role as observers and reporters of ADEs. As already noted, a reliable safety profile emerges only after a product is marketed and administered to a large population of animals. The more ADEs that are reported means that more information and data will be available about drug product safety, thus contributing to potentially greater statistical power of this observational data and more prompt identification of potential risk factors associated with the drug product. Animal drug products have a valuable role to play in the health and welfare of animals and humans. This role is enhanced by the presence of a good pharmacovigilance surveillance program, which allows for continuous monitoring of veterinary drugs. When an unexpected serious risk to the health and welfare of treated animals arises, rapid recall or removal of a product from the market may be warranted. In less serious cases, a change to the product labeling may be sufficient to allow continued safe use. The success and benefit of any pharmacovigilance system requires the constant vigilance and cooperation of all

stakeholders—veterinarians, industry, academia, animal owners, and state and federal government agencies.

Limitations of ADE Reports ADE data do have limitations. A causal relationship can be difficult to establish between a product and adverse experience for a number of reasons. Spontaneously reported data are prone to numerous biases, the most important being reporting bias. A new drug with greater publicity tends to generate more reports than older counterparts. Media attention to any reported problems tends to generate more reports. Underreporting occurs as well, and reporting in general varies over time. Some factors that may affect reporting include the severity of the reaction and the length of time the product has been marketed. The presence of confounding factors, such as concomitant products and concomitant medical conditions, must also be considered when evaluating the ADE reports. Also, because ADEs are reported from animal populations of uncertain size, it is not possible to reliably estimate incidence rates for adverse drug experiences using ADE data. The quality of the ADE reports is sometimes lacking, but quality is important for appropriate evaluation of potential signals. Good case reports include a detailed description of the adverse experience, including time to onset of signs; concomitant drugs or other products administered, including supplements and vaccines; concurrent medical conditions; patient signalment; clinical course of the adverse experience; diagnostic results and therapeutic measures; information about dechallenge and rechallenge; and patient outcome. Despite these limitations, the monitoring and evaluation of ADE reports are very important in the identification of previously unrecognized adverse events, in the identification of subgroups of animals at particular risk of adverse drug events, and to generally ensure that the risks and benefits of a particular drug remain acceptable. Additionally, they allow for communication of essential drug safety information to veterinarians and others involved in the treatment of animals.

CVM’s Communication of Drug Safety Information Drug Labeling The labeling of an approved animal drug product is the primary source of information about the drug, including directions for safe and effective use, contraindications, warnings, precautions, and adverse reactions. The drug labeling is evaluated as part of the preapproval process to ensure that it is scientifically accurate and provides clear instructions to veterinarians for prescription drugs and to consumers for over-the-counter animal drugs. Veterinarians should be able to depend on the drug label information to make sound and informed professional decisions about the risks and benefits associated with the drug for treatment of a particular patient or group of patients. Label revisions may become necessary after the product has been marketed and used in a large and diverse population of animals. As discussed earlier, the addition of a PAE

WEB CHAPTER  6  Reporting Adverse Events to the Food and Drug Administration—Center for Veterinary Medicine section to the labeling serves the important purpose of completing the drug’s safety profile. Label revisions can also include additional warnings, including boxed warnings in certain situations. Boxed warnings are the strongest type of warning statement and may be added to the labeling of a drug if the risks of a certain adverse event may in some circumstances outweigh the benefits of the drug. In addition, the packaging and formulation may require changes if they are determined to be contributing factors to the occurrence of ADEs or medication errors.

Dear Doctor Letters Dear Doctor Letters are letters drafted by drug manufacturers and sent to veterinarians to notify them of important new safety information discovered after a product has been introduced to the market. This information may include any new warnings, other safety information, or other important changes to the prescribing information of a drug product. Dear Doctor Letters are often issued by the company in conjunction with label changes, although not all labeling changes result in such a letter. Dear Doctor Letters issued since 2000 are posted on CVM’s website (FDA, CVM (j), 2011).

Client Information Sheets For some prescription animal drugs that may pose a significant risk to the health of the animals being treated or to the humans handling the animal or the drug, the FDA may require manufacturers to provide additional labeling, such as a Client Information Sheet (CIS). CISs provide animal owners with important information in a userfriendly manner regarding what can be expected from use of the drug and what side effects may occur. These information sheets are intended for distribution by the veterinarian to the client at the time of prescribing or dispensing of the drug. A few of the circumstances in which a CIS may be needed for a prescription animal drug include, but are not limited to, a drug with a narrow margin of safety, a drug that may cause adverse reactions that would necessitate prompt attention, a drug that has unusual or complicated dosing instructions, or a drug with user safety issues. An example of a CIS required for a specific drug class is that for the nonsteroidal antiinflammatory drugs (NSAIDs).

CVM Website CVM uses its website to disseminate information about ADEs and important announcements regarding animal drug product safety. One section of the website, “CVM Updates,” contains brief press releases issued by CVM on developments of interest to stakeholders and the public. “CVM Updates” may relate to any topic but are often used to convey information about drug safety issues. CVM also publishes a cumulative summary of ADE reports that is updated on a regular basis and contains the reports that CVM has received from 1987 to the present. This sum­ mary, “Cumulative ADE Summaries Report,” is posted on CVM’s website and provides a listing of the clinical signs reported for each active ingredient in the database (FDA,

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CVM (k), 2012). The Cumulative ADE Summaries Report does not currently contain ADE reports that have been received electronically. Electronic submission of ADE reports began in 2011 and the capability to add these to the Cumulative Summaries Report on the website is under development at the time of this writing. Information on unapproved products and devices is included as well. Clinical signs are listed in order from most frequently observed to least frequently observed, by species and route of administration. In addition to listing the signs, the “# of times the sign was reported” is provided as well. This information can be useful for new drugs because reported signs are listed and can be seen even before any label changes have been made. However, this report cannot be used to estimate incidence rates or estimates of drug risk because there is no accurate way to determine how many animals were given the drug.

CVM Outreach CVM scientists may also disseminate new drug safety information through publications in professional journals and presentations at professional meetings. Publications about CVM’s adverse event reporting programs help to emphasize the importance of reporting adverse events and hopefully serve to encourage veterinarians to report suspected ADEs and adverse events associated with pet food and animal feed. Members of CVM’s DVPS routinely participate in outreach programs and give presentations about CVM’s pharmacovigilance program to veterinary students and veterinary technician students, as well as to national, state, and local veterinary organizations.

Other Risk Mitigation Strategies Additional risk mitigation strategies may at times be necessary to increase the safe and effective use of animal drugs. These may include methods of communication about drug safety information as described earlier (e.g., changes in labeling, issuance of Dear Doctor Letters, drug name or packaging changes), as well as other types of measures such as restricted use or distribution of a drug or, rarely, withdrawal of a medical product from the market. Two types of special postapproval surveillance programs are Post-Approval Monitoring Programs (PAMPs) and Risk Minimization Action Plans (RiskMAPs). PAMPs may include specific postmarketing study commitments that are required of or agreed to by a drug sponsor and are conducted after the FDA has approved a product for marketing. FDA uses postmarketing study commitments to gather additional information about a product’s safety, efficacy, or optimal use. Postmarketing study commitments are currently conducted much more commonly for human drugs and biologics; only a few postmarketing studies for animal drugs have been conducted at this time (e.g., sometribove zinc suspension, ractopamine). A RiskMAP is a strategic safety program designed to meet specific goals and objectives in minimizing known risks of a product while preserving its benefits. In 2005, the FDA (CDER and CBER) published “Guidance for Industry—Development and Use of Risk Minimization

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Action Plans,” which provides recommendations to the industry about the development, implementation, and evaluation of risk minimization action plans for human prescription drug products and human biologic products (FDA website, 2005). RiskMAPs were developed basically to improve the risk : benefit ratio of drugs with special safety risks. Although this document does not specifically apply to animal drugs, manufacturers can refer to it for ideas on ways to help minimize risks associated with their products, while preserving the benefits. To date, two animal drugs, an injectable moxidectin heartworm preventive and a topical fentanyl solution, have become the subject of a RiskMAP.

Other Surveillance Methods Sentinel Initiative Although most of the FDA’s surveillance efforts are passive in nature, recent advances in scientific and information technology have created new opportunities for active surveillance methods. Currently these active surveillance methods, such as the FDA’s Sentinel Initiative, are being developed for postmarket surveillance of drugs for humans (FDA website, 2012). These methods may be developed for use in animal drug postmarket surveillance programs in the future. Although CVM was exempt from the Sentinel Initiative, CVM completed a project investigating the current electronic data sources that exist in the field of veterinary medicine. The project report, Evaluation of Potential Data Sources for Animal Drugs Used in Veterinary Medicine, can be found on the FDA Sentinel website. The report concluded that the body of veterinary medical data, as it currently exists, does not lend itself to external monitoring, mining, or analysis the way human medical data might. An industry-specific agreement regarding database content, format, and consistency standards is needed for CVM to successfully access a large enough sample size of animals to effectively query for potential drug safety issues.

Global Pharmacovigilance CVM’s International Pharmacovigilance Efforts The CVM is actively involved in international pharmacovigilance activities through its participation in the VICH program. VICH is a trilateral program concerned with developing harmonized technical requirements for the approval of veterinary medical products (drugs and biologics) in the European Union, Japan, and the United States, and includes input from regulatory and industry representatives. Canada, Australia, and New Zealand participate as active observers. The VICH program was officially developed in April 1996 and has the following full title: International Cooperation on Harmonization of Technical Requirements for Registration of Veterinary Medicinal Products. One of the five working groups initially established by the VICH Steering Committee was the VICH Pharmacovigilance Expert Working Group. This group met from 1997 to 2010, with the purpose of

standardizing the collection of ADE information and the timely sharing of that information with member and observer nations. Standardizing serves the dual purpose of vastly expanding the information available for regulators and decreasing the burden and expense to the pharmaceutical companies of meeting multiple and diverse regulatory requirements. The Pharmacovigilance Expert Working Group was formally disbanded after completion of its work in 2010. The Steering Committee subsequently appointed the Electronic Standards Implementation Expert Working Group (EWG), which is evaluating existing systems for widespread distribution so that the information can be received by the member nations, regardless of their internal processing system. VICH will continue to address pharmacovigilance topics in the future through the Electronic Standards Implementation EWG, which has the assignment to monitor and maintain the implementation.

References and Suggested Reading Bataller N, Keller WC: Monitoring adverse reactions to veterinary drugs, Vet Clin North Am Food Anim 15(1):13-30, 1999. Bate A, Evans S: Quantitative signal detection using spontaneous ADE reporting, Pharmacoepi Drug Sfty 18:427-436, 2009. European Medicines Agency, 2004: Guideline on harmonising the approach to causality assessment for adverse reactions to veterinary medicinal products. Available at: http://www.ema .europa.eu/docs/en_GB/document_library/Scientific_guideline/ 2009/10/WC500004995.pdf. European Medicines Agency (EMA) website: Guidance notes on the use of VeDDRA terminology for reporting suspected adverse reactions in animals and humans. Available at: http:// www.emea.europa.eu/docs/en_GB/document_library/Other/ 2009/10/WC500005087.pdf. Accessed April 10, 2012. FDA website, 2005: Guidance for industry—good pharmacovigilance practices and pharmacoepidemiologic assessment. Available at: http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm071696.pdf. FDA website, 2005: Guidance for industry—development and use of risk minimization action plans. Available at: http:// www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm071616.pdf. FDA website, 2012: FDA’s sentinel initiative. Available at: http:// www.fda.gov/safety/FDAsSentinelInitiative/ucm2007250.htm. FDA CVM website (a), 2010: Veterinary Adverse Event Voluntary Reporting (Form FDA 1932a). Available at: http://www.fda.gov/ downloads/AboutFDA/ReportsManualsForms/Forms/ AnimalDrugForms/UCM048817.pdf. FDA CVM website (b), 2011: Veterinary adverse event voluntary reporting. Available at: http://www.fda.gov/AnimalVeterinary/ SafetyHealth/ReportaProblem/ucm055305.htm. FDA CVM website (c), 2012. Veterinary adverse event reporting for manufacturers. Available at: http://www.fda.gov/AnimalVeterinary/SafetyHealth/ReportaProblem/ucm212682.htm. FDA CVM website (d), 2012: Minor use/minor species. Available at: http://www.fda.gov/AnimalVeterinary/DevelopmentApprovalProcess/MinorUseMinorSpecies/default.htm. FDA CVM website (e), 2011: From an idea to the marketplace: the journey of an animal drug through the drug approval process. Available at: http://www.fda.gov/AnimalVeterinary/ ResourcesforYou/AnimalHealthLiteracy/ucm219207.htm. FDA CVM website (f), 2010: Kim-Jung L: A microgram of prevention is worth a milligram of cure: preventing medication errors in animals. Available at: http://www.fda.gov/AnimalVeterinary/ ResourcesforYou/ucm214772.htm.

WEB CHAPTER  7  Respiratory Toxicants of Interest to Pet Owners FDA CVM website (g), 2012: Reportable Food Registry for Industry. Available at: http://www.fda.gov/Food/FoodSafety/ FoodSafetyPrograms/RFR/default.htm. FDA CVM website (h), 2011: Consumer Complaint Coordinators. Available at: http://www.fda.gov/Safety/ReportaProblem/ ConsumerComplaintCoordinators/default.htm. FDA CVM website (i), 2010: Pet food safety reporting frequently asked questions. Available at: http://www.fda.gov/AnimalVeterinary/SafetyHealth/ReportaProblem/ucm212664.htm. FDA CVM website (j), 2011: Dear Doctor Letters. Available at: http://www.fda.gov/AnimalVeterinar y/SafetyHealth/ ProductSafetyInformation/ucm055433.htm. FDA CVM website (k), 2012: Adverse drug experience (ADE) reports. Available at: http://www.fda.gov/AnimalVeterinary/ SafetyHealth/ProductSafetyInformation/ucm055369.htm. Hampshire VA et al: Adverse drug event reports at the United States Food and Drug Administration Center for Veterinary Medicine, J Am Vet Med Assoc 225(4):533-536, 2004. National Coordinating Council for Medication Error Reporting Prevention (NCCMERP) website: About medication errors:

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what is a medication error? Available at: http://www.nccmerp. org/aboutMedErrors.html. Accessed April 10, 2012. National Pesticide Information Center website: Veterinary pesticide incident reporting. Available at: http://pi.ace.orst.edu/vetrep/. Accessed April 10, 2012. Strom BL, Kimmel SE, editors: Textbook of pharmacoepidemiology, West Sussex, 2006, Wiley & Sons. Talbot J, Waller P, editors: Stephens’ detection of new adverse drug reactions, West Sussex, 2004, Wiley & Sons. United States Code of Federal Regulations, Title 21 Part 500. Available at: http://ecfr.gpoaccess.gov. USDA, Animal and Plant Health Inspection Service website: Adverse event reporting. Available at: http://www.aphis.usda.gov/animal_ health/vet_biologics/vb_adverse_event.shtml. Accessed April 10, 2012. Woodward KN, editor: Veterinary pharmacovigilance: adverse reactions to veterinary medicinal products, West Sussex, 2009, Wiley-Blackwell. World Health Organization (2012). Available at: http://apps.who.int/ medicinedocs/en/d/Jh2934e/14.html. Accessed April 10, 2012.

7 

Respiratory Toxicants of Interest to Pet Owners JANICE A. DYE, Research Triangle Park, North Carolina

P

oor air quality, either indoor (i.e., residential) or outdoor (i.e., ambient), can cause or contribute to development of disease in humans and pets. Consequently, owners may approach their veterinarian with questions about the potential for airborne toxins to negatively impact the health of their pets. Such toxicants include biologic materials (e.g., allergens, microbes, and mycotoxins), gas­eous pollutants, volatile organic chemicals (VOCs), particles, dust, and fibers. These agents are associated with increased risk of developing respiratory and neurologic signs, chronic respiratory inflammation, allergies, and neoplasia. The cause of these disorders can be difficult to establish because of the nonspecificity of clinical signs and because multiple etiologies may be involved. Because most birds, cats, and dogs spend the majority of their lives within the family residence, this chapter focuses on commonly encountered indoor toxicants and related home conditions. Ambient air pollutants that readily permeate indoor spaces also are included. Approaches for improving indoor air quality (IAQ) are discussed in brief.

Biologic Contaminants Allergens Data linking respiratory disease in companion animals to allergen exposure are limited in part by lack of commercially available, validated, allergen-specific antibody assays for pets. Supportive evidence comes from beneficial clinical responses to allergen avoidance, as well as from studies demonstrating that cats with bronchial disease have significantly more positive intradermal skin test reactions to dust mite (a common indoor aeroallergen) than do healthy cats (Moriello et al, 2007). Similarly, allergen-specific immunoglobulin E (IgE) testing in serum Disclaimer: This information has been reviewed by the National Health and Environmental Effects Research Laboratory, U.S. EPA, and approved for publication. Approval does not signify that the contents necessarily reflect the views and policies of the agency, nor does the mention of commercial products constitute endorsement.

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of affected cats showed strong reactivity to dust mite and regional outdoor aeroallergens (Norris Reinero et al, 2004). In humans, there is increasing evidence that IgE antibodies to dust mites, cockroaches, and pets are causally related to lung inflammation and asthma. Although pet exposure can undoubtedly worsen allergy symptoms in sensitized individuals, low levels of dog (Can f 1) or cat (Fel d I) allergens are universally present in U.S. homes—even in those without pets for long periods. Moreover, there are data to suggest that pet exposure during childhood may help to avert development of allergic sensitization. This protective pet effect is influenced by host factors (genetics, sex); the type of pet (dog, cat, or both); and the level, timing/duration, and route of allergen exposure (e.g., inhaled versus oral ingestion of allergens in dust). Through stimulation of the innate immune system early in life (especially year one), proallergic immune responses are in some manner modified, thus facilitating long-lasting species-specific immunologic tolerance (Platts-Mills, 2011; Bernstein, 2012).

Dampness and Mold As residential energy costs rose over the past 40 years, houses became more efficiently insulated and airtight. By increasing mechanical recirculation of indoor air, the volume of outdoor air entering a dwelling could be reduced, thus making homes more economical to heat and cool. Unfortunately, such changes also lead to more stagnant and humid indoor air—effects that in combination with extensive wall-to-wall carpeting allow microorganisms and house dust (including mites and their excreta) to accumulate at concentrations higher than previously encountered. Tight building syndrome is especially problematic if residential heating, ventilation, and air conditioning (HVAC) systems are not functioning optimally and when water intrusion into the home occurs (from floods, hurricanes, or plumbing, appliance, and roof leaks). Excessive moisture leads to growth of mold, other types of fungi, and bacteria, which subsequently emit spores, hyphae fragments, microbial VOCs, and endotoxin into the indoor air (Cabral, 2010). The U.S. Institute of Medicine (2004) concluded that there is sufficient evidence of an association between dampness and adverse health outcomes; however, causality has not yet been established. Home dampness may serve as a marker for generalized increases in dust and other products that accumulate during conditions of reduced ventilation. Alternatively, dampness may be a proxy for mold and its secreted metabolites, which include enzymes, hemolysins, β-D-glucans, and potent mycotoxins (e.g., macrocyclic trichothecenes, aflatoxins, satratoxins, gliotoxins, and chaetoglobosins). Linking specific biocontaminants to particular respiratory or neurologic syndromes remains an area of active investigation and debate. Microbial VOCs, for example, are known ocular and upper respiratory tract irritants. Furthermore, biocontaminants can cause respiratory and systemic infection, as epitomized by Legionnaire’s disease, (which can arise from overgrowth of the bacterium Legionella within air conditioning systems). Biocontaminants are also implicated in hypersensitivity responses (e.g.,

pneumonitis, chronic rhinosinusitis), exacerbation of allergies and asthma, and chronic neurologic conditions (Thrasher and Crawley, 2009). Cats, not unlike young children, may be exposed to these agents both through inhalation and via ingestion of house dust (cats due to extensive grooming and kids due to increased floor contact time and “mouthing” behaviors). A recent report describing acute pulmonary hemorrhage and death of two cats exposed to toxic black mold was remarkably similar to a cluster of cases in infants in the Cleveland area who also developed pulmonary hemorrhage. Indicative of Stachybotrys chartarum exposure, satratoxin G adducts were detected in archived serum samples from the cats. Concurrent stressors of cigarette smoke and inhalant anesthesia may have contributed to the lung changes observed (Mader et al, 2007). Novel approaches to define and quantify (1) indoor biocontaminant mass (e.g., quantitation of hydrophilic fungi or ergosterol in dust) (Park et al, 2008) and (2) exposure metrics (e.g., detection of mycotoxins in urine) (Straus, 2011) are critical to improving understanding of the spectrum of health effects associated with damp indoor environments.

Chemical Toxicants Combustion-Derived Products Second-hand smoke (SHS) is simply the smoke from someone else’s cigarette. It contains both gases and respirable particles that, particularly in poorly ventilated air spaces, can cause ocular and respiratory tract irritation. This is especially problematic for young children, in whom exposure is associated with wheeze, asthma exacerbation, and reduced resistance to infections, leading to increased incidence of otitis media, bronchiolitis, and pneumonia. The Surgeon General has concluded that there is no risk-free level of exposure to SHS, and thus a smoke-free environment is the only way to fully protect nonsmokers from the hazards of SHS (U.S. Department of HHS, 2010). Based on urinary levels of cotinine, a nicotine metabolite, house pets are similarly exposed to SHS, with levels in dogs increasing proportionately with the number of cigarettes smoked in the household (BertoneJohnson et al, 2008). Therefore predisposition toward analogous conditions in exposed pets is likely, and by extension pets with preexisting upper or lower respiratory disease may be especially sensitive to the irritating effects of SHS. SHS exposure has also been associated with decreased pulmonary function (e.g., functional reserve capacity) in a pilot study of healthy dogs (Abrams et al, 2007) but was not identified as a significant risk factor for canine chronic cough (Hawkins et al, 2010). Because sidestream cigarette smoke is generated at lower temperatures and under different conditions than mainstream (exhaled) smoke, SHS contains higher concentrations of certain carcinogens (e.g., polycyclic aromatic hydrocarbons [PAHs]). Hence SHS has been dually designated as a known human carcinogen and an occupational carcinogen. SHS exposure during childhood and adolescence can increase the risk of developing lung cancer as much as or more than exposure in adulthood (Asomaning et al, 2008). Limited studies associating SHS

WEB CHAPTER  7  Respiratory Toxicants of Interest to Pet Owners exposure with cancer in pets exist. In one study, increased risk for lung cancer was restricted to brachycephalic and mesocephalic dog breeds. Conversely, other reports showed dolichocephalic breeds were at increased risk for nasal cancer (Reif et al, 1998). Breed sensitivities notwithstanding, it is postulated that these associations reflect efficient trapping of carcinogens in the nasal cavity of dolichocephalic breeds, thereby minimizing lower airway deposition. Unfortunately, increased nasal retention may lead to increased risk of nasal cancer. In cats, SHS exposure is associated with risk for malignant lymphoma (Bertone et al, 2002) and oral squamous cell carcinoma (Snyder et al, 2004), likely reflecting both inhalation and oral (via grooming) routes of exposure. Relatedly, ingestion of cigarette butts is not uncommon in pets. Due to nicotine toxicity, this may prove fatal in birds and small dogs. Air Pollutants While catastrophic air pollution episodes were infamous for their toll on human life as in the London Fog of 1952, they also caused morbidity and mortality in animals. Precipitated by industrial accidents and temperature inversion patterns, North American disasters included Donora, PA (1948), when effluents from steel, zinc, and sulfuric acid plants became trapped in a valley inversion and 20 people, 10 dogs, 3 cats, and 40% of poultry in four nearby flocks died after developing respiratory signs, and Poza Rica, Mexico (1950), when hydrogen sulfide released into the ambient air during a thermal inversion led to the death of 22 people and an undetermined number of dogs, swine, and cattle, as well as nearly 100% of the canaries in the area (Catcott, 1961). Owing to pollution control regulations, present-day levels are greatly reduced but are still associated with significant economic toll due to health care costs and lost productivity. Health effects of individual air pollutants are summarized in the following section (based on epidemiologic associations and data from relatively short-term, high-dose experimental exposures). By contrast, real world exposures are chronic, are lower level, and involve multiple pollutants, which —owing to additive or synergistic effects—may culminate in significant health risk for children, the elderly, and people with cardiorespiratory disease. A recent pilot study of urban cats noted increasing prevalence of feline asthma over the last 20 years (Ranivand and Otto, 2008). Likewise, retrospective studies in dogs noted that older urban dogs (> 7 years old) had greater radiographic evidence of thoracic disease than either young dogs or older rural dogs (Reif, 1970) and that urban dogs had increased risk for oral (tonsillar) cancer (Ragland and Gorham, 1967). Nitrogen dioxide (NO2), a poisonous, corrosive, brownish gas, is both a major indoor and outdoor air pollutant. The primary indoor sources are poorly ventilated biomassburning (coal or wood fireplaces and stoves) and gas (e.g., water heaters, clothes dryers, kitchen ranges) appliances. When indoor sources combine with permeation of traffic emissions, indoor levels can exceed (by as much as five times) ambient NO2 concentrations, well in excess of levels considered safe in outdoor air by the U.S. Environmental Protection Agency (EPA). Adverse health

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effects of NO2 include impairment of immune defense mechanisms. Data suggest that infants and children with atopy or asthma are more sensitive to the respiratory effects of NO2, in part due to enhanced asthmatic reactions to inhaled allergens (Bernstein et al, 2008). NO2 is also an atherogenic risk factor, especially in obese humans, and is associated with cardiovascular events and hospi­ talization. Long-term (near-lifetime) exposure to NO2 is also purported to contribute to chronic emphysematous lung changes. Thus in pets NO2 exposure may result in increased frequency and/or severity of respiratory infection and contribute to chronic bronchial and lung pathologic changes. Carbon monoxide (CO) is a colorless, odorless gas. Unlike most air pollutants in which effects relate to lowlevel, chronic exposure, a single (likely to be encountered) exposure may prove lethal. Owing to its overt affinity for hemoglobin, CO prevents cellular oxidation, resulting in severe cellular anoxia. Initial clinical signs include vague lethargy, headache, and fatigue, progressing to confusion, nausea, and ultimately unconsciousness and death. As CO is a product of incomplete fuel combustion, its sources are similar to those of NO2, the primary one being motor vehicle exhaust. Classic cases of human poisonings, whether accidental or intentional, arise from car engines left running in attached garages or sheds. Significant exposure may also occur during use of charcoal grills or unvented kerosene heaters in relatively closed air spaces, or when chimneys or venting ducts of central heating systems are obstructed. Birds are especially sensitive to CO, as evidenced by their classic use as sentinels in coal mine shafts. CO poisoning is also an important cause of the morbidity and mortality in pets rescued from burning buildings. Having set clinic protocols in place for managing animal victims of smoke inhalation can help to ensure a successful outcome (Fitzgerald and Flood, 2006). For example, isocapnic hyperpnea with 100% O2 has been shown in dogs to double the rate of CO elimination compared with normal ventilation with 100% O2—a simple but effective means of hastening recovery of poisoned pets (Fisher et al, 1999). Cooperation with local firefighters to equip fire trucks with petsized face masks may allow for more effective O2 delivery on site, thus improving pet survival. Ozone (O3), a potent oxidant gas, is among the most injurious of the ambient air pollutants. Exposure is associated with respiratory tract irritation, injury, and inflammation. Ozone is primarily an outdoor air pollutant that is produced in the lower atmosphere by photochemical reactions involving combustion products of gasoline (and other solvents) with oxygen and sunlight. Hot temperatures and stagnant air masses contribute to increased ambient concentrations. When significant accumulations occur near ground level, the phenomenon known as smog is observed. Indoor O3 levels arise mainly from outdoor levels permeating the home during normal air exchange. Indoor levels are usually less than half that of outdoor levels, but during smog episodes they may be sufficient to impact health. Ozone can also be emitted directly indoors by, for example, electric generators and office equipment such as photocopiers and laser printers. Ironically, ionizing air-purifiers intentionally generate O3 to

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SECTION  II  Toxicologic Diseases

react with and rid air of odors, resulting in indoor O3 concentrations that can exceed levels found in smog (Britigan et al, 2006). In humans and laboratory animals, O3 has had variable effects on mucociliary clearance, a primary mechanism for clearing inhaled particles or offending microorganisms from the airways, thereby raising concerns about host resistance to infectious agents (Bernstein et al, 2008). In healthy dogs and humans, acute exposure can increase nonspecific airway responsiveness. In humans with atopic asthma, exposure to relatively low O3 concentrations (comparable to that of many urban areas) further augments the airway responsiveness increases noted during allergen challenge. Moreover, infant rhesus monkeys undergoing repeated exposure to O3, alternating with house dust mite allergen, developed significantly reduced lung capacity and long-lasting asthmalike disease (Schelegle et al, 2003). Data further suggest that O3 exposure can induce lipid oxidation and systemic vascular effects that—similar to NO2—may play a role in promoting atherosclerosis and associated cardiovascular disease. Sulfur dioxide (SO2), another ambient air pollutant, is the major precursor to acidic deposition or so-called acid rain. Veterinary concerns regarding SO2 pollution are primarily over aquatic and wildlife health. One important exception relates to the use of unvented kerosene space heaters. Such heaters emit significant SO2 and associated acid aerosols. Total airborne concentrations can be exorbitant in closed-space situations. When SO2 gas is combined with other organic acid emissions, space heater emissions can cause ocular and respiratory irritation in animals and humans alike. Additionally, acid aerosol exposure from ambient SO2 pollution may occur in pets that are either housed outdoors or exercised outside for significant periods. Again, asthmatic humans are at particular risk (Bernstein et al, 2008); thus dogs and cats with chronic bronchial disease may be similarly susceptible to this irritant gas-particulate mixture.

Off-Gassing Emissions Formaldehyde, a pungent, highly water-soluble, and reactive gas, is an ocular and upper respiratory irritant. Indoor levels increase during off-gassing of formaldehyde from resins in particleboard, fiberboard, and wood paneling. Other sources include foam insulation, carpeting, upholstery, and drapery fabrics. Mobile homes, being relatively airtight and constructed from many of these materials, are especially problematic. Acute exposure may be associated with headache, nausea, dizziness, and disorientation. VOCs are organic-based compounds that easily become vapors or gases. They are present in countless household products, for example, as propellants in aerosol sprays (e.g., butane, propane) or as fragrance materials (e.g., limonene, pinene, isoprene) in air fresheners, furniture polish, and personal care items (e.g., hair spray, deodorants). VOCs and other irritating chemicals are found in paints, paint strippers (methylene chloride), recently drycleaned clothes (trichloroethylene), cleaning compounds (e.g., stain removers, bleach [sodium hypochlorite], tile cleaners [ammonia hydroxide]), antistatic sprays,

pesticide sprays, and fumigants (e.g., insect, roach, and flea control products). VOC exposure can also occur when moving into a new home or during remodeling due to off-gassing from new carpeting, furniture, draperies, and freshly applied paint or varnish (Bernstein et al, 2008). Researchers have identified nearly 400 volatile and semivolatile compounds in indoor air (Gale et al, 2009), proving cumulative home exposure can be significant. Assuming these products are used per label instructions and in well-ventilated areas, most people (and pets) experience little untoward effects during exposure. Importantly, many VOCs are sensory irritants and, unfortunately, many owners fail to use such products as per warning label instructions. Exposure to VOC-containing products is therefore a realistic cause of illness in pets and should be considered for cases with acute onset of eye, skin, or respiratory signs. Excessive, prolonged, or combined exposures may be associated with dizziness, headache, nausea, and even allergy-like reactions. Avian veterinarians should be especially attuned to this possibility. As with carbon monoxide, pet birds may be exceedingly sensitive to aerosolized VOCs. Fumes from overheated cooking pans, self-cleaning ovens, and heat lamp bulbs lined with polytetrafluoroethylene (PTFE; Teflon or Silverstone) have been associated with acute and fatal toxicity in birds (Lightfoot and Yeager, 2008).

Particles, House Dust, and Fibers The effects of ambient particulate matter (PM) are a major human health concern. Particulate pollutants— fine (PM2.5) and coarse (PM10) particles—represent a complex, variable mixture of microscopic carbon-based particles, airborne acid droplets, and adsorbed materials (e.g., PAHs, metals) that can be inhaled deep into the lungs. Epidemiologic associations between ambient PM exposure and adverse effects include increased respiratory signs, decreased lung function, asthma exacerbation, arrhythmias, ischemic cardiac events, and premature death in people with heart or lung disease. Indoor PM represents a combination of intruded outdoor PM, plus particles from SHS, cooking, heating (fireplaces), candle burning, and so forth. Indoor cats are also exposed to particles in litter (e.g., silicates or dusty clay), which anecdotally may be associated with respiratory distress in cats with feline asthma. In human asthmatics, expiratory flow reductions were more significantly associated with indoor PM2.5 levels than outdoor levels (Ma et al, 2008). As discussed previously, it may be relevant that concurrent exposures (e.g., PM + allergens + endotoxin) can synergistically elicit lung injury and inflammation, thus triggering allergic symptoms and asthma (Ormstad, 2000). Traffic emissions (i.e., automotive and diesel exhaust) contribute significantly to ambient fine PM, and are especially harmful to children and individuals with preexisting lung inflammation (Bernstein, 2012). By extension, animals with chronic respiratory or cardiac disease may be similarly susceptible to PM, especially if exercised, housed, or kenneled near busy roadways or intersections. House dust is a mixture of lint, soil, particles, decomposing insects, and adsorbed substances that, because of

WEB CHAPTER  7  Respiratory Toxicants of Interest to Pet Owners volatilization, leaching, or débridement from household products, are ubiquitous contaminants in the indoor environment. Depending on the home, dust may be laden with metals, pesticides, semivolatile persistent chemicals (e.g., polybrominated diphenyl ethers [PBDEs], a type of flame retardant), and so forth—with pets continually exposed to these contaminants through dust exposure. Cats, similar to children, are likely to inhale and ingest dust through their grooming and mouthing behaviors, respectively. Veterinarians have long recognized that animals exposed to lead-contaminated dust may develop lead poisoning and that, if blood lead levels are elevated in the pet, home occupants (especially children) should be screened as well. Owing to the structural similarity between certain PBDE congeners and thyroxine, there is growing concern over potential endocrine dysregulation in exposed humans. A recent study showed that PBDE levels in cats were twentyfold to 100-fold greater than median levels in U.S. adults (Dye et al, 2007). PBDEs were first introduced into consumer goods nearly 35 years ago, coincident with increases in feline hyperthyroidism. Moreover, the Environmental Working Group reportedly detected neurotoxicants (methylmercury, lead), pesticides (DDT), and perfluorinated compounds (PFCs [e.g., stain-resistant products]) in pooled serum from cats and dogs. Thus companion animals may be ideal “sentinels” to assess potential health outcome related to low-level but chronic exposure to a wide variety of indoor contaminants. Radon is a type of radioactive gas emitted by soil or rock containing trace amounts of radium or uranium. The amount of radon present in soil varies widely depending on one’s geographic location. Radon may enter the home via the underlying soil through cracks in the foundation or holes in the geologic deposits beneath the home. Ionized atoms adsorb to dust particles and may be inhaled. As an alpha-emitter, radon primarily targets the lung. Despite availability of home detection kits, data associating residential radon with cancer in pets have yet to be reported. Asbestos fibers are naturally occurring mineral silicates that were used extensively in friction products (e.g., brake shoes, clutch pads) and as noncombustible insulation around pipes and in walls, flooring, and roofing materials. Of concern, asbestos fibers are small and, when abraded or disturbed, readily become airborne and are easily inhaled. Pulmonary clearance mechanisms have great difficulty removing or destroying these fibers; hence asbestosassociated diseases have long latency periods (up to 30 years in humans) and include development of pleural plaques, asbestosis (i.e., interstitial pulmonary fibrosis), bronchogenic carcinoma, and the rare malignant mesothelioma. In dogs, mesothelioma was associated with occupational exposure of owners (e.g., shipyard workers or auto mechanics), presumably due to exposure of reentrained asbestos dust from clothing. Purebred (e.g., German shepherds) and male dogs were at a higher risk for developing mesothelioma (Glickman et al, 1983). Mesothelioma is also more common in human males. To date, no predisposing causes have been identified in cats. Dogs and cats may also have peritoneal or pericardial involvement, possibly due to ingestion of fibers during

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grooming. Home asbestos removal and containment remain costly and controversial issues.

Improving Indoor Air Quality The U.S. EPA lists poor indoor air quality as a major environmental concern. Indoor air can be considerably more polluted than outdoor air (http://www.epa.gov/iaq/ pubs/). Preventive measures can help to minimize owner and pet exposure to many of these respiratory toxicants. Key elements of improved air quality are source control, appropriate ventilation, adjusting humidity to 30% to 50%, changing air filters regularly, and cleaning air ducts as needed. CO monitors can be installed and gas appliances inspected to ensure proper functioning. Gas stoves and heaters should be vented to the outside of the home, and gas ranges should never be used as heat sources. Owners should be cautioned about use of ionizing air purifiers that can increase indoor ozone concentrations well in excess of levels considered safe. Kerosene heaters should be used carefully and only as per the manufacturer’s instructions. Heaters should be refueled outdoors, using only specified low-sulfur fuel. Cars or lawn mower engines should never be left running inside a garage or shed. This is especially critical if the garage is ever used to house a pet. Pet owners need to follow the manufacturer’s directions for use of common household aerosols or flea con­ trol products, including having adequate ventilation. Avoid mixing bleach (sodium hypochlorite) and ammonia-based cleaning products to prevent generation of toxic (e.g., chloramine) fumes. Pet owners, especially of birds, should minimize use of VOC-containing products. An alternative is to use unscented and nonaerosol products, low-VOC paints, and other “green” substitutes. If cleaning products, paint, new carpeting, and so forth are associated with offensive odor, eye irritation, or headache, the owner should ensure that neither they nor their pet maintain prolonged exposure in the area until the odors dissipate. If this is not possible, efforts to improve air ventilation are vital. Health risk from exposure to biocontaminants related to indoor dampness is recognized as a significant public health problem requiring attention and mediation (WHO, 2009). Housing problems contributing to or associated with damp indoor environments include musty odors and mold growth, window condensation, structural rot, peeling paint, back-drafting appliances, damp basements, and wintertime ice buildup (e.g., in gutters or roof edges). It is critical that water leaks and conditions contributing to excess moisture levels are repaired and eliminated. Spores can remain viable long after water intrusion has been corrected, necessitating a thorough overall cleanup. Improved ventilation not only helps decrease humidity, it may also decrease accumulation of gases or chemicals arising from materials in the living space. These same principles apply to pets kept in kennels or barns with poor ventilation and excessive dampness. The above precautions may be especially important for puppies and kittens and geriatric pets, as is the case for young children and elderly humans. Pets with known respiratory or cardiac disease may be at increased risk of

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exacerbating their conditions with prolonged exposure to respiratory toxicants. The air quality index (AQI) warnings for yellow or orange ozone or PM “action” days can assist at-risk owners (and their pets) to avoid exercising during peak pollutant periods (http://airnow.gov and click on Local forecasts and conditions). Perhaps the one precaution that would result in the most benefit to affected pets as well as the owner(s) is smoking cessation, either completely or at least restricted inside the home. Again, the Surgeon General concluded that eliminating smoking in indoor spaces is the only way to fully protect nonsmokers from SHS exposure. A pilot study on owner attitudes toward smoking suggests that by informing pet owners of the risks of SHS for their pets, they may be more motivated to quit smoking and make their homes smokefree (Milberger et al, 2009).

References and Suggested Reading Abrams J et al: The effect of environmental tobacco smoke on lung function in health pet dogs: a pilot study, Proceedings of the 25th Annual Symposium of the Veterinary Comparative Respiratory Society (VCRS), 2007. Asomaning K et al: Second hand smoke, age of exposure and lung cancer risk, Lung Cancer 61:13-20, 2008. Bernstein DI: Traffic-related pollutants and wheezing in children, J Asthma 49:5-7, 2012. Bernstein JA et al: The health effects of non-industrial indoor air pollution, J Allergy Clin Immunol 121:585-191, 2008. Bertone ER et al: Environmental tobacco smoke and risk of malignant lymphoma in pet cats, Am J Epidemiol 156:5, 2002. Bertone-Johnson ER et al: Environmental tobacco smoke and canine urinary cotinine level, Environ Res 106:361-364, 2008. Britigan N et al: Quantification of ozone levels in indoor environments generated by ionization and ozonolysis air purifiers, J Air Waste Manag Assoc 56:601-10, 2006. Cabral JP: Can we use indoor fungi as bioindicators of indoor air quality? Historical perspectives and open questions, Sci Total Environ 408:4285-4295, 2010. Catcott EJ: Effects of air pollution on animals, Monogr Ser World Health Organ 46:221-231, 1961. Dye JA et al: Elevated PBDE levels in pet cats: sentinels for humans? Environ Sci Technol 41:6350-6356, 2007. Fisher JA et al: Isocapnic hyperpnea accelerates carbon monoxide elimination, Am J Respir Crit Care Med 159:1289-1292, 1999. Fitzgerald KT, Flood AA: Smoke inhalation, Clin Tech Small Anim Pract 21:205-214, 2006. Gale RW et al: Semivolatile organic compounds in residential air along the Arizona-Mexico border, Environ Sci Technol 43:30543060, 2009. Glickman LT et al: Mesothelioma in pet dogs associated with exposure of their owners to asbestos, Environ Res 32:305-313, 1983.

Hawkins EC et al: Demographic and historical findings, including exposure to environmental tobacco smoke, in dogs with chronic cough, J Vet Intern Med 24:825-831, 2010. Institute of Medicine: Damp indoor spaces and health, Washington DC, 2004, National Academy of Sciences. Lightfoot TL, Yeager JM: Pet bird toxicity and related environmental concerns, Vet Clin North Am Exot Anim Pract 11:229259, 2008. Ma L et al: Effects of airborne particulate matter on respiratory morbidity in asthmatic children, J Epidemiol 18:97, 2008. Mader DR et al: Acute pulmonary hemorrhage during isoflurane anesthesia in two cats exposed to toxic black mold (Stachybotrys chartarum), J Am Vet Med Assoc 231:731-735, 2007. Milberger SM et al: Pet owners’ attitudes and behaviors related to smoking and second-hand smoke: a pilot study, Tob Control 18:156-158, 2009. Moriello KA et al: Pilot study: prevalence of positive aeroallergen reactions in 10 cats with small-airway disease without concurrent skin disease, Vet Dermatol 18:94-100, 2007. Norris Reinero CR et al: An experimental model of allergic asthma in cats sensitized to house dust mite or Bermuda grass allergen, Int Arch Allergy Immunol 135:117-131, 2004. Ormstad H: Suspended particulate matter in indoor air: adjuvants and allergen carriers, Toxicology 152:5253-5258, 2000. Park JH et al: Hydrophilic fungi and ergosterol associated with respiratory illness in a water-damaged building, Environ Health Perspect 116:45-50, 2008. Platts-Mills TA: Allergens and their role in the allergen immune response, Immunol Rev 242:51-68, 2011. Ragland WL, Gorham JR: Tonsillar carcinoma in rural dogs, Nature 214:925-926, 1967. Ranivand L, Otto C: Feline asthma trends in Philadelphia, Pennsylvania 1996-2007, Proceedings of the 26th Annual Symposium of the VCRS, 2008. Reif JS: Canine pulmonary disease. II. Retrospective radiographic analysis of pulmonary disease in rural and urban dogs, Arch Environ Health 20:684-689, 1970. Reif JS et al: Cancer of the nasal cavity and paranasal sinuses and exposure to environmental tobacco smoke in pet dogs, Am J Epidemiol 147:488-492, 1998. Schelegle ES et al: Repeated episodes of ozone inhalation amplifies the effects of allergen sensitization and inhalation on airway immune and structural development in Rhesus monkeys, Toxicol Appl Pharmacol 191:74-85, 2003. Snyder LA et al: p53 expression and environmental tobacco smoke exposure in feline oral squamous cell carcinoma, Vet Pathol 41:209-214, 2004. Straus DC: The possible role of fungal contamination in sick building syndrome, Front Biosci (Elite Ed) 3:562-580, 2011. Thrasher JD, Crawley S: The biocontaminants and complexity of damp indoor spaces: more than what meets the eyes, Toxicol Industrial Health 25:583-615, 2009. US Department of HHS: A Report of the Surgeon General: How tobacco smoke causes disease: What it means to you, 2010. WHO guidelines for indoor air quality: dampness and mould, 2009.

WEB CHAPTER 

8 

Small Animal Poisoning: Additional Considerations Related to Legal Claims MICHAEL J. MURPHY, Stillwater, Minnesota

I

think the neighbor poisoned my pet.” Most practitioners hear this history many times in their career. Often the pertinent clinical signs are unrelated to any toxin; however, in other cases toxicosis is a possibility. This chapter considers those situations when pet toxicosis may eventually involve the legal system. Pet poisoning cases may interface the legal system through insurance claims, product liability claims, civil claims, or criminal prosecution. As an example, a criminal case is presented to highlight some of the issues that may arise when an animal toxicosis involves the legal system. “

Case Example Celinski v. State* The criminal application of the Texas animal cruelty statute was reviewed in the case of Celinski v. State. Mr. Celinski was found guilty of cruelty to animals in part for poisoning two cats with acetaminophen. He appealed the conviction. The conviction was upheld by the Texas Court of Appeals based on the evidence. The evidence cited by the Texas Court of Appeals in upholding Mr. Celinski’s conviction can be summarized as follows: “(1) The cats were in good health when Jones [the owner] left; they were very sick when she returned the following day. They had diarrhea, were foaming at the mouth, and were too weak to stand.

*Other Signs: Mr. Celinski was also convicted of putting the cats in the microwave and turning it on. The cats had blistered feet, and some of their other signs could be related to the microwave. NOTES: Criminal cases are commonly cited as State v. Doe, since the state is prosecutor and the individual accused of doing the poisoning is the defendant in the initial trial. In this case, Mr. Celinski appealed the initial court ruling to the Texas Court of Appeals; thus the case is Celinski v. State. The interest of the legal and medical professions is generally quite similar in these cases. That interest is to determine whether exposure to the suspect chemical caused the disease present in the animal. Both professions gather and analyze facts to determine whether such a conclusion can be reached.

(2) The veterinarian who treated the cats concluded that they were suffering from acetaminophen poisoning, based upon his observation of their physical symptoms and upon the results of a blood test. (3) The veterinarian was unable to reverse the results of the poisoning with an antidote. He estimated that the cats had ingested the equivalent of five to six tablets apiece some time during the afternoon of February 21, 1994. (4) Texas A&M laboratory results confirmed that Sugar Ray and Bonnie died of acetaminophen poisoning. (5) The veterinarian had seen a dozen cases of feline acetaminophen poisoning in his 14 years of practice, but had never heard of a cat voluntarily ingesting Tylenol, nor had he ever seen a case of multiple cats simultaneously ingesting Tylenol. (6) Appellant testified there were no pills lying about the apartment the day the cats became sick—pills they could have accidentally ingested. He was the only person present in the apartment with the cats on that day.” (Celinski v. State)

Conclusions from This Case This case illustrates a number of points regarding the importance of medical records in legal cases. The first four points listed by the Texas Court of Appeals may be used to determine whether the cats had a previous illness, whether they were exposed to a potentially toxic dose of acetaminophen, and whether the previously known adverse effects of acetaminophen were observed in the cats. The last two points reviewed by the court of appeals were more directly aimed at determining whether the exposure was accidental or intentional. The first point noted by the Texas Court of Appeals was that the cats were previously healthy and then became acutely ill. A preexisting medical condition that could explain the clinical signs or other adverse effects observed in the animal is likely to be considered in a legal setting. This analysis would consider whether the clinical signs of the animal could be caused by the preexisting condition, exposure to the purported toxin, or both. The second point noted by the Texas Court of Appeals was the cats were exposed to a dose of acetaminophen known to be toxic. Acetaminophen was detected in the cats, confirming exposure. Analytic e49

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chemistry confirmation of the presence of the chemical in the animal is very useful in a legal setting to confirm that the chemical was actually absorbed into the animal. Analysis of blood and urine is most commonly used to support an argument of systemic exposure to the chemical in live animals. All of this information presumably assisted the veterinarian in estimating that the cats had received five to six acetaminophen-containing tablets apiece, the third point. The fourth point noted by the Texas Court of Ap­­ peals was the cats died of acetaminophen poisoning. The “physical symptoms” observed by the veterinarian in­­cluded “dark chocolate color of a blood sample.” This blood color led the veterinarian to suspect acetaminophen toxicosis. Acetaminophen was confirmed as the cause of death by the laboratory at Texas A&M University. A thorough necropsy with appropriate supportive testing also can be very useful to both rule in the suspect toxin and rule out other possible causes of the animal’s clinical condition. The veterinarian’s medical record is likely to be an important source of facts in a legal case. Consequently, the more facts present in the medical record, the stronger the support for an argument that the suspect chemical, and not another etiology, caused the disease. The last two points (5 and 6) were used to find that death from acetaminophen was intentional and not accidental. The distinction between accidental and intentional poisoning is important in animal cruelty statutes as discussed in the following paragraphs. This criminal case raises important questions that may be considered in other toxicosis cases, specifically: • What should be included in veterinary medical records? • When is animal poisoning considered animal cruelty? • Are drugs of abuse considered poisons? • How is client confidentiality balanced with reporting animal poisoning?

Medical Records The veterinarian’s medical records will likely be thoroughly reviewed if a medical case becomes a legal case.

What Should Be Included in Medical Records? The pet’s medical record may be broader than sometimes appreciated. For example, “registration forms, consent forms, radiographs, estimate sheets, billing records, telephone consultations, controlled drug logs, laboratory results, surgery reports, discharge records, imaging re­­ cordings, patient history, treatment records, and consultation reports” all may be considered part of a pet’s medical record (Scott, 2006). Specific suggestions of facts to include in the medical record when animal cruelty is suspected are: “[w]henever nonaccidental injury is suspected, the attending veterinarian should obtain a minimum database,

including estimated age, an accurate body weight, and a body condition score, and should perform a complete physical examination, a thorough oral examination to establish the condition of the teeth, otoscopic and ophthalmic examinations to identify potential head trauma, radiographic examinations to rule out occult injuries, and other species-specific examinations as necessary” (Babcock and Neihsl, 2006).

Despite these suggestions, the requirements for a veterinary medical record may be defined by the state in which one practices. These requirements, if they exist, should be considered. For example, the Minnesota Board of Veterinary Medicine has established by Rule the minimum standards for medical records for veterinary practice in Minnesota. Some of these record-keeping requirements are: “A. A veterinarian performing treatment or surgery on an animal or group of animals, whether in the veterinarian’s custody at an animal treatment facility or remaining on the owner’s or caretaker’s premises, shall prepare a written record or computer record concerning the animals containing, at a minimum, the following information: (1) name, address, and telephone number of owner; (2) identity of the animals, including age, sex, and breed; (3) dates of examination, treatment, and surgery; (4) brief history of the condition of each animal, herd, or flock; (5) examination findings; (6) laboratory and radiographic reports; (7) tentative diagnosis; (8) treatment plan; and (9) medication and treatment, including amount and frequency.”   Minnesota Rule 9100.800 sub. 4, A

Practitioners may choose to consult their state licensing board to determine if rules or guidelines are published in that state for minimal data to include in veterinary medical records. One may consider including more than the minimal requirement if litigation is anticipated. Information to consider documenting in the record of suspected poisoning cases includes telephone consultations, laboratory test results, and consultation reports. Referral or consultation may not be required.

Referral to a Specialist The increase in the number of veterinary specialty practices has raised the question of when a practitioner has a “duty to refer” a case (Rollin, 2006; Block and Toss, 2006). The author is aware of no such obligation in pet poisoning cases. Rather the timely treatment of an animal that has been poisoned may argue against such a referral; how­ever, the practitioner should check local requirements. The author is also not aware of a “duty to consult” on poisoning cases. However, such consultation may be wise in some situations. Several sources of information for poisoning cases are summarized in Chapter 9. The practitioner may consider consulting a veterinary toxicologist (www.abvt.org), a veterinary diagnostic laboratory (www. aavld.org), or both to receive advice on which samples

WEB CHAPTER  8  Small Animal Poisoning: Additional Considerations Related to Legal Claims and what testing may be desirable to confirm a suspected toxicosis to the degree of medical certainty required in the particular case. Documenting in the medical record telephone consultations, including the results of specific toxin testing, the owner’s decision to accept or decline such testing, and any consultation reports obtained may strengthen the final diagnosis reached in a specific case. Notation of the rationale used to diagnose the toxicosis and rule out other differential diagnoses may also be useful. Sometimes the legal aspects of a case are unknown or not recognized at the time of patient presentation. Updating a medical record certainly can be proper. Subsequent reflection may suggest a need to update the record with the facts remembered but not initially recorded. However, the record should be amended only in a way that allows the original record to be read. “Entries that are completely blacked out or obliterated always raise suspicion when records are viewed by a third party….The corrected entry should be signed and dated by the person making the correction” (Scott, 2006).

Animal Cruelty Most toxic exposures in animals are accidental. Sometimes pets may ingest plants, pesticides, automotive products, and over-the-counter or prescription drugs available in or around the home despite the owner’s best efforts to prevent them from doing so. Accidental adulteration of pet food has also occurred in the United States during recent years. When Is Animal Poisoning Considered Animal Cruelty? These accidental exposures may require testing that specifically identifies the chemical causing the disease and rules out other reasonable etiologies whenever a claim against a property owner, pesticide applicator, product manufacturer, or other third party arises. The medical records and diagnostic considerations discussed in the previous paragraphs apply to these cases as well. Rarely, animals are intentionally poisoned. In some states this element of intent may support an argument that a crime of animal cruelty has been committed. Animal cruelty statutes that include a version of the term “poison” are found in Arkansas, California, Hawaii, Maine, Michigan, Minnesota, Nevada, New Mexico, North Carolina, Ohio, Pennsylvania, Texas, Utah, and Vermont at the time of this writing. (see list in references). Most of these statutes indicate that the act be “knowingly,” “willfully,” “intentionally,” or “maliciously” committed. Animal cruelty may be a misdemeanor or a felony. For example, in Minnesota: “[a]ny person who unjustifiably administers any poisonous, or noxious drug or substance to any animal, or procures or permits it to be done, or unjustifiably exposes that drug or substance with intent that the drug be taken by any animal, whether the animal is the property of the person or another, is guilty of a gross misdemeanor” (Minnesota Statutes 2005, Chapter 343.27).

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WEB BOX 8-1  Websites for At-Home Tests to Detect   Drugs of Abuse http://uritoxmedicaltesting.com/hometestkits.html http://www.firstcheckfamily.com/products.php?adtype= illegal http://www.testmyteen.com/storefront/?AffiliateID=1277&ACC =1277

In the United States, animal cruelty may rise to the level of a felony in 43 states (Babcock and Neihsl, 2006). For example, in Texas a person may be found guilty of a state jail offense if the person intentionally or knowingly: “(5) kills, seriously injures, or administers poison to an animal, other than cattle, horses, sheep, swine, or goats, belonging to another without legal authority or the owner’s effective consent …” (Texas Penal Code Ann. § 42.09).

Presumably most cases of accidental or unintentional animal poisoning would not satisfy the “intent” requirement of animal cruelty statutes. Consequently most pet poisoning cases would not likely rise to the level of animal cruelty, even in states where poisoning is recognized as one form of animal cruelty. Veterinarians should consider checking with their state licensing board to know the law in their state.

Drugs of Abuse Clinical signs related to animal ingestion of alcohol, marijuana, cocaine, or other human drugs of abuse occasionally are encountered by veterinarians. Animals may certainly experience adverse effects after exposure to alcohol or these drugs of abuse, but do these constitute poisonings? Are Drugs of Abuse Considered Poisons? Many practitioners may not equate alcohol with “poison” in the routine veterinary practice. The Maine animal cruelty statute includes the phrase “gives poison or alcohol to an animal,” apparently distinguishing alcohol from poison. It may be wise to consult the state licensing board to determine if positive findings for alcohol or human drugs of abuse, as might be identified in the pet’s urine, require reporting to anyone beyond the client. Over-the-counter kits can be used to screen a pet’s urine for drugs of abuse (Web Box 8-1). The kits are often a practical way to indicate to a concerned pet owner that such drugs are not detected in their pet’s urine when the test result is negative. Any positive results should probably be confirmed by analytic chemistry testing since most human kits have not been validated for use with animal urine. See www.aavld.org for laboratories that may be able to perform such analytical chemistry testing.

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SECTION  II  Toxicologic Diseases

Confidentiality The question of client confidentiality should be considered prior to reporting an animal’s condition to another individual or agency. Balancing Client Confidentiality with Reporting For poisoning cases, confidentiality is generally not an issue if the person or entity responsible for poisoning the pet is not the client. Clients may certainly disclose their pet’s medical records to others at their discretion. Diagnostic laboratory reports confirming toxicosis often have been used to initiate investigations by a sheriff or humane officer when warranted. Presumably routine accidental animal toxicoses do not require reporting under animal cruelty statutes in most states because they do not meet the “intent” element, as discussed previously. Balancing client confidentiality with reporting may be more difficult if the veterinarian suspects that the animal was intentionally poisoned by the client. See Requirements for Mandatory Reporting of Animal Cruelty for an expanded discussion of this issue (Babcock and Neihsl, 2006). Briefly, some states have mandatory animal cruelty reporting requirements or immunity from liability if animal cruelty is reported. Specifically Arizona, California, Illinois, Kansas, Minnesota, Oregon, West Virginia, and Wisconsin have a law requiring the reporting of animal cruelty (Babcock and Neihsl, 2006). Arizona, California, Colorado, Florida, Georgia, Idaho, Illinois, Kansas, Maine, Maryland, Massachusetts, Michigan, Mississippi, New Hampshire, New York, Oregon, Rhode Island, South Carolina, Vermont, Virginia, and West Virginia offer some immunity from liability for reporting suspected animal cruelty (Babcock and Neihsl, 2006). Veterinarians should consider consulting their state licensing board for guidance before concluding that animal poisoning is animal cruelty that requires reporting to entities other than the client. Some practice acts include very strong client confidentiality components. For example, the Texas Practice Act states: “Confidential relationship between the veterinarian and a client: Except as provided in subsection (c) of this section, a veterinarian shall not disclose any information concerning the veterinarian’s care for an animal except: (A) on written or oral authorization or other form of waiver executed by the client; or (B) on receipt by the veterinarian of an appropriate court order or subpoena. (C) A veterinarian may, without authorization by the client, disclose information contained in a rabies

certificate to a governmental entity only for purposes related to the protection of public health and safety.” (Texas Board of Veterinary Medical Examiners Rule 573.27. See also Tex Atty Gen Op JM-656. 1987 WL 269439).

In summary, the veterinarian’s medical records undergo close scrutiny when cases of pet toxicoses involve the legal system. These cases may involve insurance claims, civil action, or criminal action in your state. Veterinary medical records are most useful in each of these legal settings when the differential diagnosis is outlined and the results of examination, laboratory testing, consultation, and specific diagnosis are documented in the medical record. It may be wise for veterinarians to consult their state licensing board to determine if (1) minimal standards for medical records exist in their state, (2) detection of alcohol or drugs of abuse in a pet requires reporting to anyone other than the client, (3) poisoning an animal could be considered animal cruelty, and (4) their state requires the reporting of animal cruelty.

References and Suggested Reading Arkansas Code, Annotated § 5-62-102. Babcock SL, Neihsl A: Requirements for mandatory reporting of animal cruelty, J Am Vet Med Assoc 228(5):685, 2006. Block G, Toss J: The relationship between general practitioners and board-certified specialists in veterinary medicine, J Am Vet Med Assoc 228(8):1188, 2006. California Penal Code § 596. Celinski v. State 911 S.W.2d 177 (Tex. App. 1995). Hawaii Statute § 711-1109. Hawaii Statute § 711-1109.5. Maine Citation: ME ST Tit. 7 § 4011-4018; ME ST Tit. 17 § 1011-1046. Maine Statute Tit. 7 § 4011-4018. Maine Statute Tit. § 1011-1046. Michigan Comp. Laws 750.50b. Minnesota Statutes 2005, Chapter 343.27. Nevada ST 574.010-510. New Mexico ST § 30-18-1-15. North Carolina ST § 14-360-363.2. Ohio ST § 959.01-99. Pennsylvania ST 18 Pa.C.S.A. § 5511. Rollin B: The ethics of referral, Can Vet J 47:717, 2006. Scott JF: Veterinary Medical Records, Proceedings of the American Veterinary Medical Law Association AVMLA, 2006 CE Program. Texas Attorney General Op JM-656. 1987 WL 269439. Texas Board of Veterinary Medical Examiners Rule 573.27. Texas Penal Code Ann. § 42.09. Utah ST § 76-9-301-307. Vermont ST T 13 § 351-400.

WEB CHAPTER 

9 

Sources of Help for Toxicosis MICHAEL J. MURPHY, Stillwater, Minnesota

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ractitioners faced with questions about toxicoses can access a number of resources. These include specialists in veterinary toxicology, veterinary diagnostic laboratories, colleges of veterinary medicine (CVMs), textbooks, online references, and poison control centers. Perhaps the best source of veterinary toxicology information comes from veterinarians certified as specialists by the American Board of Veterinary Toxicology (ABVT). The ABVT is one of the more long-standing specialty boards recognized by the American Veterinary Medical Association’s Board of Veterinary Specialties. A listing of ABVT Diplomates is available at www.abvt.org. Consultation with an ABVT specialist may be particularly helpful in complicated or obscure toxicosis cases or if litigation is anticipated. Many veterinary diagnostic laboratories and CVMs include ABVT Diplomates on staff. The veterinary diagnostic laboratory accredited by the American Association of Veterinary Laboratory Diagnosticians nearest one’s practice can be identified by checking accreditation at http://www.aavld.org; CVMs can be found at http://www. avma.org/education/cvea/colleges_accredited/colleges_ accredited.asp. Many practicing veterinarians have reference texts available in their clinic. Most veterinary toxicology texts are authored by ABVT Diplomates. A partial list of such reference texts that the author recommends beyond this textbook includes A Field Guide to Common Animal Poisons by Murphy (www.blackwellprofessional.com); Clinical Veterinary Toxicology by Plumlee (Mosby, www. us.elsevierhealth.com/Veterinary); Small Animal Toxicology by Peterson and Talcott (Saunders, www.us.

elsevierhealth.com/Veterinary); and Toxicology by Osweiler (Williams & Wilkins, www.lww.com). Poison control centers are another leading source of toxicology information (see Chapters 20 and 21). Although most poison control centers specialize in human exposures, a number still receive animal exposure calls. Among the latter centers are the American Society for the Prevention of Cruelty to Animals Animal Poison Control Center (www.aspca.org/apcc) and the Pet Poison Helpline (www.petpoisonhelpline. com). Animal poison control centers may charge for services and information. The telephone number for the human poison control center in many areas is 1-800-Poison-1. The practicing veterinarian should consider in advance the various sources available for information regarding animal toxicoses. Depending on the situation, a textbook reference or direct consultation with a toxicology specialist, veterinary diagnostic laboratory, CVM, or poison control center may provide the information needed to appropriately manage toxicosis in the veterinary patient.

References and Suggested Reading American Society for the Prevention of Cruelty to Animals Animal Poison Control Center: www.aspca.org/apcc. American Association of Veterinary Laboratory Diagnosticians: www.aavld.org. American Board of Veterinary Toxicology Diplomates: www.abvt. org. American Veterinary Medical Association (accredited colleges): www.avma.org/education/cvea/colleges_accredited/colleges_ accredited.asp. Pet Poison Helpline: www.petpoisonhelpline.com.

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WEB CHAPTER 

10 

Treatment of Animal Toxicoses: Regulatory Points to Consider MICHAEL J. MURPHY, Rockville, Maryland SUSAN J. BRIGHT-PONTE, Rockville, Maryland JANICE C. STEINSCHNEIDER,* Rockville, Maryland

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eterinarians in both small and large animal practices are frequently called on to treat known or suspected animal toxicosis. A definitive diagnosis is not always established at the time of clinical presentation because many of these cases pose diagnostic or therapeutic challenges. Yet an early diagnosis and specific treatment are often keys to successful outcomes. In these efforts, veterinarians should avail themselves of diagnostic and treatment information from a variety of sources (see Web Chapter 9). When a toxicosis is suspected, obtaining a detailed clinical history is of prime importance, particularly to determine if the administration of a specific antidote is indicated. The prognosis for any animal may vary considerably depending on the toxin, exposure dose, length of time between exposure and treatment, and availability of drugs to treat the patient. Treatment generally requires stabilization of vital signs, institution of supportive care, decontamination to prevent further toxin absorption, administration of compounds to enhance the elimination of absorbed toxins, or a combination. This chapter is not intended to describe the diagnosis or treatment of animal toxicosis. The reader is directed to other chapters in this section and the references in this chapter for such information. Rather, the focus of this chapter is on the regulatory status of drugs used to treat animals with toxicoses because virtually all these drugs are not approved for that use by the Food and Drug Administration (FDA). Accordingly, regulations guiding extralabel drug use may be of interest to practitioners. This chapter considers the prevalence of toxicoses briefly, then follows with a discussion of drugs that are commonly used to treat these toxicoses. The discussion is framed by the drugs’ regulatory status: approved use, extralabel use (ELU), and unapproved use. It is hoped that this information will benefit practicing veterinarians as a reminder of the regulatory status of drugs used in these emergency situations.

*United States, Food and Drug Administration, Center for Veterinary Medicine, Rockville, MD. This article was written by the authors in their private capacity. No official support or endorsement by the FDA is intended or should be inferred.

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Drugs Used to Treat Animal Toxicoses The prevalence of toxicoses in dogs and cats is reasonably well known (see Chapters 20 and 21). Consequently, the majority of drugs needed to treat toxicoses in companion animals are known and indirectly provide information for stocking emergency drugs in practices and emergency/ critical care centers. Prevalence data of animal toxicoses also may be useful to pharmaceutical companies when considering which therapies to develop and what types and amounts of drug inventories may be needed for treating animal toxicoses. This chapter includes information on the treatment of both companion animal toxi­ coses and food animal toxicoses because the authors anticipate that some readers work in a mixed animal practice. The use of extralabel drugs and compounding drug considerations are particularly pertinent when treating food animals. The Federal Food, Drug, and Cosmetic Act (FFDCA) (Section 201 [21 U.S.C. 321(g) (1)]) defines a drug as*: (A) Articles recognized in the official United States Pharmacopeia, official Homoeopathic Pharmacopoeia of the United States, official National Formulary, or any supplement to any of them; and (B) Articles intended for use in the diagnosis, cure, mitigation, treatment, or prevention of disease in man or other animals; and (C) Articles (other than food) intended to affect the structure or any function of the body of man or other animals; and (D) Articles intended for use as a component of any articles specified in clause (A), (B), or (C). 21 U.S.C. 321(g)(1) Drugs administered to animals to treat (diagnose, cure, mitigate, treat, or prevent a disease or to affect the structure or any function of the body) a toxicosis are regulated by the FDA under the FFDCA and its implementing regulations, published in Title 21 of the Code of Federal Regulations (available on-line at http://www.gpoaccess. gov/cfr/). Practicing veterinarians often place drugs used in treating an animal toxicosis into three categories—general treatment, supportive treatment, and specific treatment. This chapter does likewise.

*NOTE: In general, the articles recognized in clause [A] also need to meet clause [B] or [C] of the definition to be considered a drug by the FDA.

WEB CHAPTER  10  Treatment of Animal Toxicoses: Regulatory Points to Consider

General Treatment General treatment is normally given irrespective of the toxin, unless there is a preexisting contraindication. General treatment is often intended to induce emesis, reduce absorption, or enhance elimination of toxins. Emetics commonly used in dogs or cats include apomorphine, xylazine, salt, syrup of ipecac, and hydrogen peroxide (see references). Activated charcoal is often used orally to reduce further absorption of toxins from the gastrointestinal tract, whereas soap and water are often used dermally to remove a toxin from the skin or reduce toxin absorption through the skin. Mineral oil, sodium sulfate, and other laxatives are often used to enhance elimination of toxins still present in the gastrointestinal tract. Gastric lavage may be used to enhance removal of toxins still present in the stomach.

Supportive Treatment Myriad drugs are given to animals with toxicoses with the intention of providing supportive treatment. Supportive treatment is also often given irrespective of the specific toxin. These drugs are normally given to correct an abnormal physiologic state. For example, fluids may be given to treat dehydration, bicarbonate may be given to treat acidosis, and furosemide may be given to treat edema or anuria.

Specific Treatment A few drugs are indicated when a specific toxin is known or suspected. These specific treatment agents are often called antidotes. (The definition of antidote used in this article is not as defined by the FDA but rather as presented in different veterinary texts). An antidote is a substance that can counteract the activity or effect of a known or suspected poison. Antidotes may be classified according to their mechanism of action: chemical or pharmacologic. Chemical antidotes interact specifically with a toxicant or neutralize a toxicant. For example, chelators combine with elements (especially heavy metals) to form complexes that can then be eliminated (as with molybdenum and sulfate for copper toxicity and calcium ethylene­ diaminetetraacetic acid [EDTA] for lead toxicity). Pharmacologic antidotes may neutralize or antagonize the metabolic or physiologic effects of a toxicant, for example (1) preventing formation of toxic metabolites as with 4-methylpyrazole for ethylene glycol toxicity; (2) competing with a toxicant’s action at a receptor site as with naloxone for opioid toxicity; (3) facilitating more rapid or complete urinary elimination of a toxicant by alkalizing the urine with sodium bicarbonate (to eliminate salicylate, phenobarbital, and 2,4-D), (4) facilitating elimination by acidifying the urine with ammonium chloride (to eliminate amphetamine, phencyclidine, and strychnine); (5) blocking receptors responsible for the toxic effect as with atropine for organophosphate toxicity; or (6) aiding in the restoration of normal detoxification mechanisms as with

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N-acetylcysteine for acetaminophen toxicity). In addition, specific antidotes may act directly on the toxin as in the case of antitoxins.

Animal Drugs That Are Biologics Some drugs used to treat toxicoses are not approved by the FDA under the FFDCA but are licensed by the U.S. Department of Agriculture (USDA) under the VirusSerum-Toxin Act (VSTA). The VSTA is implemented by the Center for Veterinary Biologics of the USDA Animal and Plant Health Inspection Service. Examples of such products include antivenins and antitoxins. Animal drugs produced and distributed in full conformance with VSTA have a USDA code rather than an FDA-assigned New Animal Drug Application [NADA] or Abbreviated New Animal Drug Application [ANADA] number. Examples include botulinum antitoxin (USDA Code 6400), tetanus antitoxin (USDA Code 6302.00 & 6302.01), and Crotalidae antivenin (USDA Code 6101.00). Antivenins for animals that are licensed as biologics by the USDA are a unique form of legally marketed animal drugs.*† More information about the USDA Center for Veterinary Biologics and a listing of licensed veterinary biologics are available at http://www.aphis.usda.gov/animal_health/ vet_biologics/.

Drugs Approved to Treat Toxicoses The limited availability of drugs approved to treat toxicoses is a long-standing problem in veterinary medicine. The drugs listed in Web Table 10-1 are approved by the FDA for use in animals for treatment of toxicoses. Use of these drugs, as indicated on labels, does not give rise to the extralabel drug use issues (discussed later in this chapter). Other than the approved uses of the seven drugs listed in Web Table 10-1, any drug used to treat animal toxicoses is likely done so in an extralabel, or an unapproved, manner. Consequently, review of extralabel drug use regulations may be of value to practicing veterinarians (see Web Table 10-1).

Extralabel Drug Use in Treating Animal Toxicoses The Animal Medicinal Drug Use Clarification Act (AMDUCA) of 1994 (Pub. L. 103-396) allows veterinarians to legally administer or prescribe any drug approved

*21 CFR x 510.4 Biologics; products subject to license control. An animal drug produced and distributed in full conformance with the animal, virus, serum, and toxin law of March 4, 1913 (37 Stat. 832; 21 U.S.C. 151 et seq.) and any regulations issued thereupon shall not be deemed to be subject to section 512 of FFDCA. † Blood and blood products are unique animal drugs. Although animal blood and blood products, such as fresh or frozen plasma, whole blood, or blood cell products, are drugs under the FFDCA, the FDA is not currently regulating blood and blood products for animals.

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WEB TABLE 10-1  Drugs Approved by the US FDA/CVM to Treat Animal Toxicoses Proprietary & (Established) Names

Reference (CFR Citation & NADA or ANADA #)

Dose

Indication

Antisedan ® (Atipamezole hydrochloride)

Inject intramuscularly the same volume as that of dexmedetomidine or medetomidine used.

For reversal of the sedative and analgesic effects of dexmedetomidine hydrochloride or medetomidine hydrochloride in dogs.

21 CFR § 522.147* NADA 141033**

Cuprate (Cupric glycinate)

200 mg (1 ml) for calves 300 # and under; 400 mg (2 ml) for calves over 300 # and adult cattle. For subcutaneous use.

For beef calves and beef cattle for the prevention of copper deficiency, or when labeled for veterinary prescription use, for the prevention and/or treatment of copper deficiency alone or in association with molybdenum toxicity. Note: Slaughter Withdrawal Time = 30 days.

21 CFR § 522.518 NADA 031-971

Antizol-Vet® (Fomepizole)

20 milligrams intravenously per kilogram initially, 15 milligrams intravenously per kilogram at 12 and 24 hours, and 5 milligrams intravenously per kilogram at 36 hours.

As an antidote for ethylene glycol (antifreeze) poisoning in dogs which have ingested or are suspected of having ingested ethylene glycol.

21 CFR § 522.1004 NADA 141-075, ANADA 200-472 ■

Narcan Injection (Naloxone hydrochloride)

It is administered by intravenous, intramuscular, or subcutaneous injection at an initial dose of 0.04 milligram per kilogram of body weight. When given intravenously, the dosage may be repeated at 2- to 3-minute intervals as necessary. Onset of action by intramuscular or subcutaneous injection is slightly longer than it is by intravenous injection, and repeated dosages must be administered accordingly.

As a narcotic antagonist in dogs.

21 CFR § 522.1462 NADA 035-825

Protopam (Pralidoxime hydrochloride)

It is administered as soon as possible after exposure to the poison. Before administration of the sterile pralidoxime chloride, atropine is administered intravenously at a dosage rate of 0.05 milligram per pound of body weight, followed by administration of an additional 0.15 milligram of atropine per pound of body weight administered intramuscularly. Then the appropriate dosage of sterile pralidoxime chloride is administered slowly intravenously. See labeling for further dosage information.

For use in horses, dogs, and cats as an antidote in the treatment of poisoning due to those pesticides and chemicals of the organophosphate class which have anticholinesterase activity in horses, dogs, and cats.

21 CFR § 522.1862 NADA 039-204

Tolazine® (Tolazoline hydrochloride)

100 milligrams per milliliter. Administer slowly by intravenous injection 4 milligrams per kilogram of body weight or 1.8 milligrams per pound.

For use in horses when it is desirable to reverse the effects of sedation and analgesia caused by xylazine.

21 CFR § 522.2474 NADA 140-994

Yobine® Antagonil® (Yohimbine hydrochloride)

0.05 milligram per pound (0.11 milligram per kilogram) of body weight intravenously.

To reverse the effects of xylazine in dogs.

21 CFR § 522.2670 NADA 140-866, NADA 140-874

*21 CFR § 522.147 = Title 21 of the Code of Federal Regulations, part 522, section 147. **NADA = New Animal Drug Application; ■ = Abbreviated New Animal Drug Application.

WEB CHAPTER  10  Treatment of Animal Toxicoses: Regulatory Points to Consider

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for use in humans or animals in an extralabel manner (“Extralabel Drug Use in Animals; Final Rule,” published in the Federal Register 61[217]:57732-46, 1996). AMDUCA and the regulations that implement it, however, require that such ELUs conform with several conditions and comply with several limitations (described later in this chapter). Because of the need to avoid potentially harmful tissue residues in food derived from foodproducing animals, there are additional conditions and limitations that apply when food animals are treated with a drug in an extralabel manner. (See the Veterinary Clinics of North America Food Animal Practice, p. 481 for a more detailed discussion of the food animal requirements.)

Extralabel Drug Use: Responsibilities and Limitations

Extralabel Drug Use: Definition

Responsibilities

ELU is defined in 21 CFR § 530.3 as actual use or intended use of a drug in an animal in a manner that is not in accordance with the approved labeling. This includes, but is not limited to, use in species not listed in the labeling; use for indications (disease or other conditions) not listed in the labeling; use at dosage levels, frequencies, or routes of administration other than those stated in the labeling; and deviation from the labeled withdrawal time based on these different uses. According to 21 CFR § 530.2, extralabel drug use is limited to treatment modalities when the health of an animal is threatened or suffering or death may result from failure to treat. When considering an ELU of an approved drug, veterinarians are encouraged to keep in mind that ELUs are permitted only for such therapeutic uses. In the authors’ view, treating animals with a toxicosis are cases in which the health of the animals is threatened or suffering or death may result from a failure to treat the animals. Consequently, treatment of animals with a toxicosis often meets the purpose of the regulation implementing the ELU statute. Only veterinarians may authorize or prescribe ELU. Laypersons may administer an approved animal or human drug in an extralabel manner only under the supervision of a licensed veterinarian.

Valid VCPR Both the scope of the ELU regulation and the provisions permitting it require that such drug use be within the context of a valid VCPR. Most practicing veterinarians are aware of what constitutes a valid VCPR under their state practice act or the American Veterinary Medical Association Principles of Veterinary Medical Ethics. These requirements may not align exactly with the requirements under the FFDCA. For purposes of ELU permitted under the FFDCA, a VCPR requires that a veterinarian has assumed responsibility for making medical judgments, the client has agreed to follow the veterinarian’s instructions, the veterinarian has made a preliminary diagnosis, and the veterinarian is readily available for follow-up.*

*Provision permitting ELU of animal drugs. An approved new animal drug or human drug intended to be used for an extralabel purpose in an animal is not unsafe under section 512 of the act and is exempt from the labeling requirements of section 502(f) of the act if such use is (a) by or on the lawful written or oral order of a licensed veterinarian within the context of a valid VCPR and (b) in compliance with this part. 21 CFR §530.10. Scope: This part applies to the ELU in an animal of any approved new animal drug or approved new human drug by or on the lawful order of a licensed veterinarian within the context of a valid VCPR. 21 CFR § 530.1. Definition of a valid VCPR(i): a valid VCPR is one in which

client (the owner of the animal or animals or other caretaker) has agreed to follow the instructions of the veterinarian; (2) There is sufficient knowledge of the animal(s) by the veterinarian to initiate at least a general or preliminary diagnosis of the medical condition of the animal(s); and (3) The practicing veterinarian is readily available for follow-up in case of adverse reactions or failure of the regimen of therapy. Such a relationship can exist only when the veterinarian has recently seen and is personally acquainted with the keeping and care of the animal(s) by virtue of examination of the animal(s), and/or by medically appropriate and timely visits to the premises where the animal(s) are kept. 21 CFR § 530.3(i).

(1) A veterinarian has assumed the responsibility for making medical judgments regarding the health of (an) animal(s) and the need for medical treatment, and the

ELU privileges come with many responsibilities for the veterinary profession. These responsibilities include establishing a valid veterinarian-client-patient relationship (VCPR), establishing extended withdrawal times when the use is in food animals, providing labeling that meets the ELU requirements, and keeping records of the ELU. In addition, veterinarians need to know when ELU is not permitted and the responsibilities and limitations of using drugs compounded from approved products. Each of these responsibilities and limitations is discussed in turn.

Extended Withdrawal Times When an ELU is for a food animal, the prescribing veterinarian must establish a substantially extended withdrawal period before marketing of milk, meat, eggs, or other edible products from the animal to be treated. Labeling ELU requires special labeling by a practitioner. Specifically, the veterinarian’s name and address, established name of the ingredients, directions for use, cautionary

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SECTION  II  Toxicologic Diseases

statements, and withdrawal times, if applicable, must be included on the label.* Adequate directions for use include the species, dosage, frequency, duration of treatment, and route of administration. Records Veterinarians are required to keep records as a condition of ELU. These records are required to contain the established name of the ingredients, condition treated, species, dosage, duration, number of animals treated, and withdrawal time provided, if applicable. These re­­ cords are to be kept for a minimum of 2 years or longer if required by state law or another federal law. The FDA is to be provided access to these records on request.

Limitations and Prohibitions Approved Drugs ELU is permitted only if there is no approved new animal drug that is labeled for such use and that contains the same active ingredient in the required dosage form and concentration except where a veterinarian finds, within the context of a valid VCPR, that the approved new animal drug is clinically ineffective for its intended use.†

Food Animals To promote the safety of animal products eaten by people, additional limits apply to ELU in food animals. ELU may not result in a residue that may present a risk to public health or that exceeds established safe levels or tolerances. Some drugs, which are listed in FDA regulations at 21 CFR sec 530.41 (a) (see http://www.access.gpo. gov/nara/cfr/waisidx_10/21cfr530_10.html), are entirely prohibited from ELU in food animals. ELU is not permitted in animal feed. Compounding Compounding of drugs from approved, finished animal, or human drugs is permitted as an ELU of approved drugs. Such compounding is permitted only when the available dosage form or concentration of the approved animal or human drug does not treat the condition diagnosed (Web Tables 10-2 and 10-3). Compounding of drugs from bulk chemicals is not permitted under the extralabel drug use regulations (discussed later in this chapter).‡ Approved Animal or Human Drugs That Are Commonly Recommended to Treat Animal Toxicoses but Are Not Approved to Treat a Toxicosis Drugs that are commonly recommended to treat animal toxicoses and that are approved for use in animals Text continued on p. e67

*21 CFR sec. 530.12 Labeling. Any human or animal drug prescribed and dispensed for extra­ label use by a veterinarian or dispensed by a pharmacist on the order of a veterinarian shall bear or be accompanied by labeling information adequate to assure the safe and proper use of the product. Such information shall include the following:

(c) ELU resulting in any residue which may present a risk to the public health; and (d) ELU resulting in any residue above an established safe level, safe concentration, or tolerance. 21 CFR 530.11

(a) The name and address of the prescribing veterinarian. If the drug is dispensed by a pharmacy on the order of a veterinarian, the labeling shall include the name of the prescribing veterinarian and the name and address of the dispensing pharmacy, and may include the address of the prescribing veterinarian; (b) The established name of the drug or, if formulated from more than one active ingredient, the established name of each ingredient; (c) Any directions for use specified by the veterinarian, including the class/species or identification of the animal or herd, flock, pen, lot, or other group of animals being treated, in which the drug is intended to be used; the dosage, frequency, and route of administration; and the duration of therapy; (d) Any cautionary statements; and (e) The veterinarian’s specified withdrawal, withholding, or discard time for meat, milk, eggs, or any other food which might be derived from the treated animal or animals.

‡

†

In addition to uses which do not comply with the provision set forth in Sec. 530.10, the following specific ELUs are not permitted and result in the drug being deemed unsafe within the meaning of section 512 of the act:

(a) ELU in an animal of an approved new animal drug or human drug by a layperson (except when under the supervision of a licensed veterinarian); (b) ELU of an approved new animal drug or human drug in or on an animal feed;

Definition: animal drug compounding is defined as a process by which a person combines, mixes, or alters ingredients to create a new animal drug that is not the subject of an application that has been approved under 512 of the FFDCA. Requirements: (a) This part applies to compounding of a product from approved animal or human drugs by a veterinarian or a pharmacist on the order of a veterinarian within the practice of veterinary medicine. Nothing in this part shall be construed as permitting compounding from bulk drugs. (b) ELU from compounding of approved new animal or human drugs is permitted if

(1) All relevant portions of this part have been complied with; (2) There is no approved new animal or approved new human drug that, when used as labeled or in conformity with criteria established in this part, will, in the available dosage form and concentration, appropriately treat the condition diagnosed. Compounding from a human drug for use in food-producing animals will not be permitted if an approved animal drug can be used for the compounding; (3) The compounding is performed by a licensed pharmacist or veterinarian within the scope of a professional practice; (4) Adequate procedures and processes are followed that ensure the safety and effectiveness of the compounded product; (5) The scale of the compounding operation is commensurate with the established need for compounded products (e.g., similar to that of comparable practices); and (6) All relevant state laws relating to the compounding of drugs for use in animals are followed. (7) Guidance on the subject of compounding may be found in guidance documents issued by FDA. 21 CFR § 530.13.

WEB CHAPTER  10  Treatment of Animal Toxicoses: Regulatory Points to Consider

e59

WEB TABLE 10-2  Extralabel Drug Use—Drugs Approved for Use in Animals, But Not Approved to Treat a Toxicosis per se

Established Name

Indication

Acepromazine maleate

Used as a tranquilizer in dogs, cats, and horses.

Used as a tranquilizer in dogs and cats. It is used in dogs as an aid in tranquilization and as a pre-anesthetic agent in dogs.

Reference (CFR Citation, NADA   or ANADA #) 21 CFR § 522.23 NADA 015-030; ANADA 200-319; ANAD 200-361 21 CFR § 520.23 NADA 032-702 21 CFR § 522.23 NADA 117-531; NADA 117-532

Dextrose

Dextrose/glycine/electrolyte is indicated for use in the control of dehydration associated with diarrhea (scours) in calves. It is used as an early treatment at the first signs of scouring. It may also be used as follow-up treatment following intravenous fluid therapy. Cattle and calves. NOTE: Withdrawal times not reported in the CFR.

21 CFR § 520.550 NADA 125-961

Furosemide

Used for the treatment of edema (pulmonary congestion, ascites) associated with cardiac insufficiency and acute noninflammatory tissue edema in dogs, cats, and horses. For treatment of edema (pulmonary congestion, ascites) associated with cardiac insufficiency and acute noninflammatory tissue edema in dogs and cats. For treatment of edema (pulmonary congestion, ascites) associated with cardiac insufficiency and acute noninflammatory tissue edema in dogs.

21 CFR § 522.1010 NADA 034-478; ANADA 200-293 21 CFR§ 520.1010 NADA 034-621 NADA 129-034

It is used for treatment of acute noninflammatory tissue edema in horses.

Used for the treatment of physiological parturient edema of the mammary gland and associated structures in cattle. NOTE: 48 hours for milk and slaughter withdrawal.

Examples of Toxicoses

Reference

Sympathomimetics (e.g., pseudoephedrine, phenylpropanolamine) Ammoniated feed syndrome (imidazoles)

4, 7

Toxins causing pulmonary edema (e.g., Japanese yew, cholecalciferol)

4, 7

Strychnine, metaldehyde, pyrethrins (cats), some mycotoxins

4, 6, 7

21 CFR § 520.1010 NADA 102-380; ANADA 200-373; ANADA 200-382 21 CFR § 520.1010 NADA 118-550; NADA 127-034 21 CFR § 520.1010 NADA 045-188

Gelatin solution

It is used to restore circulatory volume and maintain blood pressure in animals being treated for shock. Horses, small animals, cattle, sheep. NOTE: Withdrawal times not reported in the CFR.

21 CFR § 522.1020 NADA 006-281

Methocarbamol

As an adjunct for treating acute inflammatory and traumatic conditions of the skeletal muscles and to reduce muscular spasms in dogs, cats, and horses. As an adjunct to therapy for acute inflammatory and traumatic conditions of the skeletal muscles in order to reduce muscular spasms in dogs and cats.

21 CFR § 522.1380 NADA 038-838 21 CFR § 520.1380 NADA 045-715

Continued

e60

SECTION  II  Toxicologic Diseases

WEB TABLE 10-2  Extralabel Drug Use—Drugs Approved for Use in Animals, But Not Approved to Treat a Toxicosis   per se—cont’d

Established Name

Indication

Neostigmine

The drug is intended for use for treating rumen atony; initiating peristalsis which causes evacuation of the bowel; emptying the urinary bladder; and stimulating skeletal muscle contractions. It is a curare antagonist in horses. Sheep, cattle, swine, horses. NOTE: Not for use in animals producing milk.

Pentobarbital

The drug is indicated for use as a general anesthetic in dogs and cats. Although it may be used as a general surgical anesthetic for horses, it is usually given at a lower dose to cause sedation and hypnosis and may be supplemented with a local anesthetic. It may also be used in dogs for the symptomatic treatment of strychnine poisoning. It is used as an anesthetic for intravenous administration to dogs during short to moderately long surgical procedures in dogs and cats. For humane, painless, and rapid euthanasia.

General anesthesia and as a sedative-relaxant in horses and cattle. Prednisone

It is used for conditions requiring an antiinflammatory agent in dogs cats, and horses. It is used for conditions requiring an antiinflammatory agent in dogs, cats, and horses. It is used for conditions requiring an antiinflammatory agent in dogs, cats, and horses.

Reference (CFR Citation, NADA   or ANADA #)

Examples of Toxicoses

Reference

21 CFR § 522.1503 NADA 008-097

Larkspur, neuromuscular blockers (curare, others), ivermectin (cats)

4, 6

21 CFR § 522.1704 NADA 004-536; NADA 045-737

Strychnine, chlorinated hydrocarbons

6

Cholecalciferol

4, 6

As an emetic in cats

6, 7

21 CFR § 522.2444b NADA 010-346 21 CFR § 522.900 NADA 119-807; ANADA 200-071: ANADA 200-280 21 CFR § 522.380 NADA 046-789 21 CFR 522.1890 21 CFR § 522.1881 NADA 010-312 21 CFR § 522.1885 NADA 011-080

Prednisolone

Inflammatory, allergic, or other stress conditions in horses, dogs, or cats.

21 CFR § 522.1884 NADA 011-593

Methylprednisolone

For use as an antiinflammatory agent in dogs and cats.

21 CFR § 520.1408 NADA 011-403 21 CFR § 522.1410 NADA 012-204

Treatment of inflammation and related disorders in dogs; treatment of allergic and dermatologic disorders in dogs; and as supportive therapy to antibacterial treatment of severe infections in dogs. Xylazine

Dogs: To produce sedation, as an analgesic, and as a pre-anesthetic to local or general anesthesia. Cats: The drug is used in cats to produce sedation, as an analgesic, and a pre-anesthetic to local anesthesia. It may also be used in cats as a pre-anesthetic to general anesthesia. To produce sedation, as an analgesic, and as a pre-anesthetic to local or general anesthesia in dogs and cats.

21 CFR § 522.2662

21 CFR § 522.266 NADA 047-955 ANADA 200-184

WEB CHAPTER  10  Treatment of Animal Toxicoses: Regulatory Points to Consider

e61

WEB TABLE 10-2  Extralabel Drug Use—Drugs Approved for Use in Animals, But Not Approved to Treat a Toxicosis per se—cont’d

Established Name

Reference (CFR Citation, NADA   or ANADA #)

Indication To produce sedation, as an analgesic, and as a pre-anesthetic to local or general anesthesia in dogs, cats, and horses. Fallow deer (Dama dama), Mule deer (Odocoileus hemionus), sika deer (Cervus nippon), and white-tailed deer (Odocoileus virginianus), Elk (Cervus canadensis): Indications: To produce sedation, as an analgesic, and as a pre-anesthetic to local anesthesia. To produce sedation, accompanied by a shorter period of analgesia. May be used to calm and facilitate handling of fractious animals for diagnostic procedures, for minor surgical procedures, for therapeutic medication, for sedation and relief of pain following injury or surgery, and as a preanesthetic to local anesthetic. At the recommended dosages, can be used in conjunction with local anesthetics, such as procaine or lidocaine. To produce sedation, as an analgesic, and as a pre-anesthetic to local or general anesthesia.

Examples of Toxicoses

Reference

21 CFR § 522.2662 NADA 047-956; NADA 139-236; ANADA 200-088; ANADA 200-139

NADA 140-442

NOTE: Withdrawal times are based on use at the label dosage. Longer withdrawal times may be required if higher or longer dosages are used.

WEB TABLE 10-3  Extralabel Drug Use: Established Names of Drugs Approved for Use in Humans, But Not in Animals Active Ingredient

Dosage Form/ Route

Concentration

Use in Animals with Toxicosis

Toxicosis

Acetic acid, glacial

Solution, drops / Otic

2%

Acidify

Ammonia and other alkylinating agents

Acetic acid, glacial

Solution / Irrigation, urethral

250 mg / 100 ml (0.25%)

Acidify

Ammonia and other alkylinating agents

Aminophylline

Enema / Rectal

300 mg / 5 ml*

Bronchodilator

Fog Fever

Aminophylline

Injectable / Injection

25 mg / ml

Bronchodilator

Fog Fever

Aminophylline

Solution / Oral

105 mg / 5 ml*

Bronchodilator

Fog Fever

Aminophylline

Suppository / Rectal

250* mg and 500* mg / suppository

Bronchodilator

Fog Fever

Aminophylline

Tablet, Delayed Release / Oral

100* and 200* mg / tablet

Bronchodilator

Fog Fever

Aminophylline

Tablet, Extended Release / Oral

225 mg / tablet*

Bronchodilator

Fog Fever

Aminophylline

Tablet / Oral

100 and 200 mg / tablet

Bronchodilator

Fog Fever

Aminophylline in sodium chloride 0.45%

Injectable / Injection

100* mg and 200* mg and 400* mg and 500* mg / 100 ml

Bronchodilator

Fog Fever

Continued

e62

SECTION  II  Toxicologic Diseases

WEB TABLE 10-3  Extralabel Drug Use: Established Names of Drugs Approved for Use in Humans, But Not in Animals—cont’d Active Ingredient

Dosage Form/ Route

Concentration

Use in Animals with Toxicosis

Toxicosis

Ammonium chloride

Injectable / Injection

900 mg / 100 ml (0.9%)*; 40 meq / 100 ml (2.14% or 21.4 mg/ml)*; 3 meq / ml (160.5 mg/ml)*; and 5 meq/ml (267.5 mg/ml)

Urine Acidification

Apomorphine hydrochloride

Injectable / Subcutaneous

20 mg/2 ml* and 30 mg/3 ml [Note: both products 10 mg/ml]

Emetic

Most

Atropine

Injectable / Injection

Eq to 0.5 mg sulfate / 0.7 ml (0.71 mg/ ml); Eq to 0.25 mg sulfate/0.3 ml (0.83 mg/ml); Eq to 1 mg sulfate / 0.7 ml (1.43 mg/ml); Eq to 2 mg sulfate / 0.7 ml (2.86 mg/ml)

Anticholinergic

Cholinesterase Inhibitors, Pyrethroids

Atropine and Pralidoxime chloride

Injectable / Intramuscular

2.1 mg atropine / 0.7 ml and 600 mg pralidoxime chloride / 2 ml

Reactivation of cholinesterase activity

Cholinesterase inhibitors

Atropine sulfate

Aerosol, metered / Inhalation

Eq to 0.36 mg base / inh*

Anticholinergic

Cholinesterase Inhibitors, Pyrethroids

Atropine sulfate

Injectable / IM-IV-SC

0.05 mg and 0.1 mg / ml

Anticholinergic

Cholinesterase Inhibitors, Pyrethroids

Calcitonin human

Injectable / Injection

0.5 mg / vial*

Hypercalcemia

Vitamin D

Calcitonin salmon

Injectable / Injection

400 IU / vial*; 100 IU / ml*; and 200 IU / ml

Hypercalcemia

Vitamin D

Calcitonin salmon

Metered Spray / Nasal

200 IU / spray

Hypercalcemia

Vitamin D

Calcitonin salmon recombinant

Metered Spray / Nasal

200 IU / spray

Hypercalcemia

Vitamin D

Calcium chloride

Injectable / Injection

100 mg / ml

Hypocalcemia

Oxalis

Cholestyramine

Powder / Oral

Equivalent to 4 gm resin / packet and equivalent to 4 gm resin / scoopful

Cholestyramine

Chewable Bar / Oral

Equivalent to 4 gm resin / bar*

Cholestyramine

Tablet / Oral

Equivalent to 1 gm resin / tablet* and equivalent to 800 mg resin / tablet*

Cimetidine

Tablet / Oral

100 mg*, 200 mg, 300 mg, 400 mg, and 800 mg / tablet

Gastric protectant

NSAID/ Vitamin D

Cimetidine

Suspension / Oral

200 mg / 20 ml*

Gastric protectant

NSAID/ Vitamin D

Cimetidine HCl

Solution / Oral

Equivalent to 300 mg base / 5 ml

Gastric protectant

NSAID/ Vitamin D

Cimetidine HCl

Injectable/ Injection

Equivalent (EQ) to 90 mg base / 100 ml*; EQ to 120 mg base / 100 ml*; EQ to 180 mg base / 100 ml*; EQ to 240 mg base / 100 ml*; EQ to 360 mg base / 100 ml*; EQ to 480 mg base / 100 ml*; EQ to 6 mg base / ml; and EQ to 300 mg base / 2 ml (150 mg / ml)

Gastric protectant

NSAID/ Vitamin D

Cyanocobalamin

Gel, Metered / Nasal

0.5* mg / inh

Cyanide

WEB CHAPTER  10  Treatment of Animal Toxicoses: Regulatory Points to Consider

e63

WEB TABLE 10-3  Extralabel Drug Use: Established Names of Drugs Approved for Use in Humans, But Not in Animals—cont’d Active Ingredient

Dosage Form/ Route

Concentration

Use in Animals with Toxicosis

Toxicosis

Cyanocobalamin

Injectable / Injection

0.03* mg / ml and 0.05* mg / ml and 0.1* mg / ml and 0.12* mg / ml and 1 mg / ml

Cyanide

Cyanocobalamin

Spray, Metered / Nasal

25* mcg (micrograms) / spray and 0.5 mg (500 mcg) / spray

Cyanide

Cyanocobalamin

Tablet / Oral

1* mg / tablet

Cyanide

Cyproheptadine HCl

Tablet / Oral

4 mg / tablet

Antihistamine

Cyproheptadine HCl

Syrup / Oral

2 mg / 5 ml

Antihistamine

Dantrolene sodium

Capsule / Oral

25 mg, 50 mg, and 100 mg / capsule

Muscle relaxant

Dantrolene sodium

Injectable / Injection

20 mg / vial

Muscle relaxant

Dapsone

Gel / Topical

5%

Brown recluse spider

Dapsone

Tablet / Oral

25 mg and 100 mg / tablet

Deferoxamine mesylate

Injectable / Injection

500 mg / vial and 2 gm / vial

Digoxin

Capsule / Oral

0.05* mg / capsule; 0.1 mg / capsule; 0.15* mg / capsule; and 0.20 mg / capsule

Congestive heart failure

Digoxin

Injectable / Injection

0.1 mg / ml and 0.25 mg / ml

Congestive heart failure

Digoxin

Tablet / Oral

0.0625* mg / tablet; 0.125 mg / tablet; 0.1875* mg / tablet; 0.25 mg / tablet; 0.375* mg / tablet; and 0.5* mg / tablet

Congestive heart failure

Dimercaprol

Injectable / Injection

10% (100 mg / ml)

Sulfhydryl group binding

Arsenic, Mercury

Diphenhydramine HCl

Syrup / Oral

12.5 mg / 5 ml*

Muscle fasciculations

Nicotine

Diphenhydramine HCl

Elixir / Oral

12.5 mg / 5 ml

Muscle fasciculations

Nicotine

Diphenhydramine HCl

Capsule / Oral

25 mg* and 50 mg / capsule

Muscle fasciculations

Nicotine

Diphenhydramine HCl

Injectable / Injection

10 mg / ml and 50 mg / ml

Muscle fasciculations

Nicotine

D-penicillamine

Capsule / Oral

125 mg* and 250 mg / capsule

Chelate Divalent Cations

Lead

Edrophonium chloride

Injectable / Injection

10 mg / ml

Reversal of nondepolarizing agents

Epinephrine

Aerosol, metered / Inhalation

0.25* mg / inh

Anaphylaxis

Epinephrine

Injectable / IM-SC

0.15 mg and 0.3 mg / delivery

Anaphylaxis

Epinephrine

Injectable / Injection

1.5* mg / amp and 5* mg / ml

Anaphylaxis

Epinephrine

Injectable / Intramuscular

0.15* mg and 0.3* mg / delivery

Anaphylaxis

Epinephrine bitartrate

Aerosol, metered / Inhalation

0.3* mg / inh

Anaphylaxis

Etidronate disodium

Injectable / Injection

50 mg / ml*

Hypercalcemia

Etidronate disodium

Tablet / Oral

200 mg and 400 mg / tablet

Hypercalcemia Continued

Brown recluse spider Chelate Divalent Cations

Iron, Aluminum

e64

SECTION  II  Toxicologic Diseases

WEB TABLE 10-3  Extralabel Drug Use: Established Names of Drugs Approved for Use in Humans, But Not in Animals—cont’d Dosage Form/ Route

Concentration

Ferric hexacyanoferrate (II) (Prussian Blue)

Capsule / Oral

500 mg / capsule

Flumazenil

Injectable / Injection

0.5 mg/5 ml and 1 mg/10 ml [both 0.1 mg/ml]

Benzodiazepine

Folic Acid

Injectable / Injection

5 mg / ml

Folic acid deficiency

Folic Acid

Tablet / Oral

1 mg / tablet

Glucagon HCl

Injectable / Injection

Equivalent to 1 mg* and 10 mg* base / vial

Hypocalcemia

Glucagon HCl Recombin.

Injectable / Injection

Equivalent to 1 mg base / vial

Hypocalcemia

Glucagon Recombinant

Injectable / Injection

1 mg / vial

Hypocalcemia

Hydroxocobalamin

Injectable / Injection

2.5 g / vial and 2.5 g / vial (5 gm kit) and 1 mg / ml

Lactated Ringer’s

Injectable / Injection AND Solution / Irrigation

Calcium chloride—20 mg / 100 ml; potassium chloride—30 mg / 100 ml; sodium chloride—600 mg / 100 ml; sodium lactate—310 mg / 100 ml

Leucovorin calcium

Injectable / Injection

Equivalent to 3* mg base / ml and 5* mg base / ml and 50 mg base / vial and 100 mg base / vial and 350 mg base / vial

Reverse dihydrofolate reductase inhibitors

Leucovorin calcium

(for) Solution / Oral

Equivalent to 60* mg base / vial

Reverse dihydrofolate reductase inhibitors

Leucovorin calcium

Tablet / Oral

Equivalent to 5 mg base / tablet and 10 mg base / tablet and 15 mg base / tablet and 25 mg base / tablet

Reverse dihydrofolate reductase inhibitors

Levoleucovorin calcium

Powder / IV (infusion)

Equivalent to 50 mg base / vial

Reverse dihydrofolate reductase inhibitors

Magnesium sulfate

Injectable / Injection

4 gm / 100 ml (40 mg / ml); 4 gm / 50 ml (80 mg / ml); 2 gm / 50 ml (40 mg / ml); and 500 mg / ml

Hypomagnesemia

Magnesium sulfate in dextrose 5%

Injectable / Injection

1 gm / 100 ml (10 mg / ml); and 2 gm / 100 ml (20 mg / ml)

Hypomagnesemia

Mannitol

Injectable / Injection

5 gm / 100 ml (50 mg / ml or 5%); 10 gm / 100 ml (100 mg / ml or 10%); 15 gm / 100 ml (150 mg / ml or 15%); 20 gm / 100 ml (200 mg / ml or 20%); 12.5 gm / 50 ml (250 mg / ml or 25%)

Cerebral edema

Mannitol

Solution / Irrigation

5 gm / 100 ml (50 mg / ml or 5%)

Cerebral edema

Misoprostol

Tablet / Oral

0.1 mg and 0.2 mg / tablet

Prostaglandin deficiency

NSAIDs

N-Acetylcysteine

Injectable / Intravenous

6 gm / 30 ml (200 mg / ml)

Donate sulfhydryl groups, maintain cellular glutathione, reduced organ damage

Acetaminophen, other toxins that deplete glutathione

Active Ingredient

Use in Animals with Toxicosis

Toxicosis

Folic acid deficiency

Cyanide Dehydration

WEB CHAPTER  10  Treatment of Animal Toxicoses: Regulatory Points to Consider

e65

WEB TABLE 10-3  Extralabel Drug Use: Established Names of Drugs Approved for Use in Humans, But Not in Animals—cont’d Active Ingredient

Dosage Form/ Route

Concentration

Use in Animals with Toxicosis Donate sulfhydryl groups, maintain cellular glutathione, reduced organ damage

Toxicosis

N-Acetylcysteine

Solution / Inhalation, Oral

10% and 20%

Acetaminophen, other toxins that deplete glutathione

Norepinephrine Bitartrate

Injectable / Injection

Equivalent (EQ) to 1 mg base / ml

Pamidronate disodium

Injectable / Injection

30 mg / 10 ml (3 mg / ml); 60 mg / ml (6 mg / ml); 90 mg / 10 ml (9 mg / ml); 30 mg / vial; 60 mg / vial; and 90 mg / vial

Phentolamine mesylate

Injectable / Injection

0.4 mg / 1.7 ml and 5 mg / vial

Phytonadione (vitamin K1)

Injectable / Injection

1 mg / 0.5 ml (2 mg / ml) and 10 mg / ml

Hypovitaminosis K

Anticoagulant Rodenticides

Phytonadione (vitamin K1)

Tablet / Oral

5 mg / tablet

Hypovitaminosis K

Anticoagulant Rodenticides

Pilocarpine

Insert, extended release / Ophthalmic

5 mg* and 11 mg* / insert

Miotic agent

Pilocarpine HCl

Gel / Ophthalmic

4%

Miotic agent

Pilocarpine HCl

Solution / Ophthalmic

1%, 2%, and 4%

Miotic agent

Pilocarpine HCl

Tablet / Oral

5 mg and 7.5 mg / tablet

Pralidoxime chloride

Injectable / Injection

300 mg / ml and 1 gm / vial

Reactivate acetylcholinesterase enzyme

Organophosphates

Pralidoxime chloride

Tablet / Oral

500* mg / tablet

Reactivate acetylcholinesterase enzyme

Organophosphates

Protamine sulfate

Injectable / Injection

10 mg / ml; and 50* and 250* mg / vial

Heparin overdose, Bracken fern

Pyridostigmine bromide

Injectable / Injection

5 mg / ml

Myasthenia gravis

Pyridostigmine bromide

Syrup / Oral

60 mg / 5 ml (12 mg / ml)

Myasthenia gravis

Pyridostigmine bromide

Tablet, Extended Release / Oral

180 mg / tablet

Myasthenia gravis

Pyridostigmine bromide

Tablet / Oral

30* and 60 mg / tablet

Myasthenia gravis

Pyridoxine HCl

Injectable / Injection

50* and 100 mg / ml

Isoniazid, crimidine, doxorubicin

Ranitidine

Solution / Oral

15 mg / ml**

Reduce gastric acid secretion

NSAIDs, Vitamin D

Ranitidine

Syrup / Oral

15 mg / ml**

Reduce gastric acid secretion

NSAIDs, Vitamin D

Ranitidine bismuth citrate

Tablet / Oral

400 mg / tablet*

Reduce gastric acid secretion

NSAIDs, Vitamin D

Ranitidine HCl

Capsule / Oral

Equiv. to 150 and 300 mg base / capsule

Reduce gastric acid secretion

NSAIDs, Vitamin D

Hypercalcemia –especially associated with hypervitaminosis D

Miotic agent

Continued

e66

SECTION  II  Toxicologic Diseases

WEB TABLE 10-3  Extralabel Drug Use: Established Names of Drugs Approved for Use in Humans, But Not in Animals—cont’d Active Ingredient

Dosage Form/ Route

Concentration

Use in Animals with Toxicosis

Toxicosis

Ranitidine HCl

Granule, Effervescent/ Oral

Equivalent to 150 mg base / packet*

Reduce gastric acid secretion

NSAIDs, Vitamin D

Ranitidine HCl

Injectable / Injection

Equivalent (Eq) to 1 mg & 25 mg base/ ml; Eq to 50 mg base / 100 ml* (0.5 mg / ml)

Reduce gastric acid secretion

NSAIDs, Vitamin D

Ranitidine HCl

Syrup / Oral

Equivalent to 15 mg base / ml

Reduce gastric acid secretion

NSAIDs, Vitamin D

Ranitidine HCl

Tablet / Oral

Equivalent to 150 mg base / ml and 300 mg base / ml

Reduce gastric acid secretion

NSAIDs, Vitamin D

Ranitidine HCl

Tablet, Effervescent / Oral

Equivalent to 25 and 75* and 150* mg base / tablet

Reduce gastric acid secretion

NSAIDs, Vitamin D

Salt (sodium chloride)

Injectable / Injection

450 mg / 100 ml (4.5 mg / ml); 45 mg / 50 ml & 112.5 mg / 125 ml & 900 mg / 100 ml & 9 mg / ml (all equal to 9 mg / ml); 3 gm / 100 ml (30 mg / ml); 5 gm / 100 ml (50 mg / ml); 2.5 meq / ml (146.1 mg / ml); 20 gm* / 100 ml (200 mg / ml); and 234* mg / ml

Hyponatremia

Salt (sodium chloride)

Solution / Irrigation

450 mg / 100 ml (4.5 mg / ml); 900 mg / 100 ml (9 mg / ml)

Hyponatremia

Sodium bicarbonate

Injectable / Injection

0.9 and 1 meq / ml

Sodium polystyrene sulfonate

Powder / Oral, Rectal

453.6 and 454 gm / bottle

Hyperkalemia

Sodium polystyrene sulfonate

Suspension / Oral, Rectal

15 gm / 60 ml (250 mg / ml)

Hyperkalemia

Sodium thiosulfate

Injectable / Injection

250 mg / ml* [Note: 7 drugs already marketed, but without an approved NDA.]

Sulfur Donor

Cyanide, arsenic

Succimer (DMSA; mesodimercaptosuccinic acid)

Capsule/Oral

100 mg / capsule

Chelate Divalent Cations

Lead, other metals

Sucralfate

Suspension / Oral

1 gm / 10 ml (100 mg / ml)

Reduce gastric acid secretion

NSAIDs, Vitamin D

Sucralfate

Tablet / Oral

1 gm / tablet

Reduce gastric acid secretion

NSAIDs, Vitamin D

Thiamine HCl

Injectable / Injection

100 and 200 mg / ml

Thiamine Deficiency

Bracken fern

Trientine hydrochloride

Capsule / Oral

250 mg / capsule

Alkalinize blood

Acidosis

Copper chelation

* = marketing status is discontinued. ** = tentative approval with a marketing status of none. NOTE: established names of drugs in this table are based on an approved product at: http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm. The site should be consulted to determine whether a given product has been discontinued. Dosage form and concentration are based on all approved products whether or not they have become discontinued.

WEB CHAPTER  10  Treatment of Animal Toxicoses: Regulatory Points to Consider or humans, but are not approved to treat a toxicosis per se, are listed, respectively, in Web Tables 10-2 and 10-3.

Beyond Extralabel Drug Use— Unapproved Drugs The limited availability of approved safe and effective drugs to treat animal toxicoses has been a long-standing problem for veterinarians. This almost complete lack of approved drugs is in part due to the cost incurred to provide the evidence required to adequately evaluate human food safety concerns and to a small and unpredictable market for the finished products. Consequently, practitioners have few legal options when treating animals with a toxicosis. Practicing veterinarians may have an interest in potential solutions to the problem of scarcity of legal drugs to treat animals with toxicoses. Several options existing under or related to the Minor Use and Minor Species (MUMS) Act (see http://www.fda.gov/AnimalVeterinary/NewsEvents/CVMUpdates/ucm048420.htm) may potentially alleviate this problem. These options include conditional approval, indexing, designation, and the National Research Support Project 7 (NRSP-7). There are a number of chemicals and other products that contemporary veterinary reference texts recommend for use to treat toxicoses but for which no FDA human or animal approval currently exists. These products can be grouped into three broad categories: drugs that were approved but have been withdrawn, bulk chemicals for which enforcement discretion* has historically been exercised by the FDA, and bulk chemicals for which enforcement discretion has not historically been exercised. This list of products is not exhaustive. Because the chemicals or other products listed are commonly recommended in contemporary veterinary texts to treat toxicoses, the authors hope that inclusion of them in this chapter illustrates the limit of the extralabel drug use regulations as a legal foundation for the treatment of animals with toxicoses.

Withdrawn Drugs Drug approvals may be voluntarily withdrawn by a sponsor. If a drug is withdrawn, it is no longer an approved new animal drug. An example of a withdrawal relevant to this chapter is calcium EDTA, formerly approved as Havidote Injection (NADA 010-540). If an animal drug approval is withdrawn and no human approval exists, the drug is then outside the scope of the ELU regulations (discussed previously).

*For a variety of reasons, agencies do not enforce laws in all instances; enforcement discretion is a phrase used to refer to those particular times when an agency makes a choice to not fully enforce the law. Agencies’ exercise of enforcement discretion does not make the product or activity legal and may be reversed at any time.

e67

WEB TABLE 10-4  Unapproved Drugs: Bulk Chemicals that Are Included in Appendix A of the Compliance   Policy Guide 608.400 Bulk Chemical Ammonium molybdate Ammonium tetrathiomolybdate Methylene blue Picrotoxin Pilocarpine Sodium nitrite Sodium thiosulfate Tannic acid

Bulk Chemicals with Historic Enforcement Discretion Web Table 10-4 lists bulk chemicals commonly recommended for the treatment of animals with toxicoses for which no animal or human drug approval by the FDA exists but for which enforcement discretion has historically been exercised by the FDA. Veterinary practitioners should be aware that use of these chemicals is outside the scope of the federal ELU regulations (discussed previously). These chemicals do, however, fall within the scope of a Compliance Policy Guide (CPG) published by the FDA. CPGs are policy documents issued by the FDA that describe the agency’s enforcement approach to a particular set of products or activities that violates the FFDCA. CPG section 608.400, titled “Compounding of Drugs for Use in Animals,” explains the FDA’s policies with regard to compounding of animal drugs by veterinarians and pharmacists that violate the FFDCA (http://www.fda.gov/ ICECI/ComplianceManuals/CompliancePolicyGuidanceManual/ucm117042.htm). Because drugs compounded from bulk chemicals do not have approvals, their manufacture, distribution, and use violate the FFDCA (as discussed previously, drugs compounded from approved, finished drugs may meet the requirements for legal ELU). There is a potential for causing harm to public health and to animals when drug products are compounded, distributed, and used in the absence of adequate and wellcontrolled safety and effectiveness data or adherence to the principles of contemporary pharmaceutical chemistry and current good manufacturing practices. Use of compounded drugs in animals can result in adverse reactions and animal deaths. Furthermore, because the pharmacokinetics and depletion times for residues from compounded products intended for use in food-producing animals are not known, the assignment of an extemporaneous withdrawal time may result in potentially harmful residues in food. Inactive ingredients, such as excipients and vehicles, from unapproved or unknown origins may also pose additional risk (e.g., Freund adjuvant, a carcinogen).

e68

SECTION  II  Toxicologic Diseases

WEB TABLE 10-5 

WEB TABLE 10-6 

Unapproved Drugs: Bulk Chemicals That Are NOT in Appendix A of the Compliance Policy Guide 608.400 General Treatment Adsorbent

Activated Charcoal

Emetics

Syrup of Ipecac Hydrogen Peroxide

Laxatives

Mineral oil Sodium sulfate

Demulcents

Egg whites Milk

Drugs Exempted from Some Labeling Requirements When Used to Treat   Animal Toxicoses Established Name

Indication

Reference

Atropine sulfate

As an injectable should not be in excess of 15 mg per dosage unit for cattle, goats, sheep, horses, and pigs; and not in excess of 0.6 mg per dosage unit for dogs and cats.

21 CFR § 500.55

Epinephrine

Injection should be at the concentration of 1 : 1000 for cats, dogs, cattle, goats, horses, pigs, and sheep. Epinephrine 1 : 1000 in 10-milliliter containers for emergency treatment of anaphylactoid shock in cattle, horses, sheep, and swine can be made available for over-thecounter sale.

21 CFR § 500.55

Supportive Treatment Ammonium acetate

Methylthionium Chloride

Amyl nitrite

Milk Thistle

Ascorbate

Oxygen

Calcium gluconate

Pentylenetetrazol

Calcium lactate

Physostigmine Salicylate

Calcium phosphate

Sterile saline

Diphenylthiocarbazone Specific Treatment Ethanol Calcium EDTA

The FDA recognizes, however, that in some circumstances compounded animal drugs are important to veterinary practice and are necessary to prevent the suffering and death of animals. The FDA’s CPG on compounding of animal drugs describes factors the FDA considers in deciding whether to take enforcement action against illegally compounded drugs. In addition, Appendix A of the CPG includes a list of substances for compounding and subsequent use in animals to which the FDA does not normally object. These bulk chemicals are listed in Web Table 10-4. The FDA periodically revisits and updates such guidance, particularly as new information comes to the attention of the agency, so enforcement discretion may not be applied in the future in the same way it has in the past. Also, the Center for Veterinary Medicine has recently requested public comment on a potential policy change regarding unapproved animal drugs (http://www.regulations.gov/#!documentDetail;D5FDA-2010-N-0528-0001).

Bulk Chemicals without Historic Enforcement Discretion Web Table 10-5 lists some bulk chemicals identified by veterinary texts as useful as antidotes for which enforcement discretion has not historically been exercised by the FDA.

21 CFR § 500.65

The Unique Status of Epinephrine and Atropine Epinephrine and atropine have historically been marketed without approval. They are two examples of a few drugs that the FDA has exempted from certain labeling requirements generally applicable to animal drugs and instead provided the labeling by regulation. See Web Table 10-6 for the specific indications for epinephrine and atropine.

References and Suggested Reading Murphy MJ: A field guide to common animal poisons, Ames, IA, 1996, Iowa State University. Osweiler GD: Antidotes. In Owseiler GD, editor: Toxicology, Philadelphia, 1996, Williams & Wilkins. Peterson ME, Talcott PA, editors: Small animal toxicology, ed 2, Philadelphia, 2006, WB Saunders. Plumlee KH: Clinical veterinary toxicology, St Louis, 2004, Mosby. Hall K: Toxin exposures and treatments: a survey of practicing veterinarians. In Bonagura JD, Twedt DC, editors: Kirk’s current veterinary therapy XIV, Philadelphia, 2009, WB Saunders, p 95. Plumb DC: Plumb’s veterinary drug handbook, ed 6, Stockholm, WI, 2008, PharmaVet.

SECTION III Endocrine and Metabolic Diseases Chapter 39: Chapter 40: Chapter 41: Chapter Chapter Chapter Chapter Chapter Chapter Chapter Chapter Chapter Chapter Chapter

42: 43: 44: 45: 46: 47: 48: 49: 50: 51: 52:

Chapter Chapter Chapter Chapter Chapter Chapter

53: 54: 55: 56: 57: 58:

Bilaterally Symmetric Alopecia in Dogs 164 Imaging in Diagnosis of Endocrine Disorders 167 Approach to Critical Illness–Related Corticosteroid Insufficiency 174 Canine Hypothyroidism 178 Feline Hyperthyroidism and Renal Function 185 Canine Diabetes Mellitus 189 Diabetic Monitoring 193 Diet and Diabetes 199 Insulin Resistance 205 Feline Diabetes Mellitus  208 Feline Hypersomatotropism and Acromegaly 216 Occult Hyperadrenocorticism: Is It Real? 221 Canine Hyperadrenocorticism Therapy 225 Ectopic ACTH Syndrome and Food-Dependent Hypercortisolism in Dogs 230 Canine Hypoadrenocorticism 233 Feline Primary Hyperaldosteronism 238 Feline Idiopathic Hypercalcemia 242 Approach to Hypomagnesemia and Hypokalemia 248 Obesity 254 Approach to Canine Hyperlipidemia 261

The following web chapters can be found on the companion website at www.currentveterinarytherapy.com Web Chapter 11: Web Chapter 12: Web Chapter 13: Web Chapter 14: Web Chapter 15: Web Chapter 16: Web Chapter 17: Web Chapter 18: Web Web Web Web Web Web

Chapter Chapter Chapter Chapter Chapter Chapter

19: 20: 21: 22: 23: 24:

Hypercalcemia and Primary Hyperparathyroidism in Dogs Clinical Use of the Vasopressin Analog Desmopressin for the Diagnosis and Treatment of Diabetes Insipidus Complicated Diabetes Mellitus Complications and Concurrent Conditions Associated with Hypothyroidism in Dogs Large Pituitary Tumors in Dogs with Pituitary-Dependent Hyperadrenocorticism Differential Diagnosis of Hyperkalemia and Hyponatremia in Dogs and Cats Hyperadrenocorticism in Ferrets Interpretation of Endocrine Diagnostic Test Results for Adrenal and Thyroid Disease Medical Treatment of Feline Hyperthyroidism Nutritional Management of Feline Hyperthyroidism Radioiodine for Feline Hyperthyroidism Treatment of Hypoparathyroidism Treatment of Insulinoma in Dogs, Cats, and Ferrets Alternatives to Insulin Therapy for Diabetes Mellitus in Cats

163

CHAPTER 

39 

Bilaterally Symmetric Alopecia in Dogs ROBERT ALLEN KENNIS, Auburn, Alabama

E

ndocrine diseases are among the many causes of symmetric alopecia in the dog. In certain situations the cutaneous manifestations of endocrine disease provide some of the most obvious clinical signs. However, the clinician must consider a number of common and uncommon disorders when approaching the dog with symmetric alopecia (Box 39-1). As with most dermatologic disorders, signalment, historical information, and physical findings are the starting points to a diagnosis, followed by performance of appropriate laboratory tests and the collection of a dermatologic minimum database. This chapter provides a concise and rational guide for achieving a diagnosis when confronted with a canine patient with bilaterally symmetric alopecia. More details about these specific conditions can be found in this section and in Section V of this textbook.

Pruritic Alopecia By definition, alopecia means hair loss. It must be determined if the dog was pruritic and created the alopecia from trauma (e.g., biting, scratching, rubbing) or if the hair fell out spontaneously. Most endocrine and metabolic causes of alopecia are nonpruritic unless complicated by other lesions. For example, dogs with spontaneous hyperadrenocorticism may become pruritic if calcinosis cutis is present. Likewise, dogs with various metabolic disorders including hyperadrenocorticism may develop pruritus if secondary infection from bacteria or yeast occurs. The only pruritic endocrine disorder is hyperestrogenism. Pruritus in general is usually symmetric, and therefore trauma-induced alopecia may mimic metabolic causes of symmetric alopecia. Regardless of the cause, bilaterally symmetric alopecia is rarely identical on both sides. The presence of similar appearing lesions on both sides of the midline allows us to use this terminology. The presence of pruritus leads to a list of differential diagnoses that include myriad allergic, parasitic, and infectious diseases. Historical evidence supports traumainduced pruritus. A trichogram (sometimes referred to as a KOH prep) is an easy diagnostic procedure used to determine if the tips of the hairs are broken due to traumatic causes. Normal hairs should have a fine taper at the tip of the hairshaft, whereas broken hairs have blunted ends. Hairs are grasped at their base with hemostats or thumb forceps and removed with traction. They are then placed on a glass slide with a few drops of mineral oil or potassium hydroxide (KOH). Care should be taken to place the hairs in the same direction so that they can be examined from base to tip. The application of a cover slip 164

aids in viewing. The hairs can be examined under the microscope using either 4× or 10× magnification objectives. Lowering the light condenser makes viewing easier by increasing the refractivity. A KOH prep also can be used to identify other conditions. For example, in dermatophyte-infected hairs fungal spores (microconidia) may be visible. Affected hairs have a damaged cuticle, are asymmetric, and are usually much wider than normal hairs. The presence of macromelanosomes along with a damaged hair cuticle may assist in the diagnosis of color-dilution alopecia (Figure 39-1); however, the definitive diagnosis is based on clinical signs and histopathologic evaluation. Interestingly, large melanosomes may be seen in color-dilute breeds such as the weimaraner, but the cuticle is not damaged; therefore these breeds do not exhibit color-dilution alopecia (with rare exceptions). If broken hairs are present due to pruritic causes, every effort should be made to identify and treat the underlying cause of the pruritus. Of note is the historical use of glucocorticoid medications because such treatment could potentially interfere with interpretation of prior and future laboratory results.

Clinical Evaluation Historical information is important in all dermatologic cases. Questionnaire templates are available for clinical use in virtually every veterinary dermatologic textbook. These are an efficient way to collect the necessary data to help formulate a list of differential diagnoses. They also provide the client an opportunity to reflect on the history, which hopefully leads to a more accurate account of the clinical problem. The signalment alone may provide important data and should not be overlooked. Many endocrine skin disorders can be considered more likely based on the age of onset. Likewise, many breeds are overrepresented for certain endocrine causes of alopecia. Atypical coloration, such as a “blue” or “fawn” Doberman pinscher, may predispose the dog to color dilution alopecia at a later age. Although the Doberman is one of the most common breeds associated with this disorder, the Chihuahua, chow-chow, and Yorkshire terrier have increased prevalence. Any dog that exhibits a dilution pattern may develop color dilution alopecia. As puppies, affected dogs have a normal hair coat (other than color) and they may develop alopecia as the adult hairs replace the puppy coat. It is impossible to predict the age of onset or severity of the alopecia in color-dilute situations.

CHAPTER  39  Bilaterally Symmetric Alopecia in Dogs

BOX 39-1  Causes of Nonpruritic Canine   Symmetric Alopecia Hypothyroidism Hyperadrenocorticism Hypotestosteronism Hyperestrogenism Sertoli cell tumor–associated skin disease Alopecia X Color dilution alopecia Cyclical flank alopecia Anagen or telogen defluxion Post-clipping alopecia Traction alopecia Follicular dysplasia Acquired pattern alopecia

Figure 39-1  Photomicrogram of a hair. The base of the hair is

at the bottom. Note the damaged cuticle (arrow). Macromelanosomes can be seen within the hair; the melanosomes are large and clumped compared with the normal appearance (being much smaller, punctate, and distinct from each other).

The sex status of the dog is also important when considering hyperestrogenism. Sertoli cell tumor is a testicular neoplasm more common in male dogs with retained testicles. Female dogs may develop postpartum hair defluxion. Lastly, traction alopecia may occur from the exuberant use of rubber bands or hair clips on some canine breeds; therefore the grooming and maintenance history is helpful in making this diagnosis. A thorough investigation of all topical and systemic medications is required. Topical glucocorticoid medications can lead to local or systemic clinical signs such as skin atrophy, alopecia or follicular atrophy, changes in skin pigmentation, calcinosis cutis, and the development of secondary infections or demodicosis. Topical glucocorticoid medications have been responsible for inducing

165

some spectacular symmetric alopecias and should not be ignored when investigating the underlying cause of the problem. Topical steroids also can have a profound influence on serum biochemical test results, especially serum alkaline phosphatase. Other commonly used medications such as ketoconazole may not directly lead to the development of symmetric alopecia but may influence laboratory results.

Diagnostic Tests Once pruritic causes of alopecia have been removed or ruled out, additional baseline information is needed. Several deep skin scrapings should be collected to search for Demodex mites. This is a mandatory diagnostic procedure for all alopecic dogs because Demodex mites may be associated with a roughly symmetric alopecia. Identification of the mites is easier if the light condenser is lowered, similar to the technique used for a trichogram discussed earlier. If mites are found, the possibility of an endocrinopathy as the true cause of the symmetric alopecia is still high. Hyperadrenocorticism, hypothyroidism, and the use of glucocorticoid medications are the most frequent underlying causes of generalized demodicosis in an adult dog. Conversely, adult-onset generalized demodicosis may be idiopathic in some cases. Dermatophytosis may be associated with a symmetric alopecia. The presence of fungal spores may be identified with a trichogram. Dermatophytosis may be associated with endocrinopathies, with glucocorticoid administration, or with other medications exerting an immunosuppressive effect. A fungal culture (i.e., dermatophyte test media [DTM]) is inexpensive and easy to perform and should be included as a part of a minimum database for dogs presenting with alopecia regardless of the cause of the problem. Direct impression samples collected for cytologic evaluation are a quick and easy procedure to identify bacterial or yeast organisms that may be contributing to the development of alopecia. A glass slide is pressed firmly against the skin surface or any moist surface lesion. If epidermal collarettes are present, the leading margin should be gently lifted using the side of the slide and the impression cytology collected from that site. The sample should be allowed to air dry before staining with a modified Wright’s stain. The oil objective will be necessary to identify bacteria or yeast organisms. Another option for sample collection is the tape preparation, especially when the lesions are dry and scaly or located in a difficult-to-sample site such as the interdigital regions. Clear acetate tape is pressed to the skin surface 2 to 3 times and placed sticky-side down onto a few drops of the third (purple) stain of the modified Wright’s stain kit. The tape should be pressed firmly to the slide with paper towels to remove excess stain. The tape preparation can be evaluated at oil immersion without a cover slip. Canine bacterial folliculitis is usually associated with focal or patchy-to-diffuse alopecia rather than bilaterally symmetric alopecia. Secondary infections may be a result of an underlying endocrinopathy. It is usually best to resolve any secondary infections with appropriate topical or parenteral medications before performing routine

166

SECTION  III  Endocrine and Metabolic Diseases

blood work or specific serum laboratory testing for endocrine diseases. Also, it is best to resolve these infections before biopsy samples are collected for histopathologic evaluation. Secondary infections may mask the underlying cause of the alopecia.

Skin Biopsy Samples Submission of skin biopsy samples for histopathology is sometimes helpful in diagnosing the cause of canine symmetric alopecia. Because biopsy samples must be evaluated in light of available historical and serum biochemical results, all pertinent historical information also should be sent to the pathologist. Digital images of the alopecia and skin lesions also may be useful because many pathologists consult with clinical dermatologists to provide the best diagnostic service. Many causes of canine symmetric alopecia share similar histopathologic findings. Therefore it is essential to use the signalment, history, and laboratory and clinical findings to achieve a diagnosis. Occasionally histopathology alone is helpful in making a diagnosis. Cyclical flank alopecia, color dilution alopecia, and hyperadrenocorticism (if calcinosis cutis is present) can all be readily diagnosed with standard histopathology methods. However, alopecia X, hyperestrogenism, Sertoli cell tumor–associated skin disease, and hyperadrenocorticism (spontaneous or iatrogenic) are impossible to differentiate on histopathology without additional data. In short, endocrinopathies, acquired pattern alopecia, and post-clipping alopecia can be very difficult to sort out with histopathology alone. Before the biopsy, the skin surface should not be surgically prepared. Long hairs may be clipped and gently brushed away from the collection site. A 6- to 8-mm Baker biopsy punch usually provides an adequate sample size. Samples should be taken from sites exhibiting early, middle, and late stages of the disease process (or mildly affected to severely affected regions). The location and description of each skin biopsy site should be noted and each sample placed in a separate container of formalin. This is especially important when attempting to differentiate endocrine causes of alopecia from acquired pattern alopecias (i.e. pattern baldness). Submitting a sample from a nonaffected area in this instance may be beneficial as a comparison to the other samples. It is imperative to submit samples in separate containers to avoid confusion about site of origin.

Laboratory Tests Baseline laboratory data are usually needed to achieve a diagnosis for a dog presenting with bilaterally symmetric alopecia. A complete blood count (CBC), serum chemistry, and urinalysis provide the minimum data base. Abnormalities may provide clues that help direct selection of additional diagnostic procedures such as an adrenocorticotropic hormone (ACTH) stimulation test or low-dose dexamethasone suppression test when hyperadrenocorticism is suspected (see Chapters 42 and 51). In the diagnosis of hypothyroidism, a total thyroxine (T4), free T4, and thyroid-stimulating hormone (TSH) provide the minimum database. Some reference laboratories

provide additional information such as autoantibodies. It is important to not rely on a single thyroid value (such as a T4 or TSH) in making a definitive diagnosis. The data are best evaluated alongside the clinical signs. Even with values from quality reference laboratories, the diagnosis of hypothyroidism may be challenging (see Chapter 42 and Web Chapter 14). History, clinical findings, histopathology, and ruling out other causes of symmetric alopecia are important in achieving a diagnosis. Because they can greatly affect the aforementioned tests, topical or parenteral glucocorticoid medications usually should not be used for 4 to 6 weeks prior to submitting laboratory tests. Milder topical glucocorticoids such as hydrocortisone are less likely to cause side effects. There are several potent topical steroids such as triamcinolone, betamethasone, and mometasone that increase the likelihood of developing iatrogenic Cushing’s disease. The potency of the steroid and the duration of usage will be determining factors in evaluating the necessary withdrawal period, and it may be longer than 4 to 6 weeks. Clearly there are conditions to consider before suddenly stopping glucocorticoids, such as the dog with adrenal suppression that may need to be managed with physiologic doses of prednisone (see Chapter 53) and monitored closely with ACTH stimulation tests prior to complete withdrawal. Some laboratories provide sex hormone panels to help sort out challenging cases of canine symmetric alopecia. A standard ACTH stimulation test is performed. Serum is then submitted chilled to the laboratory for evaluation. Both pre- and post-ACTH concentrations are provided for cortisol and several sex hormones. The interpretation of these data can be challenging and consultation with an endocrinologist or internal medicine specialist or with a dermatologist is recommended. A recent publication demonstrated elevations in 17-hydroxyprogesterone (17OHP) in healthy bitches during the normal reproductive cycle. Therefore all previously discussed diagnostic procedures should be evaluated before considering measurement of sex hormones. In a related issue, a report of miniature poodles and Pomeranians with clinical signs of alopecia X indicated that these dogs had elevations of 17OHP post-ACTH stimulation. In these cases, trilostane therapy led to complete hair regrowth in all of the miniature poodles and 85% of the Pomeranians within a 4- to 8-week period (Cerundolo et al, 2004; see Chapter 115). However, trilostane may not improve the clinical signs associated with alopecia X in all dogs.

References and Suggested Reading Bromel C et al: Serum 17α-hydroxyprogesterone concentrations during the reproductive cycle in healthy dogs and dogs with hyperadrenocorticism, J Am Vet Med Assoc 236(11):1208-1214, 2010. Cerundolo R et al: Treatment of canine Alopecia X with trilostane, Vet Dermatol 15:285-293, 2004. Behrend EN, Kennis RA: Atypical Cushing’s syndrome in dogs: arguments for and against, Vet Clin Small Anim 40(2):285-296, 2010. Kooistra HS, Galac S: Recent advances in the diagnosis of Cushing’s syndrome in dogs, Vet Clin Small Anim 40(2):259-267, 2010.

CHAPTER 

40 

Imaging in Diagnosis of Endocrine Disorders JIMMY H. SAUNDERS, Merelbeke, Belgium

Imaging Modalities in Endocrinology Radiography has little value for imaging endocrine organs and is mainly used to detect lung metastases. Ultrasonography (US) is the most commonly used imaging modality for diagnosis of endocrine disorders because of its availability and relative low cost. Major endocrine organs such as the thyroid gland, parathyroid glands, and adrenal glands are superficially located, which makes them easily accessible with US using high-resolution transducers (≥10 MHz). Additionally, US allows for fine-needle aspiration, tissue-core biopsy, or interventional procedures of endocrine organs to be performed in real-time. Two newer US techniques, which are still under clinical investigation, can help to improve the accuracy of gray-scale diagnostic US. Contrast-enhanced US involves intravenous injection of gas microbubbles as vascular contrast agents to improve the detection of perfusion and vascularity of both normal and abnormal organs. Changes in vascularity and blood flow are frequently seen secondary to pathology and are represented in time-intensity curves as alterations of the shape of the curve on contrast-enhanced US. The second method, elastography, is an US technique that evaluates the stiffness of tissues by measuring the displacement of ultrasound echoes before and after compression. Elastography thereby provides information about the mechanical properties of tissues and is currently used in people to differentiate malignant from benign lesions in thyroid tissue. Computed tomography (CT) and magnetic resonance imaging (MRI) are very useful for evaluation of the ex­­ tent, local invasiveness, and local or distant metastases of neoplastic processes. CT is the modality of choice for detection of lung metastases, whereas MRI provides excellent delineation of anatomic structures because of inherent high-contrast resolution and is the modality of choice for evaluation of presurgical tissue and vascular invasion. Both modalities allow visualization of intracranial structures and are particularly suited for imaging the pituitary gland. Dynamic CT contrast studies including targeted angiography or dual-phase CT are useful for examination of adrenal glands, pituitary gland, and pancreatic disorders. The routine use of nuclear medicine in veterinary endocrinology is limited to thyroid scintigraphy. This modality is extremely useful to determine unilateral or bilateral lobe involvement, the status of the gland, the location of hyperfunctioning ectopic or accessory tissue, and distant metastases of thyroid tumors. Availability of

scintigraphy is limited in veterinary medicine. Box 40-1 lists some useful imaging tips for evaluating endocrine disorders in dogs and cats.

Imaging the Thyroid Gland The thyroid gland is composed of two separate lobes except in a few large-breed dogs in which an isthmus connects both lobes caudally. Thyroid lobes are oblong and span the dorsolateral aspect of the trachea, medial to the common carotid arteries, from the first to the eighth tracheal ring. The thyroid gland is supplied with arterial blood from a large cranial and a smaller caudal thyroid artery, both branches of the common carotid artery. The caudal thyroid artery is absent in cats. Venous drainage is via the cranial and caudal thyroid veins. US is the primary modality for evaluation of the thyroid gland. The gland appears on US as a homogeneous, well-delineated, hyperechoic (compared with the surrounding musculature), fusiform structure. Measurements of the height (dorsoventral axis) of the thyroid gland and calculation of its volume using the formula of a rotation ellipse have the lowest variability and should be preferred in comparative and follow-up studies. On CT, the normal thyroid gland is homogeneous, ovoid or triangle-shaped, and hyperattenuating compared with the surrounding tissues (Table 40-1). The hyperattenuation is due to its natural high iodine content, which is an element with a high atomic number (53) compared with most other elements in the body (Figure 40-1, A). After intravenous injection of iodinated contrast medium, the gland shows usually diffuse enhancement. On MRI, the thyroid gland may appear heterogeneous, particularly on T2-weighted images, or homogeneous. On T1-weighted images, the thyroid gland is isointense to surrounding muscles in half of cases and shows intermediate signal intensity between fat and muscle in the other half. After contrast medium administration (gadolinium-based), the thyroid gland shows intensity between muscle and fat or is isointense to fat. On T2-weighted images, the thyroid gland shows intensity between muscle and fat. MRI is the best modality to evaluate local tissue invasion, detect cervical lymphadenopathy, and detect recurrent thyroid carcinoma after treatment. Radionuclide iodine (123I, 131I) or pertechnetate (99mTcO4) is taken up by thyroid tissue and can be used for thyroid scintigraphy. In contrast to pertechnetate, iodine isotopes are incorporated in thyroglobulin (organification), enabling the determination of “true” uptake, 167

168

SECTION  III  Endocrine and Metabolic Diseases

BOX 40-1  Imaging Tips for Evaluation of   Endocrine Disorders • Follow-up US studies of the thyroid gland should be performed by the same individual. • Always perform radiography of the thorax or, even better, CT scan of the lungs in patients with a neoplastic process. • Perform dynamic CT scans for examination of the adrenal glands, pituitary gland, and pancreas. • Use vascular landmarks to find the adrenal glands on US. • CT and MRI of the pituitary gland should be performed using thin slices (1 to 2 mm). • The sensitivity of US for detection of metastasis within lymph nodes is greatly improved by use of contrastenhanced US.

T T

A

TABLE 40-1  Computed Tomography Attenuation Values of the Normal Thyroid Gland Thyroid Gland

Canine

Feline

Precontrast attenuation (HU)

108

123

Postcontrast attenuation (HU)

169

169

1150*

—

3

Volume (mm )

*

*Dog weighing 30 kg.

which could be more reflective of thyroid physiology. Despite this advantage of iodine, pertechnetate routinely is preferred because it is easily obtainable from an in-house molybdenum generator, is cheaper, and has a shorter half-life compared with iodine isotopes. On a normal scintigraphic study, the thyroid-to-salivary uptake ratio is less than 1. Injection of iodinated contrast medium on CT scan influences the results of nuclear imaging for 6 to 8 weeks. Gadolinium-based MRI contrast agents do not interfere with thyroid function and subsequent nuclear imaging.

Canine Thyroid Neoplasia In dogs, thyroid neoplasia (mostly carcinomas, less commonly adenomas) is associated with a unilateral (66%) or bilateral (33%) mass caudal to the pharynx. Clinically detectable neoplasms usually are nonsecreting, resulting in euthyroidism throughout the course of the disease. In dogs with thyroid neoplasia, diagnostic imaging is used (1) to define the thyroid origin of the cervical mass, (2) to detect local or distant metastases, and (3) to evaluate local tissue invasion. Whatever imaging modality is used, it is sometimes difficult to document the thyroidal origin of the mass when its size severely disrupts the normal anatomy of the cervical area. Scintigraphy, CT, and to a lesser extent US may be indicated to determine whether large cervical masses arise from the thyroid gland or from other tissues. When the mass arises from tissues

B Figure 40-1  CT images of the thyroid gland. A, Precontrast CT

scan of a normal adult dog shows the hyperattenuating thyroid glands (T). B, Precontrast CT study of an adult dog with a large mass (asterisk) located dorsally to the trachea and extending from the caudal part of the pharynx to the level of the sixth cervical vertebra. Both thyroid glands (arrows) were entirely visible excluding a thyroid origin. An ectopic thyroid origin is also unlikely because of the dorsal location. The mass was a paraesophageal abscess. (Courtesy Olivier Taeymans, Tufts University.)

other than the thyroid, both thyroid lobes should be visible exhibiting a normal pattern (Figure 40-1, B). Additionally, US and CT can be used to guide a fine-needle aspiration or a core biopsy of a cervical mass. With thyroid neoplasia, radiography may reveal a (sometimes mineralized) mass and possibly show displacement or compression of the trachea or the esophagus (mostly ventrally) or deformation of the larynx. Thyroid neoplasia appears as a large, heterogeneous mass involving most commonly the entire lobe or gland, with variable delineation, hypoechoic (US), isoattenuating to hypoattenuating (CT), or hyperintense (all routine MRI sequences); the mass sometimes may contain multiple

CHAPTER  40  Imaging in Diagnosis of Endocrine Disorders cystic areas of necrosis or hemorrhage that alternate with areas of normal parenchyma, dense connective tissue, or mineralization. Thyroid carcinoma shows strong vascularization on power or color Doppler, contrast-enhanced US, and contrast-enhanced CT. CT is highly specific (100%) and MRI is highly sensitive (93%) in diagnosing thyroid carcinoma, whereas US has a moderate sensitivity (79%) and a poor specificity (33%). Main differential diagnosis is a carotid body tumor. On scintigraphy, thyroid tumors are of various sizes with irregular areas of pertechnetate uptake and usually heterogeneous distribution of radioactivity. Diffuse increased and decreased uptake patterns also have been described. If the tumor is secreting excessive amounts of thyroid hormones, moderate to extensive areas of increased, usually uniform, tracer uptake are detected, and the contralateral lobe exhibits suppressed uptake because of negative feedback onto the pituitary gland and resultant lack of thyroid-stimulating hormone (TSH) secretion. Unfortunately, increased uptake of radionuclide does not always correlate with increased production of thyroid hormones by the tumor. For instance, if the thyroid tumor destroys enough of the thyroid gland (≥75%) to cause subnormal thyroxine concentration, the pituitary gland increases its TSH release, and the remaining normal tissue is stimulated. The nonsecreting thyroid neoplasm shows decreased uptake, and the remaining normal tissue has increased uptake. Diagnostic imaging cannot reliably differentiate adenoma from carcinoma. Distant pulmonary metastases from local invasion of the thyroid veins are common, and thoracic radiographs or lung CT scan should always be performed in cases of thyroid carcinoma. If a cranial mediastinal mass is present, neoplastic transformation of ectopic thyroid tissue should be considered. The second most common site of metastases is the retropharyngeal lymph nodes, which are best imaged on CT, MRI, and Doppler or contrast-enhanced US. Other sites of metastatic spread include abdominal organs (liver, kidneys, spleen, and adrenal glands), justifying standard abdominal US or CT to be performed, and also bone, bone marrow, brain, and spinal cord. Thyroid scintigraphy is a specific tool for identification of metastasis but is not considered sensitive. Scintigraphic visualization of metastases in the presence of an intact trapping mechanism in thyroid tumor cells indicates a high trapping ability of iodine in the tumor tissue, and this may be considered a predictive factor of radioiodine therapy effectiveness. Even with the use of US, CT, or MRI, the detection of local tissue invasion by a thyroid carcinoma may be challenging. US is less sensitive than MRI and CT for detecting capsule disruption and local tissue invasion. US strongly depends on the skill of the operator and the quality of the US equipment, and it is limited for detection of retrotracheal and intrathoracic extension of the thyroid malignancy. The extension of tumor into adjacent soft tissues and vessels of the neck is the main purpose of CT and MRI in assessing patients with thyroid carcinoma, with MRI having the best contrast resolution. Posttreatment imaging should be performed at 3 to 6 months and include thoracic radiography and pertechnetate scintigraphy.

169

Canine Hypothyroidism Hypothyroidism in adult dogs is almost always the result of a primary dysfunction of the thyroid gland resulting from an immune-mediated lymphocytic thyroiditis or idiopathic atrophy of the gland. With much practice and skill, US is a sensitive and quick test for the diagnosis of primary hypothyroidism. US features include decreased echogenicity, gland inhomogeneity, irregular capsule delineation, abnormal lobe shape, and decreased relative thyroid volume. These five parameters combined result in an overall sensitivity of 94.1% in hypothyroid dogs. A continuous decrease of thyroid volume is seen over time after treatment with levothyroxine, whereas the other features do not change significantly with time. Scintigraphy should show decreased or absent uptake of pertechnetate in primary hypothyroidism. However, the value of thyroid scintigraphy for detection of acquired primary hypothyroidism is controversial, and scintigraphic studies should be interpreted with caution. In juvenile dogs, congenital primary hypothyroidism is only rarely diagnosed and can be the result of dysgenesis of the gland, dyshormonogenesis, or iodine deficiency. Radiography of the skeleton in patients with congenital hypothyroidism shows delayed closure of the sutures in the skull, delayed epiphyseal ossification, and epiphyseal dysgenesis (i.e., irregularly formed, fragmented, or stippled epiphyseal centers), mostly seen in the proximal tibia, humerus, femoral condyles, and vertebral bodies. The overall length of the long bones and vertebral bodies is reduced, and the skull is shortened and broad. Valgus limbs are common and result from retarded ossification of the carpal and tarsal bones. Thickening of the radial and ulnar cortices with increased medullary opacity and bowing of these bones also can be seen. Degenerative joint disease may develop at a later stage. Scintigraphy can be used to differentiate dysgenesis (minimal uptake) and dyshormonogenesis (normal or increased uptake).

Feline Hyperthyroidism Hyperthyroidism is the most common endocrine disorder in cats; it is typically caused by functional thyroid ade­ nomatous hyperplasia or hyperfunctioning adenoma. Thyroid lesions are bilateral in 70% of patients. Additionally, intrathoracic ectopic tissue has been reported in 8% to 25% of hyperthyroid cats (Figure 40-2). Ectopic thyroid tissue may be found everywhere between the base of the tongue and the base of the heart in a ventral location. On US, the thyroid glands of hyperthyroid cats initially appear increased in size, rounder, heterogeneous with hypoechoic or anechoic areas, and with an increased vascularity. Scintigraphy is characterized by increased radiopharmaceutical uptake in the area of the gland and allows assessment of bilateral versus unilateral disease, estimation of thyroid size or functional activity, identification of ectopic thyroid tissue, and potential detection of metastatic disease (see Figure 40-2). The mean thyroidto-salivary ratio of abnormal lobes in hyperthyroid cats is 5.25 : 1 (range, 1.2 : 1 to 12.1 : 1). There is a good correlation between US and scintigraphy in differentiating

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SECTION  III  Endocrine and Metabolic Diseases

T

Figure 40-2  Scintigraphic image of a thyroid adenoma in an adult cat. Marked uptake is visible at the level of the left thyroid gland (T). There are two areas of focal uptake at the entrance of the thorax corresponding to ectopic thyroid tissue (arrows).

normal from abnormal thyroid lobes. Thyroid glands show decreased size, reduced rounding, reduced heterogeneity, and decreased vascularity 3 to 12 months after radioactive iodine treatment.

Imaging the Parathyroid Glands US is a powerful tool for visualization of the normal parathyroid glands and for diagnosis of parathyroid tumors. The small (1.9 cm in vertical height) combined with other criteria such as age. More commonly, normalization to a body index (brain area) is performed to evaluate the pituitary gland leading to the use of a height-to-brain ratio (P/B ratio = pituitary gland height in mm × 100/brain area in mm2). This ratio is used on postcontrast images to distinguish normal (P/B ratio ≤0.31 mm−1) from enlarged (P/B ratio >0.31 mm−1) pituitary glands. A small or missing pituitary gland is observed in approximately 3% of dogs and is considered an incidental variant. However, care must be taken not to confuse an empty sella with a cystic malformation (Rathke’s cleft) or cystic mass occupying the fossa. Pituitary cysts are not unusual in healthy dogs, particularly brachycephalic breeds, but they are also seen in dogs with congenital growth hormone deficiency (pituitary dwarfism). Low-field MRI and dynamic CT provide comparable information regarding the diagnosis of pituitary adenoma in the diagnosis of PDH. Pituitary macroadenomas are characterized by suprasellar extension of a pituitary “mass” of variable size, homogeneity, and margination that may compress or invade the diencephalon. Macroadenomas are usually hyperintense on T2-weighted se­­ quences and isointense on T1-weighted sequences (Figure 40-4, A and B). Most macroadenomas are enhanced after contrast administration (Figure 40-4, C). Because the normal pituitary naturally enhances after contrast administration, some contrast agent uptake in some adenomas may not be as great as for normal, surrounding tissues. Pituitary macroadenomas and rare adenocarcinomas share the same imaging features, although any osseous involvement or presence of metastases is consistent with carcinoma. Concurrent findings (e.g., hemorrhage, hydrocephalus, brain edema, mass effect) are similar to findings of other extraaxial brain tumors. A diagnosis of pituitary microadenoma is usually made by exclusion in dogs if no pituitary enlargement is identified on imaging. Both the pituitary flush on dynamic CT and the bright spot on precontrast T1-weighted MRI can identify an absent or displaced pituitary (neurohypophyseal) flush and indirectly suggest the presence of a microtumor. A normal CT study (conventional and dynamic) does not rule out PDH.

Imaging the Pancreas Imaging the pancreas in patients with diabetes mellitus may provide useful information regarding the potential presence of an underlying pancreatitis that is usually of the chronic form and less likely of the acute form (Table 40-2). Acute pancreatitis causes a pancreatic mass effect or enlargement, changes in echogenicity (US) or density (CT), and lack of contrast enhancement on US and CT. Pancreatic enlargement also may be suspected on radiography when the duodenum is laterally displaced and the transverse colon is caudally displaced. Another feature can be peritonitis causing peritoneal effusion directly visible on US and CT and local inflammation of the mesentery, which appears hyperechoic on US

CHAPTER  40  Imaging in Diagnosis of Endocrine Disorders

173

*

* B

A

* C Figure 40-4  Transverse MRI of a pituitary macroadenoma (asterisks) in an adult dog. A, On

T1-weighted image, the mass appears isointense (compared with surrounding musculature).  B, On T2-weighted images, the mass is hyperintense. C, Postcontrast T1-weighted image shows moderate uptake of contrast agent.

and hazy or ill-defined on CT. Peritonitis secondary to pancreatitis is suspected radiographically when serosal detail is lost in the right cranial hemiabdomen and the descending duodenum is dilated and static. In severe cases, peripancreatic vasculature thrombosis is observed on CT. Pain on transducer pressure localized over the area of the pancreas is often a notable feature during US examination. Chronic pancreatitis can be associated with a reduced size of the pancreas, irregular widening of the pancreatic duct, the presence of intraparenchymal or extraparenchymal mineralization, and a mixed or mottled echogenicity (US) or density (CT) of the pancreatic parenchyma, best illustrated on postcontrast US and CT studies.

TABLE 40-2  Sensitivity of Imaging Modalities for Diagnosis of Pancreatic Disorders Sensitivity

Acute Pancreatitis

Chronic Pancreatitis

Radiography

Low

Low

Ultrasonography

70% in dogs 10%-30% in cats

Low

Computed tomography

NR

Low

NR, Not reported.

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SECTION  III  Endocrine and Metabolic Diseases phy are indicated to define the primary tumor and metastatic lesions.

Pancreatic Endocrine Neoplasia Insulinoma is the most common canine pancreatic endocrine tumor; it is rare in cats. This tumor often metastasizes (liver, kidneys, regional lymph nodes) and is fre­­quently accompanied by hypoglycemia and hyperinsulinemia. US can be used for the initial evaluation of dogs with hypoglycemia including detection of metastases. Insulinomas appear on US as solitary or multiple nodules or ill-defined areas of abnormal echogenicity, mainly smaller than 2.5 cm in diameter. Because of these features, the diagnosis of insulinomas using gray-scale US is challenging and often disappointing. It is the author’s experience that contrast-enhanced US or dual-phase contrast CT greatly improves the detection of these tumors. Using these techniques, neuroendocrine tumors appear hypervascular showing a marked contrast-enhancing mass in the arterial phase and early decrease in enhancement in the portal phase contrary to the mildly contrastenhancing pancreatic adenocarcinoma. SPECT appears as effective as US and CT in detecting insulinoma. However, intraoperative inspection and palpation of the pancreas remains more sensitive than the imaging modalities. Gastrinoma (Zollinger-Ellison syndrome) is a rare gastrin-producing, non–β islet cell pancreatic tumor that results in gastric acid hypersecretion and gastrointestinal ulceration. US, CT, and somatostatin receptor scintigra-

CHAPTER 

References and Suggested Reading Auriemma E et al: Computed tomography and low-field magnetic resonance imaging of the pituitary gland in dogs with pituitary-dependent hyperadrenocorticism: 11 cases (20012003), J Am Vet Med Assoc 235:409, 2009. Barthez PY, Nyland TG, Feldman EC: Ultrasonography of the adrenal glands in the dog, cat, and ferret, Vet Clin North Am Small Anim Pract 28:869, 1998. Harvey AM et al: Scintigraphic findings in 120 hyperthyroid cats, J Feline Med Surg 11:96, 2009. Pey P et al: Contrast-enhanced ultrasonography of the normal canine adrenal gland, Vet Radiol Ultrasound 52:560, 2011. Robben JH et al: Comparison of ultrasonography, computed tomography, and single-photon emission computed tomography for the detection and localization of canine insulinoma, J Vet Intern Med 19:15, 2005. Schwarz T, Saunders J: Veterinary computed tomography, Chichester, UK, 2011, Wiley-Blackwell. Taeymans O, Peremans K, Saunders JH: Thyroid imaging in the dog: current status and future directions, J Vet Intern Med 21:673, 2007. Taeymans O, Penninck DG, Peters RM: Comparison between clinical, ultrasound, CT, MRI and pathology findings in dogs presented for suspected thyroid carcinoma, Vet Radiol Ultrasound 54:61, 2013.

41 

Approach to Critical Illness– Related Corticosteroid Insufficiency LINDA G. MARTIN, Pullman, Washington

C

ritical illness–related corticosteroid insufficiency (CIRCI), previously known as relative adrenal insufficiency, is a topic of debate in both human and veterinary medicine. The clinical syndrome of CIRCI is controversial, but it has been reported in critically ill human patients with systemic inflammation associated with sepsis or septic shock, acute respiratory distress syndrome or acute lung injury, trauma, severe hepatic disease, and acute myocardial infarction, as well as following cardiopulmonary bypass. More recently, insufficient adrenal or pituitary function has been identified in dogs with sepsis or septic shock (Burkitt et al, 2007; Martin et al,

2008), trauma (Martin et al, 2008), gastric dilationvolvulus (Martin et al, 2008), and neoplasia (lymphoma and several types of nonhematopoietic tumors) (Boozer et al, 2005) and in cats with sepsis or septic shock (Costello et al, 2006), trauma (Durkan et al, 2007), and neoplasia (lymphoma) (Farrelly et al, 1999). In contrast to patients with hypoadrenocorticism, patients with CIRCI usually have a normal or elevated basal serum cortisol concentration and a blunted cortisol response to an adrenocorticotropic hormone (ACTH) stimulation test. This syndrome is characterized by an inadequate production of cortisol in relation to an

CHAPTER  41  Approach to Critical Illness–Related Corticosteroid Insufficiency increased demand during periods of severe stress, such as critical illnesses. After recovery, hypothalamic-pituitaryadrenal (HPA) dysfunction resolves. The HPA dysfunction is transient and relative.

Pathophysiology and Causes The pathogenesis of CIRCI in dogs and cats is unknown but it is most likely multifactorial, involving complex interactions between endocrine and immune systems. Possible mechanisms for the development of CIRCI in humans and animals include the following: 1. Proinflammatory cytokine-mediated inhibition of corticotropin-releasing hormone (CRH) and ACTH secretion resulting in decreased cortisol production 2. Proinflammatory cytokine-mediated corticosteroid receptor dysfunction and reduction in receptor numbers, whereby a reduction in the activity or number of receptors would reduce the ability of cells to respond appropriately to cortisol 3. Corticostatin-mediated (peptide produced by immune cells) ACTH receptor antagonism, resulting in impaired adrenocortical function via corticostatin competing with ACTH and binding to its receptor 4. Leptin-mediated (adipose-derived hormone) inhibition of HPA axis during stress or illness 5. Tissue resistance to the actions of cortisol, whereby several factors may be involved, including decreased cortisol access to tissues secondary to a reduction of circulating cortisol-binding globulin and increased cytokine-mediated conversion of cortisol (active) to cortisone (inactive) 6. Disruption of pituitary or adrenal gland function secondary to extensive tissue destruction by infection, infarction, hemorrhage, or thrombosis The ABCB1 gene mutation that results in lack of P-glycoprotein (Pgp) at the blood-brain barrier may also be a contributing factor in some dog breeds (e.g., collies, Shetland sheepdogs, Australian shepherds, Old English sheepdogs, English shepherds, German shepherds, longhaired whippets, silken windhounds). Pgp restricts the entry of cortisol into the brain, limiting cortisol’s feedback inhibition of CRH and ACTH. In ABCB1 mutant dogs, Pgp is not present, allowing greater concentrations of cortisol within the brain. There is greater feedback inhibition of the HPA axis and, ultimately, inhibition of sufficient cortisol secretion, potentially leading to the inability to respond appropriately to critical illness and stress.

Clinical Signs Clinical signs of CIRCI can be vague and nonspecific, such as depression, weakness, fever, vomiting, diarrhea, and abdominal pain. In addition, clinical signs that are secondary to the underlying disease process responsible for CIRCI (e.g., septic shock, hepatic disease, trauma) can mask the clinical features of CIRCI. The most common clinical abnormality associated with CIRCI in critically ill human patients is hypotension refractory to fluid resuscitation, requiring vasopressor therapy. Hyponatremia

175

and hyperkalemia, abnormalities consistent with aldosterone deficiency, are uncommon in humans with CIRCI and, to date, have not been reported in canine or feline critically ill patients with insufficient adrenal or pituitary function. Laboratory assessment of critically ill human patients with CIRCI may demonstrate eosinophilia or hypoglycemia or both, but these abnormalities are not consistently found in all humans with CIRCI. Eosinophilia and hypoglycemia have not been reported in critically ill veterinary patients with CIRCI.

Diagnosis CIRCI should be considered as a differential diagnosis in all critically ill patients requiring vasopressor support. At the present time, there is no consensus regarding the identification of patients with CIRCI in human or veterinary medicine, and normal reference ranges do not exist for basal and ACTH-stimulated cortisol concentrations in critically ill dogs and cats. Various tests have been recommended for diagnosing CIRCI, including random serum or plasma (total) basal cortisol concentration, serum free cortisol concentration, ACTH-stimulated cortisol concentration, delta cortisol concentration (the difference when subtracting basal from ACTH-stimulated cortisol concentration), the cortisol-toendogenous ACTH ratio, and combinations of these methods. The optimal way to identify critically ill veterinary patients with CIRCI has yet to be determined. Evaluation of adrenal function in veterinary patients typically involves administration of an ACTH stimulation test. The most commonly used protocol for ACTH stimulation testing in dogs involves intravenous administration of 5  µg/kg of cosyntropin, up to a maximum of 250  µg. In cats, intravenous administration of 125  µg/ cat of cosyntropin is commonly used. Serum or plasma is obtained for cortisol analysis before and 60 minutes after ACTH administration for both dogs and cats. The standard doses of cosyntropin (5  µg/kg in dogs and 125  µg/cat) currently used are greater than the doses necessary to produce maximal adrenocortical stimulation in healthy small animals. Doses of 0.5  µg/kg in healthy dogs (Martin et  al, 2007) and 5  µg/kg in healthy cats (DeClue et  al, 2011) have been shown to induce maximal adrenocortical cortisol secretion. The use of higher doses is considered supraphysiologic and may hinder the identification of dogs and cats with CIRCI. Low-dose (0.5  µg/kg IV) ACTH stimulation testing has been compared with standard-dose (5  µg/kg IV) testing in critically ill dogs (Martin et  al, 2010). Every critically ill dog that was identified to have insufficient adrenal function (i.e., ACTH-stimulated serum cortisol concentration below the reference range or 0.15 ng/ml using the DPC canine assay). Cats that were hypothyroid and azotemic had shorter survival times than cats that were hypothyroid and remained nonazotemic (Figure 43-1, B). The number of hypothyroid cats included in the study was small, so ideally these results should be replicated in a larger group before conclusions are drawn. In practical terms, such a study would be difficult because of the long follow-up periods required. What is unclear is why the survival of these cats was worse; the azotemia was relatively mild, and in the group of cats as a whole (i.e., euthyroid and hypothyroid combined) the survival of the azotemic cats was no worse than that of the cats that were nonazotemic. It is possible that although the clinical signs associated with hypothyroidism in cats are very subtle, hypothyroidism does contribute to patient morbidity, and in association with the azotemia it played a role in the patients’ decline. Although overall cats that develop azotemia with treatment of hyperthyroidism do very well, the same is not true of cats that are azotemic before treatment. Williams and colleagues (2010a) found that the survival time of cats that were azotemic (on the basis of plasma or serum creatinine concentration) before diagnosis and treatment was approximately 6 months (median survival, 178 days; range, 0 to 1505 days), which is considerably shorter than survival in cats that were not azotemic (median survival, 612 days; range, 0 to 2541 days).

Choice of Treatment Modality It has been widely recommended that hyperthyroid cats be treated initially with drugs (methimazole or carbimazole) so that the effect of treatment can be reversed if necessary. This approach seems advisable in cats that are azotemic before they are treated for hyperthyroidism because survival times in these cats are known to be very poor, and a reversible treatment is warranted. Although clinical experience with the use of iodine-deficient diets

SECTION  III  Endocrine and Metabolic Diseases

188

Euthyroid nonazotemic Euthyroid azotemic

1.0

Proportion surviving

0.8

0.6

0.4

0.2

0.0 0

500

1000

A

1500

2000

2500

3000

Survival (days) Hypothyroid nonazotemic Hypothyroid azotemic

1.0

Proportion surviving

0.8

0.6

0.4

0.2

0.0 0

B

500

1000

1500

2000

Survival (days)

Figure 43-1  A, Kaplan-Meier survival curves of 47 cats treated

for hyperthyroidism that were euthyroid after 6 months of treatment. Cats were grouped according to whether or not they were azotemic at the end of the 6-month follow-up period. Circles represent censored individuals. B, Kaplan-Meier survival curves of 28 cats treated for hyperthyroidism that were hypothyroid after 6 months of treatment. Cats were grouped according to whether or not they were azotemic at the end of the 6-month follow-up period. Circles represent censored individuals. (Data from Williams TL et al: Survival and the development of azotemia after treatment of hyperthyroid cats, J Vet Intern Med 24:863, 2010, with permission.)

(i.e., Hill’s Y/D) is not yet widespread, this could also be a useful treatment in this setting (see Web Chapter 20). In most cats in which azotemia develops only after treatment, the recommendation to use only a reversible form of treatment initially may be overly cautious because many of these cats have long survival times, and the development of azotemia is not related to outcome except

in cats that become hypothyroid. However, a reversible form of treatment has been the author’s usual practice unless the cat’s owner is reluctant to attempt medical therapy. Medical or dietary treatment of cats before surgical thyroidectomy is generally advised to reduce the risks associated with general anesthesia. Reversible treatment may also be advised before radioactive iodine treatment, particularly if there are long waiting times for appointments, so the owner can be educated about the significance of azotemia if it develops with treatment. In many situations medical treatment for hyperthyroidism before permanent therapy is inappropriate. First, if the cat cannot tolerate medical treatment with methimazole or carbimazole because of the development of serious side effects (e.g., facial excoriations, blood dyscrasias, hepatopathies), drug therapy must be permanently discontinued. A second situation is when the owner is unable or unwilling to medicate a cat with sufficient regularity to control the hyperthyroidism. In these situations, provided that the owner is aware that a proportion of cats develop azotemia with treatment for hyperthyroidism, the use of a definitive treatment modality (i.e., radioactive iodine or bilateral thyroidectomy) as first-line therapy is reasonable. In most patients the consequences of untreated or poorly controlled hyperthyroidism far outweigh the risks associated with definitive treatment. In addition, development of azotemia with a reversible form of treatment should not preclude the definitive treatment of hyperthyroidism. Patients that have been treated with drugs or diet and have developed mild, stable renal azotemia may benefit from surgery or radioactive iodine therapy. However, if the patient is relatively poorly controlled with medical treatment (i.e., total T4 concentration remains in the upper half of the laboratory reference range), the azotemia is likely to worsen if the patient is subsequently well controlled with surgery or radioactive iodine therapy. One potential disadvantage of definitive methods of treatment for hyperthyroidism (radioactive iodine or bilateral thyroidectomy) is that a relatively large proportion of treated cats may develop hypothyroidism. Until recently, development of hypothyroidism after treatment was not considered to be of any great clinical significance, but the observation that hypothyroid azotemic cats have poorer survival than euthyroid or nonazotemic cats has altered this perception. Although hypothyroid cats do not typically become alopecic, they do exhibit other changes consistent with the diagnosis; they have lower heart rates and packed cell volumes, in addition to having higher creatinine concentrations. Decreased endogenous creatinine production has been demonstrated in hypothyroid dogs resulting in serum concentrations that are lower than would be predicted on the basis of GFR. It is unknown whether the same is true in cats, but if it is, the effects of hypothyroidism on renal function in the cat may be underestimated.

Treatment of Hypothyroidism Azotemic, hypothyroid cats have been found to have shorter survival times than nonazotemic hypothyroid cats. However, it is uncertain if reversing hypothyroidism

CHAPTER  44  Canine Diabetes Mellitus (by giving less methimazole or carbimazole or supplementing thyroxine after definitive therapy) would im­­ prove outcomes. Reversing the hypothyroid state would be expected to ameliorate the azotemia, if not resolve it entirely; whether this is beneficial has yet to be investigated. Probably most cats treated with radioactive iodine or bilateral thyroidectomy demonstrate, at least transiently, subnormal total T4 concentrations. Hyperthyroidism causes suppression of pituitary TSH secretion, and recovery of pituitary thyrotrophs is likely to take several months in most instances. Differentiation between transient and permanent hypothyroidism is impossible (at least on the basis of endocrine testing) immediately after treatment for hyperthyroidism. Additionally, differentiating hypothyroidism from the effects of nonthyroidal illness (resulting in subnormal total T4 concentrations) may be difficult. A protocol for TSH stimulation testing in cats is described, but the length of time needed following treatment to confirm that a patient has developed hypothyroidism is unknown. Observational data suggest that total T4 concentrations generally return to normal or near-normal levels by 3 months after radioactive iodine treatment, so TSH stimulation testing after this time interval is probably reasonable.

CHAPTER 

189

References and Suggested Reading Boag AK et al: Changes in the glomerular filtration rate of 27 cats with hyperthyroidism after treatment with radioactive iodine, Vet Rec 161:711, 2007. Panciera DL, Lefebvre HP: Effect of experimental hypothyroidism on glomerular filtration rate and plasma creatinine concentration in dogs, J Vet Intern Med 23:1045, 2009. Riensche MR, Graves TK, Schaeffer DJ: An investigation of predictors of renal insufficiency following treatment of hyperthyroidism in cats, J Feline Med Surg 10:160, 2008. van Hoek I et al: Short- and long-term follow-up of glomerular and tubular renal markers of kidney function in hyperthyroid cats after treatment with radioiodine, Domest Anim Endocrinol 36:45, 2009. van Hoek IM et al: Thyroid stimulation with recombinant human thyrotropin in healthy cats, cats with non-thyroidal illness and in cats with low serum thyroxin and azotaemia after treatment of hyperthyroidism, J Feline Med Surg 12:117, 2010. Wakeling J et al: Diagnosis of hyperthyroidism in cats with mild chronic kidney disease, J Small Anim Pract 49:287, 2008. Williams TL, Elliott J, Syme HM: Association of iatrogenic hypothyroidism with azotemia and reduced survival time in cats treated for hyperthyroidism, J Vet Intern Med 24:1086, 2010a. Williams TL et al: Survival and the development of azotemia after treatment of hyperthyroid cats, J Vet Intern Med 24:863, 2010b.

44 

Canine Diabetes Mellitus WILLIAM E. MONROE, Blacksburg, Virginia

Definition, Epidemiology, and Pathophysiology Diabetes mellitus in dogs is a persistent defect of carbohydrate metabolism associated with an absolute deficiency of insulin in nearly all cases. Almost every affected dog requires administration of exogenous insulin for management of the disease. The underlying cause in dogs is poorly understood but is likely multifactorial, including genetic predisposition; infectious, toxic, or inflammatory damage to the pancreatic islets with progressive immunemediated destruction; or predisposing conditions, such as natural or iatrogenic endocrine disorders, obesity, and hyperlipidemia that cause insulin resistance with subsequent β-cell exhaustion. The prevalence in North American teaching hospitals seems to have increased between 1970 (19 dogs per 10,000) and 1999 (64 dogs per 10,000) (Guptill et al, 2003). The prevalence in Europe is similar, although perhaps slightly variable depending on location. Females, neutered or intact, and neutered males are

overrepresented, although female predisposition may be declining. The peak age of occurrence is 7 to 11 years, with 70% of patients older than 7 years at the time of diagnosis. Diabetes occurs rarely in dogs younger than 1 year of age. Absolute insulin deficiency associated with canine diabetes mellitus is also associated with an increase in glucagon concentration. Together these changes lead to hyperglycemia, both from increased hepatic glucose production and from lack of peripheral use. When blood glucose concentration exceeds the renal threshold (180 to 220 mg/dl), osmotic diuresis occurs, leading to polyuria with secondary polydipsia. There is also fatty acid mobilization with consequent increased production of ketoacids by the liver because the peripheral tissues become energy starved. In addition, ketoacid production is increased because of the lack of the effects of insulin on lipoprotein lipase and hormone-sensitive lipase to facilitate the storage of fatty acids in adipocytes. As ketoacid production exceeds the quantity used for energy

190

SECTION  III  Endocrine and Metabolic Diseases

metabolism, acidemia occurs, and spillover of ketones into the urine contributes to polyuria. Without insulin, the ability of cells to use glucose is markedly diminished. Insulin deficiency reduces fatty acid deposition in adipocytes and decreases the incorporation of amino acids into protein. These metabolic abnormalities create a catabolic state with resultant weight loss despite adequate or excessive food consumption.

Diagnosis and Management Plan The diagnosis of diabetes mellitus is based initially on a combination of clinical signs that generally include polyuria and polydipsia, weight loss despite a good appetite, and the demonstration of persistent hyperglycemia with glucosuria. Repeat blood and urine glucose testing to confirm the persistence of hyperglycemia is unnecessary if the clinical signs of polyuria, polydipsia, and polyphagia have been noted. Ketonuria may be present in 66% of dogs with uncomplicated diabetes mellitus. Increased serum alkaline phosphatase and alanine transaminase and hypertriglyceridemia are also common. Once the diagnosis of diabetes mellitus has been established, it is important to determine if the dog has complicated diabetes (see Web Chapter 13). This determination is critical because diabetic ketoacidosis requires aggressive management in the hospital. Conversely, uncomplicated cases are better managed as outpatients. The major clinical criteria for determining if a dog requires aggressive management relate to clinical findings: Is the patient ill, anorexic, or vomiting, or, conversely, is the dog eating and drinking well and exhibiting a generally healthy attitude? Dogs that appear generally well and show a good appetite can be managed as uncomplicated diabetics even in the presence of ketonuria. Morbidity in these patients is rarely severe enough to require hospitalization and intensive care. Before initiating therapy, it is important to discuss the effort and cost of management of a diabetic dog with the owner and identify comorbid conditions. Lifestyle or financial circumstances may prevent some owners from successfully managing a diabetic pet. Foremost, it is important that the clinician have a clear understanding of the owner’s lifestyle and daily schedule so that a feasible treatment and monitoring protocol can be developed. Additionally, many older dogs manifest concurrent disease that can affect control of the diabetes or may influence the owner’s decision to treat or not. A thorough medical evaluation should be conducted to identify concurrent diseases. In addition to the history and physical examination, recommended studies include a complete blood count, serum chemistries (including canine pancreatic lipase immunoreactivity), urinalysis, urine culture, thoracic radiographs, and abdominal ultrasonography or radiography.

Diet, Feeding Schedule, and Exercise Diets that are high in fiber, low in simple sugars, and moderately restricted in fat and protein are generally recommended for diabetic dogs, although they may not

provide an advantage over diets with moderate fiber and low carbohydrates (see Chapter 46). However, the most important aspect of diet for diabetic dogs is that it be a balanced diet that the dog will eat consistently. If dogs receive insulin twice daily, it is recommended to feed two equal meals at the time of insulin administration. Some clinicians recommend that the dog be fed before injecting insulin and withholding the insulin injection anytime the dog does not eat its entire meal. Although this may work well for a dog that is a gluttonous eater, it is less effective for finicky eaters or dogs that eat small amounts throughout the day. The latter type of eaters may be given insulin routinely without having eaten their entire meal after it has been established that their eating pattern is consistent and glucose curves have confirmed hypoglycemia does not occur. Even when insulin is given once daily, it is recommended that the dog be fed twice daily. The second meal should approximately coincide with the glucose nadir depending on when the owner can be home to feed. For patients that have a variable time to glucose nadir, the second meal of the day should be fed at a consistent time that approximates the average time of the nadir. Alternatively, the second meal should be presented 12 hours after the insulin injection. Feeding a larger portion of the daily diet around the time of the glucose nadir may lead to a glucose curve with less fluctuation. However, if Lente insulin given once daily provides adequate control, the glucose response can be improved in some cases by feeding the larger meal at the time of the insulin injection. Lente insulin contains 30% short-acting insulin (Semilente) and 70% long-acting insulin (Ultralente) and is absorbed in many dogs such that there are two peaks of insulin activity, with the earlier peak leading to the higher insulin concentration. Exercise affects both the absorption of insulin and the metabolic use of glucose. Consequently, exercise levels should be kept constant with activity provided at the same times every day.

Insulin Therapy As stated previously, virtually all diabetic dogs require insulin therapy. Both recombinant human insulin and porcine insulin have been advocated for canine diabetes. There is very little experience or published information about the use of synthetic insulin analogs in dogs (see later). The use of compounded insulin products is not recommended because of a lack of both consistency between batches and stringent control of the formulation. The recommendation for insulin treatment in dogs involves administration of an insulin with intermediate duration of action twice daily. The only currently available intermediate-duration product is recombinant human neutral protamine Hagedorn (NPH) insulin (used extralabel for dogs). Porcine Lente insulin (Vetsulin) has been approved for use in dogs but cannot be sold in the United States at the present time because of concerns with stability and bacterial contamination associated with the manufacturing process. It is uncertain when or if the product will again be available in the United States.

CHAPTER  44  Canine Diabetes Mellitus There is some experience with this product because it has been and remains in use in Canada and many European countries under the brand name Caninsulin. Using Vetsulin, most dogs require injections every 12 hours for adequate control of blood glucose, with a median dose between 0.75 and 0.78 U/kg per injection (range, 0.28 to 1.4 U/kg) for dogs receiving insulin every 12 hours (Monroe et al, 2005). Using recombinant human NPH insulin, most dogs also appear to require two injections per day, with a median time to glucose nadir of 4 hours (range, 1 to ≥10 hours) and a range for duration of action 4 to 10 hours or longer. The median dose reported for well-controlled dogs is 0.63 U/kg every 12 hours (range, 0.4 to 0.97 U/kg) (Palm et al, 2009). The long-acting protamine zinc insulin made with recombinant human insulin and approved for veterinary use in cats (ProZinc) may be useful for dogs for which intermediate-duration insulins provide too short of a duration of action (90% digestibility) designed for GI disease may result in greater postprandial hyperglycemia; they are likely not the best diets for diabetic dogs. Conversely, diets with less than 80% nutrient digestibility and low fat concentrations may not be sufficient to help a thin diabetic dog regain lost BW. Finally, it is ideal to choose a diet that has a fixed formula (as opposed to an open formula) so that there are fewer variations in the diet formulation that can affect the individual response from batch to batch. Openformula diets are diets found in a typical grocery store or pet specialty supply store, and their formulation changes with market prices. The glycemic index changes with the formulation over time, which may result in a variable insulin response. Once the diet is chosen, the next most important aspect of dietary management is to impress on the owner the importance of feeding consistent amounts of food at consistent times. Giving treats can be accommodated, as long as the type (preferably low in fat and sugar) and the number of treats given are consistent every day. Ideally, diabetic dogs should be fed one half of their total daily energy requirement at a specified time in the morning at the time of insulin administration. The second half of the dog’s energy requirements should be given at the evening meal, approximately 12 hours later, coinciding with the evening insulin administration. Calculation of energy requirements for diabetic dogs should be based on maintenance energy needs of the dog’s ideal BW (Table 46-2). However, if the dog fails to gain weight despite an appropriate amount of insulin and food, an increase in the energy density of the food or increased daily caloric intake will be required. A final key point for a successful dietary management strategy for diabetic dogs is simply to monitor the BW, body condition (muscle and fat mass), and glycemic control and adjust the diet as needed, but to maintain as much consistency as possible not only in the food type but also in the timing and amount.

Dietary Management of Feline Diabetes As in diabetic dogs, dietary therapy is a very important aspect of successful management of diabetic cats. How­ ever, in contrast to dietary therapy of dogs for which multiple dietary strategies are available, dietary management of diabetic cats is aimed at improving metabolism,

CHAPTER  46  Diet and Diabetes correcting obesity, and reversing persistent hyperglycemia by using high-protein, low-carbohydrate foods. There is strong and increasing evidence that a diet containing protein as the primary energy source and very low concentrations of carbohydrate is highly effective in achieving these goals in cats. In addition, because many diabetic cats are obese and have obesity-induced insulin resistance as part of their disease, high-protein diets are essential to preserving muscle mass, preventing hepatic lipidosis, and increasing metabolism to help promote fat burning. Although dietary therapy of feline diabetes has similar goals to that in dogs, the approach is specifically tailored to provide diets that more closely mimic their natural carnivorous diet. Dietary therapy of feline diabetes has several major goals, as follows: 1. To correct or normalize BW—for most cats this means to achieve weight loss 2. To minimize hyperinsulinemia and hyperamylinemia that occurs secondary to persistent hyperglycemia resulting from obesity or other factors associated with insulin resistance 3. To use protein as the primary insulin secretagogue to stimulate endogenous insulin secretion by feeding a diet high in arginine (an amino acid found prominently in meat source proteins) 4. To provide a continuous source of gluconeogenic amino acids from meat source proteins to allow removal of all starches from the diet—reducing the degree and duration of postprandial hyperglycemia. Obesity is a major medical problem in domestic cats. Most cats that live indoors with free access to food are either overweight (15% to 20% over ideal BW) or obese (>20% over ideal BW). Because obesity-induced insulin resistance is a major risk factor for development of diabetes mellitus, both from the perspective of prevention and from the perspective of treatment, weight loss is a key aspect of dietary therapy. To induce weight loss in cats, a dietary strategy must be include the following: (1) feeding a diet high in protein (>45% metabolizable energy) to decrease muscle mass loss and prevent lipid and energy metabolism derangements that occur during calorie restriction, (2) feeding a diet that is reduced in energy (both fat and carbohydrates) to stimulate fat mobilization, and (3) monitoring and adjusting the food consumption to BW and response to food reduction. Lean muscle tissue is an essential element of basal metabolism and is necessary for normal insulin function. Many weight-loss diets are low calorie but not high enough in protein to preserve lean muscle tissue. In studies of cats comparing high-protein and moderateprotein diets during weight loss, cats consuming highprotein diets had greater success in achieving weight loss, lost fat mass while preserving lean tissue, and had a greater tendency to maintain stable weight after weight loss. Many diets may be acceptable for preservation of lean muscle tissue, but the goal should be to have fat less than 4 g/100 kcal, starch less than 5 g/100 kcal, and protein content greater than 10 g/100 kcal (in dry-matter terms it is equivalent to protein > 40% to 45%, depending

203

on the energy in the diet). Diets with this profile are easily obtained using canned food diets, and many options exist; however, extruded dry food diets require a minimum amount of carbohydrate in processing for the creation of the shape and texture. Dry foods often have larger amounts of carbohydrates or fat and can make calorie control or reduction of postprandial hyperglycemia difficult, if not impossible. The other essential aspect of achieving weight loss is to control energy intake. In obese cats, meal feeding is required to be able to provide the specified calories needed to achieve restriction. Maintenance energy needs for indoor neutered cats that are of ideal BW are estimated to be 40 to 50 kcal/kg/day (or for the average 4- to 5-kg cat an intake of 160 to 200 kcal/day) (see Table 46-2). However, to achieve weight loss, the caloric intake must be restricted further, with a reduction in calories from this maintenance rate by 10% to 40%—which may mean intakes of 130 to 140 kcal/day for some cats. If the cat has been eating free choice food, the first step is to establish a meal feeding regimen with intake aimed at the ideal. Many canned diets have a high-protein, low-fat to moderate-fat, and low-carbohydrate profile and provide a way to control calories by volume; they are a good dietary choice for a feline weight-loss program. In addition, canned foods contain a large amount of water, which serves to dilute calories and still allow a larger portion size that helps increase satisfaction. In a comparison between a high-fiber food and a canned food with equal ingredients, cats fed the canned diets begged less and showed more signs of satiety than cats fed the dry high-fiber diets. Because caloric intake can be easily controlled, it is easier to create a high-protein and lowcarbohydrate profile, and the increased water adds both moisture and volume to the meal, canned diets are a highly desirable option for cats needing to lose weight or to help manage diabetes. Table 46-3 lists the caloric differences among several high-protein, low-carbohydrate canned and dry diets and other diets that are fed to cats for weight loss. In addition to weight loss, another major goal of a diet for diabetic cats is to control blood glucose levels and reduce hyperinsulinemia and associated hyperamylinemia, both of which are very important in preserving β-cell function. Previously, diets high in fiber and complex carbohydrates were recommended for dietary management of diabetic cats, similar to the approach in dogs. Although these diets may reduce postprandial hyperglycemia, it is not to the same degree as high-protein and low-carbohydrate diets, and they do not result in consistent weight loss without loss of muscle mass. In addition, they are not associated with a high percentage of cats reverting to a preclinical (non–insulin-requiring) diabetic state. Recent studies have shown that cats fed highcarbohydrate diets have a much longer postprandial hyperglycemia period (up to 8 to 10 hours), and this period is prolonged even further when the cat is obese (up to 18 hours) (Hewson-Hughes, 2011). This physiologic difference in carbohydrate handling creates an even greater strain on their pancreatic β cells under conditions of chronicity or inflammation. Thus, in contrast to dogs, the primary strategy in diabetic cats is to achieve clinical

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SECTION  III  Endocrine and Metabolic Diseases

TABLE 46-3  Selected Feline Diabetic Diet Comparisons of Prescription Products* Protein (% DM)

CHO (% DM)

Fat (% DM)

Calories (kcal/Cup or Can)

Hill’s prescription diet m/d dry

51.1

15.1

21.8

495

Hill’s prescription diet m/d canned

52.8

15.7

19.4

156

Purina veterinary diets DM dry

57.9

14.9

17.9

592

Purina veterinary diets DM   canned

53.4

4.5

32.9

191

Royal Canin   diabetic DS 44 dry

44.0

23.1

11.0

239

CHO, Carbohydrate; DM, dry matter. *Based on product guides.

diabetic remission and normalize β-cell production, and the key dietary strategy in cats is reduction of postprandial blood glucose levels by feeding diets with extremely low levels of carbohydrate and replacing dietary carbohydrate with protein. In several more recent studies of newly diagnosed diabetics, cats placed on insulin and a high-protein and low-carbohydrate diet were four times more likely to achieve clinical remission; in cats that did not achieve remission, the amount of insulin required to control their diabetes was reduced by half. In addition to the amount of carbohydrate, the type of carbohydrate in the diet appears to be important. For cats that consume only dry food diets and have some carbohydrate in their food, the source should be a complex carbohydrate with a low glycemic index (e.g., whole grains such as barley). However, studies in diabetic cats comparing these types of diets with complex carbohydrates with low-carbohydrate diets are lacking, and because cats do not require any carbohydrates in their diet and normally would eat very little in their natural diet, it seems reasonable to try to achieve that ideal. Another major aspect of dietary therapy of feline diabetes—stimulation of insulin secretion—is also achieved by feeding a high-protein, low-carbohydrate diet because arginine is a potent insulin secretagogue. Even in cats with chronic, persistent hyperglycemia and resultant hyposecretion of insulin secondary to glucose stimulation, insulin secretion in response to arginine is normal to increased. Feline diets that are rich in animal source proteins contain abundant arginine, which contributes to endogenous insulin secretion in diabetic cats and subsequently may help lead to diabetic remission. In addition, the feeding of a high-protein, lowcarbohydrate diet to diabetic cats ensures the presence of gluconeogenic amino acids for production of glucose for energy throughout the day; this is particularly important

for diabetic cats because of their ability to regain their own insulin secretory function at any time. A hypoglycemic crisis may be even more likely than in dogs, especially if cats are consuming high-carbohydrate diets that provide an immediate postprandial increase in blood glucose but do not provide a readily available energy source later in the day. Finally, although cats prefer to eat small frequent meals (nibble or graze), it is very important that all diabetic cats are meal-fed so that the owner can observe the cat at the time of insulin administration and can be sure that the cat is eating appropriately at least twice daily. If the cat is prone to hypoglycemia or prefers small frequent meals, it is reasonable to divide the daily energy requirement into four separate feedings. This is easily done by using timed feeders, so the cat has the opportunity to eat multiple times per day while controlling intake but at the same time providing an energy source midday should the cat attain diabetic remission. Because diabetic remission is an important goal, especially in newly diagnosed obese or previously obese cats, frequent monitoring (both of weight loss and glycemic control) and access to small amounts of food is the best strategy. The specific techniques used to monitor successful control of blood glucose in diabetic cats are beyond the scope of this chapter but represent an essential aspect of diabetic management in cats (see Chapter 48). However, with appropriate use of diet in the management of feline diabetes, the goals of successful control, which include clinical remission of the diabetes, can be achieved.

References and Suggested Reading Benner N et al: Use of a low-carbohydrate versus high-fiber diet in cats with diabetes mellitus, J Vet Intern Med 15:297, 2001. Biourge VC: Feline diabetes mellitus: nutritional management, Waltham Focus 15:36, 2005. Farrow HA, Rand JS, Sunvold GD: The effect of high-protein, high-fat, or high-carbohydrate diets on postprandial glycemia and insulin concentrations in normal cats, J Vet Intern Med 16:360, 2002. Fleeman LM, Rand JS: Beyond insulin therapy: achieving optimal control in diabetic dogs, Waltham Focus 15:12, 2005. Frank G et al: Use of a high-protein diet in the management of feline diabetes mellitus, Vet Ther 2:238, 2001. Hewson-Hughes AK et al: The effect of dietary starch level on postprandial glucose and insulin concentrations in cats and dogs, Br J Nutr 12:51, 2011. Kimmel SE et al: Effects of insoluble and soluble dietary fiber on glycemic control in dogs with naturally occurring insulindependent diabetes mellitus, J Am Vet Med Assoc 216:1076, 2000. Marshall R, Rand JS: Insulin glargine and high-protein low carbohydrate diet are associated with high remission rates in newly diagnosed diabetic cats, J Vet Intern Med 18:401, 2004. Mazzaferro EM et al: Treatment of feline diabetes mellitus using an alpha-glucosidase inhibitor and a low-carbohydrate diet, J Feline Med Surg 53:183, 2003. Nelson RW et al: Effect of dietary insoluble fiber on control of glycemia in dogs with naturally occurring diabetes mellitus, J Am Vet Med Assoc 212:380, 1998. Rand JS, Marshall R: Understanding feline diabetes mellitus: pathogenesis and management, Waltham Focus 15:5, 2005. Remillard RL: Nutritional management of diabetic dogs, Compend Contin Educ 21:699, 1999.

CHAPTER 

47 

Insulin Resistance RICHARD W. NELSON, Davis, California

I

nsulin resistance is defined as a condition in which a normal amount of insulin produces a subnormal biologic response. Insulin resistance may result from problems occurring before the interaction of insulin with its receptor (e.g., circulating insulin-binding antibodies), at the receptor (e.g., altered insulin receptor binding affinity or concentration), or at steps distal to the interaction of insulin and its receptor (e.g., block in insulin signal transduction). Postreceptor problems are difficult to differentiate clinically from receptor problems, and both often coexist. In dogs and cats, receptor and postreceptor abnormalities are usually attributable to obesity, inflammation such as pancreatitis or gingivitis, or a disorder causing excessive or deficient secretion of one or more insulin-antagonistic hormones, specifically glucagon, catecholamines, cortisol, and growth hormone. Clinically relevant problems caused by insulin resistance include development of diabetes mellitus, stimulation of ketogenesis and development of diabetic ketoacidosis (DKA), and interference with the effectiveness of exogenous insulin injections for treating diabetes mellitus.

Role in the Pathogenesis of Feline Diabetes and Diabetic Remission Amylin is a polypeptide produced by pancreatic β cells in cats. It is stored in secretory granules that contain insulin and is cosecreted with insulin. Stimulants of insulin secretion stimulate the secretion of amylin. Chronic increased secretion of insulin and amylin, as occurs with obesity and other insulin-resistant states, results in aggregation and deposition of amylin in the pancreatic islets as amyloid. Amyloid fibrils cause apoptotic islet cell death. Deposition of islet amyloid and subsequent loss of β cells is progressive with persistent insulin-resistant states and ultimately results in diabetes mellitus. The severity of islet amyloidosis and loss of β cells determines, in part, a cat’s need for insulin treatment to control hyperglycemia and the potential for diabetic remission once treatment is initiated. Total destruction of the islets results in insulindependent diabetes mellitus and the need for insulin treatment for the rest of a cat’s life. Partial destruction of the islets may or may not result in clinically evident diabetes, insulin treatment may or may not be required to control hyperglycemia, and diabetic remission may or may not occur when treatment is initiated. The presence, severity, and reversibility of insulin resistance is an important variable that influences the severity and progression of islet amyloidosis, treatment options at the time diabetes is diagnosed, and likelihood of diabetic remission in cats. Any chronic insulin-resistant disorder

can have a deleterious impact on the population and function of β cells and play a role in the development of diabetes. Identification and correction of concurrent problems that cause insulin resistance is critical to the successful treatment of diabetes in cats (Box 47-1). Correction and subsequent avoidance of insulin resistance may result in diabetic remission in cats with partial loss of pancreatic β cells, and recurrence of insulin resistance may result in recurrence of symptomatic diabetes.

Role in Diabetic Ketoacidosis Insulin is a powerful inhibitor of lipolysis and ketone production. A deficiency of insulin or the presence of insulin resistance, or both, promotes lipolysis, ketogenesis, and development of DKA. Virtually all dogs and cats with DKA have a relative or absolute deficiency of insulin and insulin resistance at the time DKA is diagnosed. Some diabetic dogs and cats develop ketoacidosis despite receiving daily injections of insulin, and circulating insulin concentrations may be increased. In these dogs and cats, insulin deficiency results from insulin resistance caused by an increase in insulin-antagonistic hormones, most notably glucagon, and the presence of concurrent disorders such as pancreatitis. Insulin dosages that were effective in controlling hyperglycemia become inadequate with development of insulin resistance and predispose a diabetic dog or cat to developing DKA. Almost all dogs and cats with DKA have some coexisting disorder, such as pancreatitis, infection, or hormonal excess or deficiency. Recognition and treatment of disorders that coexist with DKA are critical for successful management (see Box 47-1).

Role in Control of Hyperglycemia Insulin resistance interferes with the actions of exogenously administered insulin, resulting in persistent hyperglycemia; glycosuria; clinical signs (polyuria, polydipsia, and weight loss); and development of complications of chronic diabetes, such as cataracts in dogs and peripheral neuropathy in cats. Persistent problems with diabetic regulation should raise suspicion for insulin resistance. However, other issues with the insulin treatment regimen should also be considered, such as an inadequate or excessive dosage of insulin and a short or prolonged duration of effect of the insulin preparation. There is no insulin dosage that clearly defines insulin resistance. For most diabetic dogs and cats, control of hyperglycemia can usually be attained using a dosage of 1.0 U or less of an intermediate-acting or long-acting 205

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SECTION  III  Endocrine and Metabolic Diseases

BOX 47-1  Recognized Causes of Insulin Resistance in Diabetic Dogs and Cats Conditions Typically Causing Severe Insulin Resistance Hyperadrenocorticism Acromegaly (cat) Progesterone excess (diestrus in female dog) Diabetogenic drugs*

Conditions Typically Causing Mild or Fluctuating Insulin Resistance Obesity Infections Chronic pancreatitis Chronic inflammation Disease of the oral cavity Renal insufficiency Liver insufficiency Cardiac insufficiency Hypothyroidism (dog) Hyperthyroidism (cat) Pancreatic exocrine insufficiency Hyperlipidemia Neoplasia Glucagonoma Pheochromocytoma Insulin autoantibodies

*Most notably glucocorticoids and progestins.

insulin preparation per kilogram of body weight given twice daily. Insulin resistance should be suspected if control of hyperglycemia is poor despite an insulin dosage greater than 1.5 U/kg, when excessive amounts of insulin (i.e., insulin dosage >1.5 U/kg) are necessary to maintain the blood glucose concentration less than 300 mg/dl, and when control of hyperglycemia is erratic and insulin requirements are constantly changing in an attempt to maintain control. Failure of the blood glucose concentration to decrease below 300 mg/dl is suggestive of, but not definitive for, the presence of insulin resistance. Failure of blood glucose concentration to decrease after insulin administration can also result from stress-induced hyperglycemia, induction of the Somogyi response, and other problems with insulin therapy. Similarly, a decrease in the blood glucose concentration to less than 300 mg/dl does not rule out insulin resistance because responsiveness to insulin may be present with disorders causing mild insulin resistance (e.g., obesity, chronic pancreatitis). Serum fructosamine concentrations are typically greater than 500 µmol/L in dogs and cats with insulin resistance and can exceed 700 µmol/L if resistance is severe. However, serum fructosamine concentrations can also be greater than 500 µmol/L with other problems involving the insulin treatment regimen. The severity of insulin resistance depends in part on the underlying etiology. Insulin resistance may be mild and easily overcome by increasing the dosage of insulin or may be severe, causing persistent severe hyperglycemia regardless of the type and dosage of insulin administered. Some causes of insulin resistance are readily apparent at the time diabetes is diagnosed, such as obesity and the administration of insulin-antagonistic drugs (e.g.,

glucocorticoids). Other causes of insulin resistance are not readily apparent and require an extensive diagnostic evaluation to be identified. Generally, any concurrent inflammatory, infectious, hormonal, neoplastic, or organ system disorder can interfere with the effectiveness of insulin. The most common concurrent disorders interfering with insulin effectiveness in diabetic cats include diabetogenic drugs (e.g., glucocorticoids), severe obesity, chronic pancreatitis, kidney failure, hyperthyroidism, oral infections, acromegaly, and hyperadrenocorticism. The most common concurrent disorders interfering with insulin effectiveness in diabetic dogs include diabetogenic drugs (i.e., glucocorticoids), severe obesity, hyperadrenocorticism, diestrus, chronic pancreatitis, kidney failure, oral and urinary tract infections, hyperlipidemia, and insulin antibodies in dogs treated with beef insulin. Obtaining a complete history and performing a thorough physical examination is the most important step in identifying these concurrent disorders. If the history and physical examination fail to identify the underlying problem, a complete blood count, serum biochemical analysis, serum thyroxine concentration (cat), serum pancreatic lipase immunoreactivity (IDEXX Spec cPL), serum progesterone concentration (intact female dog), abdominal ultrasound, and urinalysis with bacterial culture should be considered to screen further for concurrent illness. Additional tests depend on the results of the initial screening tests. Treatment and reversibility of insulin resistance depend on the etiology. Insulin resistance is reversible with treatable disorders (e.g., sodium levothyroxine treatment in a diabetic dog with concurrent hypothyroidism or ovariohysterectomy in an intact female diabetic dog in diestrus. In contrast, insulin resistance often persists with disorders that are difficult to treat, such as chronic recurring pancreatitis in diabetic dogs and cats or acromegaly in diabetic cats. In some situations, measures can be taken to prevent insulin resistance, such as avoidance of glucocorticoids in diabetic dogs and cats or performing an ovariohysterectomy at the time diabetes mellitus is diagnosed in an intact female dog.

Insulin Dosage Adjustments In most diabetic dogs and cats, insulin resistance is not suspected until insulin dosages exceed 1.5  U/kg per injection and problems with hyperglycemia persist. Two common exceptions are obesity, which is readily recognizable, and treatment with insulin-antagonistic drugs, most notably glucocorticoids. Adjustments in the insulin dosage should always be considered at the time treatment of the insulin-resistant disorder is initiated. How much to decrease the insulin dosage is variable and depends in part on the severity of insulin resistance, the amount of insulin being administered, and the expected rapidity of improvement in insulin resistance after treatment of the disorder. For example, dogs with poorly controlled diabetes and newly diagnosed hypothyroidism have a rapid improvement in insulin resistance after initiating thyroid hormone treatment. Failure to decrease the insulin dosage may result in symptomatic hypoglycemia within days of starting thyroid

CHAPTER  47  Insulin Resistance hormone treatment. In contrast, correction of obesity and subsequent improvement in insulin resistance is a slow process associated with a gradual reduction in the insulin dosage over time as obesity im­­proves. Avoiding hypoglycemia is the primary goal when adjusting the insulin dosage. I always err on the side of caution by not decreasing the insulin dosage too much rather than too little, recognizing that hyperglycemia is not lifethreatening, but severe hypoglycemia can be. When in doubt, I decrease the insulin dosage to approximately 0.5  U/kg per injection for diabetic dogs and cats and rely on owner observations regarding the overall health of their pet and the presence of clinical signs suggestive of hypoglycemia. Home blood glucose monitoring and monitoring random urine samples for negative glycosuria may also be considered.

Glucocorticoids and Hyperadrenocorticism Diabetic dogs and cats are often treated with glucocorticoids for treatment of concurrent disease (e.g., allergic skin disease). Glucocorticoids have the potential to cause severe insulin resistance, creating a tendency for large amounts of insulin to be administered in an attempt to control hyperglycemia. If glucocorticoids are required for treatment of a concurrent disease, the glucocorticoid dosage should be kept as low as possible and administered as infrequently as possible to minimize the severity of insulin resistance. Insulin dosage requirements are higher in the presence of insulin resistance to maintain some semblance of glycemic control. It is important to remember the interplay between dosage adjustments of glucocorticoids and the impact of the adjustment on severity of insulin resistance and insulin dosage requirements. Appropriate adjustments in the insulin dosage should be made whenever the glucocorticoid dosage is increased or decreased to minimize hyperglycemia or hypoglycemia, respectively. Naturally occurring hyperadrenocorticism and diabetes mellitus are common concurrent diseases in dogs. For most dogs, glycemic control remains poor despite insulin therapy, and good glycemic control is generally not possible until the hyperadrenocorticism is controlled. The initial focus should be on treating the hyperadrenal state in a dog with poorly controlled diabetes and hyperadrenocorticism. Insulin treatment is indicated; however, aggressive efforts to control hyperglycemia should not be attempted. Rather, a conservative dosage (0.5 to 1.0 U/ kg) of intermediate-acting insulin (i.e., NPH or Lente) should be administered twice a day to prevent ketoacidosis and severe hyperglycemia. Monitoring water consumption and frequency of urination is unreliable because both diseases cause polyuria and polydipsia, and polyuria and polydipsia may persist if poor control of hyperglycemia persists despite attaining control of hyperadrenocorticism. As control of hyperadrenocorticism is achieved, insulin resistance resolves, and tissue sensitivity to insulin improves. Home blood glucose monitoring and testing urine for the presence of glucose can be done by the owner to help prevent hypoglycemia and identify when insulin resistance is resolving. Any blood glucose concentration less than 150 mg/dl or urine sample found

207

to be negative for glucose should be followed by a 20% to 25% reduction in the insulin dosage and evaluation of control of the hyperadrenocorticism. Critical assessment of glycemic control and adjustments in insulin therapy should be initiated after hyperadrenocorticism is controlled.

Feline Acromegaly Chronic excess secretion of growth hormone (GH) by a functional adenoma of the somatotropic cells of the pituitary pars distalis causes acromegaly in adult cats (see Chapter 49). Clinical manifestations of acromegaly result from the catabolic effects of GH and the anabolic effects of insulin-like growth factor-1 (IGF-1). GH-induced catabolic effects include insulin resistance, carbohydrate intolerance, hyperglycemia, and diabetes mellitus. Most cats are diabetic at the time acromegaly is diagnosed, and most have poorly controlled diabetes because of GH-mediated insulin resistance, which is usually severe. Cats typically have blood glucose concentrations that remain greater than 400 mg/dl regardless of the dosage or type of insulin being administered. Insulin dosages of 20 to 40 units per injection are common at the time acromegalic cats are referred to our hospital; these dosages have been attained in an effort to decrease the blood glucose concentration to less than 300 mg/dl. In my experience, control of hyperglycemia cannot be attained in most acromegalic cats. The goal of insulin treatment is to avoid severe hyperglycemia (blood glucose concentrations >600 mg/dl) and hypoglycemia, not to attain control of the diabetic state. I start with a long-acting insulin preparation at an initial dosage of 0.5 to 1.0 U/kg administered twice a day. I increase the insulin dosage based on the owner’s perception of how the cat is doing as it relates to activity, grooming, and interactions with family members, not based on severity of polyuria, polydipsia, or polyphagia or persistent hyperglycemia or glycosuria. Severe hyperglycemia causes lethargy, obtundation, and the perception that the cat is “not feeling well.” I consider increasing the insulin dosage if owners report these problems, especially if the blood glucose concentration is greater than 600 mg/dl. I am cautious when increasing the insulin dosage because of concerns for the development of severe life-threatening hypoglycemia that can occur unexpectedly in acromegalic cats, presumably as a result of sporadic reductions in GH secretion and subsequent improvement in insulin resistance. I rarely exceed 12 units of insulin per injection and then only because of owner concerns that their cat is “not feeling well” and only after measuring blood glucose concentrations to confirm the presence of severe hyperglycemia. Home blood glucose monitoring and testing urine for the presence of glucose by the owner should be encouraged to help prevent hypoglycemia and identify when insulin resistance has improved.

References and Suggested Reading Appleton DJ et al: Insulin sensitivity decreases with obesity and lean cats with low insulin sensitivity are at greatest risk of glucose intolerance with weight gain, J Feline Med Surg 3:211, 2001.

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Davison LJ et al: Anti-insulin antibodies in diabetic dogs before and after treatment with different insulin preparations, J Vet Intern Med 22:1317, 2008. Durocher LL et al: Acid-base and hormonal abnormalities in dogs with naturally occurring diabetes mellitus, J Am Vet Med Assoc 232:1310, 2008. Henson MS et al: Evaluation of plasma islet amyloid polypeptide and serum glucose and insulin concentrations in nondiabetic

CHAPTER 

cats classified by body condition score and in cats with naturally occurring diabetes mellitus, Am J Vet Res 72:1052, 2011. Hess RS et al: Concurrent disorders in dogs with diabetes mellitus: 221 cases (1993-1998), J Am Vet Med Assoc 217:1166, 2000. Lowe AD et al: A pilot study comparing the diabetogenic effects of dexamethasone and prednisolone in cats, J Am Animal Hosp Assoc 45:215, 2009.

48 

Feline Diabetes Mellitus JACQUIE S. RAND, Queensland, Australia

D

iabetes mellitus is the second most common endocrinopathy in cats and affects approximately 1 in 50 to 1 in 400, depending on the population studied. Risk factors include advanced age, male sex, breed, obesity, physical inactivity, confinement indoors, and administration of glucocorticoids or progestins. Breeds reported at risk are Burmese in Australia, New Zealand, and the United Kingdom and Maine coon, domestic longhair, Russian blue, and Siamese in the United States. Diagnosis of diabetes mellitus is based on the finding of persistently increased blood glucose concentration. In most cats, diabetes is usually not diagnosed until relatively late in the disease process when extensive β-cell function has been lost. The diagnosis is typically made when blood glucose concentration is above the renal threshold (i.e., >250 to 290 mg/dl [14 to 16 mmol/L]) and signs of polyuria, polydipsia, and weight loss are apparent. In contrast, in humans with type 2 diabetes, diagnosis is made earlier in the disease process. Because of this difference in diagnosis and extent of β-cell failure, most humans but only the minority of cats can be managed satisfactorily with oral hypoglycemic drugs. At the present time, there is no consensus in the veterinary literature regarding the minimal blood glucose concentration in cats that should be classed as diabetic. Based on data in other species, blood glucose concentrations below the renal threshold but persistently greater than normal are likely associated with adverse effects, such as glucotoxic damage to β cells. Persistently mild hyperglycemia (e.g., >117 mg/dl fasted or >145 mg/dl unfasted to 6.5 mmol/L fasted or >8.0 mmol/L unfasted to 144 mg/dl [8 mmol/L] unfasted), and the diet is fed to achieve an ideal body weight. Cats should be monitored on a regular basis (e.g., every 3 to 6 months).

Pathogenesis of Diabetes in Cats To manage diabetic cats effectively, an understanding of the pathogenesis and main features of feline diabetes is required. In developed countries, most owned cats with diabetes likely have type 2 diabetes, which is characterized by a relative lack of insulin secretion and insulin resistance. Insulin resistance reduces the glucose-lowering effect of a given amount of insulin. Diabetic cats are on average six times less sensitive to insulin than healthy cats, representing a similar magnitude of insulin resistance to that identified in humans with type 2 diabetes. Insulin resistance results from numerous mechanisms, and more than one mechanism is likely operating in most diabetic cats. A small percentage of cats have other specific types of diabetes resulting from β-cell destruction associated with pancreatitis and neoplasia or have marked insulin resistance from excess growth hormone or

CHAPTER  48  Feline Diabetes Mellitus corticosteroids. In referral practice, cats with other specific types of diabetes account for a substantial proportion of diabetic cats; acromegaly (growth hormone–producing tumor) has been reported in 25% to 30% of diabetic cats, and pancreatic neoplasia was reported in necropsy specimens of 8% to 18% of diabetic cats at referral institutions in the United States. Pancreatitis is likely an underdiagnosed cause of diabetes, and anecdotal data indicate it might be a cause of diabetes in cats that achieve remission as well as cats that remain dependent on insulin throughout their life. Hyperthyroidism results in glucose intolerance and insulin hypersecretion, both of which are exacerbated in some cats after treatment of hyperthyroidism and might be the result of weight gain and resultant obesity.

Insulin Resistance In humans, the most important causes of insulin resistance are genotype, obesity, and physical inactivity. These same factors are also the most likely causes of insulin resistance in cats. It is important to be aware of these predisposing factors so that they are appropriately managed. Obesity markedly decreases insulin sensitivity in cats. An increase in body weight from an ideal weight of 4 kg to 6 kg decreases insulin sensitivity by 50% in cats. Management of body condition is a vital part of therapy for prevention and management of feline diabetes as well as prevention of relapse in cats that have achieved diabetic remission. Physically inactive cats have been shown to be at risk of diabetes, and increasing physical activity improves insulin sensitivity in other species. One study in cats also found that active play for 10 minutes daily produced the same rate of weight loss as calorie restriction. Genetic predisposition is likely a risk factor for insulin resistance and diabetes in cats. Lean cats with insulin sensitivity values below the median of the population were at three times greater risk of developing impaired glucose tolerance when they gained weight than cats with higher insulin sensitivity. Impaired glucose tolerance is the glycemic state between normal and diabetic. It is likely that these cats had underlying insulin resistance associated with genotype and that obesity would result in diabetes in some of these cats with time. Burmese cats are at increased risk of diabetes in Australia, New Zealand, and the United Kingdom and appear to have underlying insulin resistance. High blood glucose concentration also contributes to insulin resistance. In dogs, it has been shown that this effect has a relatively short-term influence, with insulin resistance related more closely to glycemia over the previous 48 hours rather than over longer periods. This finding is relevant especially in the initial phases of treatment, and clinicians need to be aware that insulin sensitivity is increased with decreasing blood glucose concentration. Drugs such as glucocorticoids and progestins produce insulin resistance and increase the risk of diabetes particularly when administered as long-acting preparations or given repeatedly. Glucocorticoids and progestins increase the risk of relapse in cats that have achieved diabetic remission.

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Impaired Insulin Secretion Insulin secretion is decreased in feline diabetes through many mechanisms, some of which are reversible. Loss of β cells in type 2 diabetes is thought to result from apoptosis triggered by factors associated with obesity and insulin resistance, including release of inflammatory adipokines. Loss of β cells also occurs as a result of islet amyloid deposition and intracellular formation of toxic amyloid fibrils. Reversible suppression of insulin secretion occurs when blood glucose or lipid concentrations are high. These conditions are called glucotoxicity and lipotoxicity, and both may act through similar intracellular mechanisms in the β cell. With time, chronic hyperglycemia irreversibly damages β cells, and they are per­ manently lost, which can lead to insulin-dependent diabetes. Loss of β cells also occurs through pancreatitis, and approximately 50% of diabetic cats have histologic evidence of pancreatitis. In most cats, the severity of the lesion is not sufficient by itself to cause diabetes but potentially contributes to loss of β cells. However, pancreatitis is likely an underdiagnosed cause of diabetes in cats, and it is recommended that feline pancreatic lipase be measured in all newly diagnosed diabetic cats, especially cats with any signs that could be consistent with pancreatitis. When insulin resistance is not involved, clinical signs of diabetes ensue once approximately 80% to 90% of β cells are lost. If insulin sensitivity is reduced, clinical signs of diabetes occur earlier with smaller loss of β cells. With obesity-induced insulin resistance, cats need 30% more insulin to maintain fasting glucose concentration than when they were lean, and so logically, they would develop diabetes earlier with less β-cell loss. Veterinarians need to impress on owners the importance of attaining an ideal body condition in their diabetic cats, cats at risk of diabetes, and cats in diabetic remission.

Diabetic Remission Within days to months of beginning treatment with insulin, a proportion of diabetic cats are able to maintain euglycemia without therapy. This is called diabetic remission. The proportion of cats that achieve diabetic remission depends on how early tight glycemic control is instituted, the type of therapy, and the underlying cause of the diabetes. Cats require functioning β cells to attain remission. It is believed that reversal of glucotoxicity and lipotoxicity leads to diabetic remission. Therapies that provide the best glycemic control are likely to lead to the highest remission rates. Factors shown to be associated with increased probability of remission include institution of rigorous glycemic control within 6 months of diagnosis (remission rate 84% compared with 34% after 6 months), use of a long-acting insulin (glargine or detemir), feeding a low-carbohydrate diet, and careful monitoring of blood glucose concentrations together with appropriate adjustment of insulin dosage. Recent treatment with corticosteroids was positively associated with remission in one study. Other factors associated with remission are mean

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blood glucose less than 290 mg/dl (16 mmol/L) within 3 weeks of initiation of treatment and older age of cat. Cats less likely to achieve remission have increased serum cholesterol concentration, evidence of plantigrade stance, and requirement of a higher maximum dosage of insulin to gain glycemic control (median dosage was 50% higher—0.66 U/kg versus 0.43 U/kg). Cats in remission may relapse in weeks to months, and it is important that they are carefully monitored and managed in remission, ideally with weekly home blood glucose monitoring. With early reinstitution of insulin therapy, some cats can achieve remission again. Persistent mildly increased blood glucose concentrations, that is, impaired fasting glucose (145 to 180 mg/dl [8 to 10 mmol/L]); more severe glucose intolerance (first return to baseline glucose concentration at 5 hours after 1 g/kg glucose intravenously); obesity; and use of glucocorticoids or progestins likely increase the probability of relapse.

Management of Diabetes The most important goals of therapy are to achieve diabetic remission in cats with newly diagnosed diabetes; resolve clinical signs; and avoid clinical hypoglycemia, which can be life-threatening. The best way to resolve clinical signs is to achieve diabetic remission. Treatments available for management of feline diabetes include dietary modification, insulin, and oral hypoglycemic drugs. The prevalence of diabetes is increasing as risk factors such as obesity and physical inactivity become more common. These risk factors also need to be addressed in management and prevention of diabetes. Maintaining ideal body weight and avoiding drugs such as cortico­ steroids and progestins are important for maintaining remission.

Diet Diet is an important component of therapy, and a lowcarbohydrate diet is vital for cats achieving diabetic remission because it decreases mean daily glucose concentration, an important contributor to recovery of β cells from glucose toxicity (see also Chapter 46). A highcarbohydrate diet (50% of energy from carbohydrate) can increase mean blood glucose concentrations 4 to 18 hours after eating by 20% to 25% and peak glucose concentrations by more than 30% compared with a moderate-carbohydrate diet (25% energy from carbohydrate); comparison with a low-carbohydrate diet is even more pronounced. Remission rates were significantly higher (68% versus 42%) in cats fed a low-carbohydrate diet (12% of energy from carbohydrate; 3.5 g/100 kcal ME) compared with cats fed a higher carbohydrate diet (26% of energy from carbohydrate; 7.6 g/100 kcal ME), despite similar protein content of the two diets. Cats eating an ultra-low-carbohydrate diet (5% of energy; 1.8 g/100 kcal ME) have even greater reduction in blood glucose concentration; however, no studies comparing remission rates in cats fed low-carbohydrate and ultralow-carbohydrate diets have been published. Ultra-lowcarbohydrate diets are often nearly all meat or fish, may

not be complete or balanced, and are high in phosphorus, which is of concern given the frequency of chronic kidney disease in diabetic cats. Reducing carbohydrate content of the diet also decreases the demand on β cells to secrete insulin. Cats in diabetic remission likely have reduced β-cell mass. From the limited testing reported, most of these cats have impaired glucose tolerance, and about one third have impaired fasting glucose, meaning a glucose concentration above normal (117 mg/dl [6.5 mmol/L]) but less than diabetic (180 mg/dl [10 mmol/L]). It is vital that cats in remission be fed diets that minimize the amount of insulin required to be secreted to control postprandial glycemia. Feeding a low-carbohydrate diet once diabetic remission is achieved would likely prolong remission. To achieve and maintain remission, it is important to attain an ideal body weight because of the negative impact of obesity on insulin sensitivity. Diet is also important for achieving weight loss. A minority of cats fed canned low-carbohydrate, high-protein diets self-restrict energy intake and lose weight spontaneously after their diet is changed. For most cats, energy intake needs to be restricted to achieve weight loss. Physical activity promotes weight loss and improves insulin sensitivity in other species, independent of body weight. Encouraging owners to engage in active play with their cat is likely beneficial.

Insulin Therapy Insulin therapy is the mainstay of therapy in diabetic cats. Veterinary insulin preparations available for maintenance treatment of diabetic cats include porcine Lente insulin (40 U/ml; Caninsulin/Vetsulin) in Europe and Canada and human recombinant protamine zinc insulin (PZI) (40 U/ml; ProZinc) in North America. Human insulin preparations used for long-term maintenance of diabetic cats include neutral protamine Hagedorn (NPH), glargine, and detemir. Human Lente and Ultralente insulin preparations have been removed from the market in most countries. In Europe, veterinarians are legally required to use an insulin registered for veterinary use as the first line of therapy.

Choice of Insulin Type In a trial of 24 cats, all 8 cats with newly diagnosed diabetes treated with glargine and an ultra-lowcarbohydrate diet (5% of energy from carbohydrate; Nestle Purina DM canned) achieved remission compared with 3 of 8 treated with PZI and 2 of 8 treated with porcine Lente. These findings compare with 20% to 30% remission rates reported using other insulin preparations and a standard feline maintenance diet (typically 30% to 40% of energy from carbohydrate). One study reported 60% remission rates using PZI or Lente insulin and a lowcarbohydrate diet. Trials using either glargine or detemir in cats previously treated with other insulins, predominantly Lente, achieved remission rates of 84% and 81% if cats were changed to intensive blood glucose monitoring and glargine or detemir therapy within 6 months of diagnosis of diabetes.

CHAPTER  48  Feline Diabetes Mellitus Glargine and detemir are long-acting insulins, and although their long duration of action is achieved by different modifications to the insulin molecule, they have similar clinical effects in cats. In cats with newly diagnosed diabetes, remission rates of greater than 80% to 90% often can be achieved using glargine or detemir combined with a low-carbohydrate or ultra-lowcarbohydrate diet and frequent monitoring of blood glucose concentration and appropriate adjustment of insulin dosage. Lower remission rates occur in cats with long-term diabetes changed to glargine or detemir therapy. Diabetic remission is rare in cats that have been diabetic for more than 2 years. Because of the huge advantage to the client and the cat in achieving diabetic remission, it is strongly recommended that the first choice of insulin for diabetic cats be glargine or detemir. If there is a legal requirement to use a veterinary insulin product first, PZI would be the first choice because it has a longer duration of action than Lente insulin. However, recombinant PZI is not yet licensed for veterinary use in Europe. Lente and NPH insulins have too short a duration of action for optimal blood glucose control in cats. Using Lente or NPH insulin, even with an optimal dosage and the nadir glucose concentration in the normoglycemic range, most cats have a period of at least 2 to 4 hours before each insulin injection when there is no exogenous insulin action, and high blood glucose concentrations ensue, often 360 mg/dl (20 mmol/L) or greater. Because the blood glucose concentration is very high, administering a potent insulin such as Lente or NPH may result in a rapid decrease in blood glucose concentration. The hypothalamic neurons detect a decreasing blood glucose concentration and trigger counterregulatory mechanisms before hypoglycemia occurs. These neurons control their intracellular glucose concentration by limiting glucose uptake when plasma glucose concentration is high; with a rapidly decreasing blood glucose concentration, the neurons become hypoglycemic even at relatively high blood glucose concentration, and the resultant counterregulatory mechanisms are often triggered when blood glucose concentration is still above the normal range. Cortisol, epinephrine, and glucagon are released, increasing blood glucose concentrations. The end result is further shortening of insulin action, which for some cats treated with Lente insulin is only about 3 hours. The counterregulatory response also results in insulin resistance, and the following insulin injections may result in little appreciable glucose-lowering effect.

Recommendations for Using Glargine and Detemir Glargine and detemir are long-acting insulins designed to provide basal insulin concentrations in humans with type 1 and 2 diabetes. Administration in humans is coupled with prandial administration of an ultra-short-acting insulin or oral hypoglycemic drug. In cats, because the postprandial period is so prolonged (12 to 24 hours) compared with humans, administration of an ultra-rapidacting insulin at the time of eating is unlikely to be useful.

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Glargine (Lantus) is produced by recombinant deoxyribonucleic acid (DNA) technology using Escherichia coli. The insulin molecule is modified by replacing asparagine at position 21 with glycine and by adding two arginine residues at the terminal portion of the B chain. It is supplied as a clear, colorless solution of monomeric insulin with a pH of 4.0. When injected into the subcutaneous tissues with a pH of 7.0, glargine forms hexamers, and microprecipitates deposit in the tissues. These microprecipitates slowly break down, releasing monomeric glargine into solution, which gives glargine its long duration of action. Because of this, the manufacturers state that glargine cannot be diluted or mixed with other insulin. Glargine is available only at a concentration of 100 U/ml, which makes accurate dosing a problem in cats, particularly when very low dosages are being administered close to remission. Some human patients dilute or mix glargine with other insulin. This causes glargine to precipitate and the solution to become cloudy, but it appears to retain some efficacy. Dilution is not recommended for feline patients except as a last resort, and dilution should occur just prior to injection. Detemir (Levemir) is also produced by recombinant DNA technology but using yeast (Saccharomyces cerevisiae). The insulin molecule is modified via addition of an acylated fatty acid chain, which facilitates reversible binding to plasma proteins, particularly albumin, from where it is released slowly into plasma. It also selfassociates at the injection site, which helps prolong its absorption and duration of action. Detemir can be diluted using the Insulin Diluting Medium supplied by the manufacturer or with sterile water or saline just prior to administration. Glargine and detemir have been used successfully in cats with a starting dosage of 0.5 U/kg twice daily if blood glucose is 360 mg/dl (20 mmol/L) or greater, and 0.25 U/ kg for lower blood glucose concentrations. The initial starting dosage should not exceed 3 U/cat twice daily. It is strongly recommended that glargine and detemir be administered twice daily in the first 4 months of therapy to maximize glycemic control and diabetic remission. Glargine administered once daily has been shown to be similar in effectiveness to Lente insulin twice daily. The dosage generally should not be increased in the first week unless little or no glucose-lowering effect is evident after the third day. In many cats, the dosage needs to be reduced in the first 7 days. If the dosage is increased after the third day, it is important that intensive glucose monitoring be done. Increasing the dosage without monitoring can result in clinical hypoglycemia. It is recommended that close monitoring occur in the first 4 to 8 weeks of treatment with appropriate dosage adjustments because many cats achieve diabetic remission within this time. It is prudent to keep the cat in the hospital and check blood glucose concentration for the first 3 days after institution of treatment to check for evidence of hypoglycemia, or if the owner is capable, careful home monitoring of blood glucose concentration can be performed. If monitoring of blood glucose concentration is not possible, one can closely monitor urine glucose concentration and water drunk as indicators of glycemic control. If a marked decrease in water drunk occurs in the

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BOX 48-1  Current Recommendations for Adjusting Dosage of Glargine, Detemir, and PZI in Diabetic Cats Home blood glucose monitoring is highly recommended to provide additional data for insulin dosage adjustments. Blood glucose measurements are based on using a portable meter calibrated for feline blood or a serum chemistry analyzer. If using a meter calibrated for human blood, adjust glucose cut-points as required based on validation of the meter with a serum chemistry analyzer. 1.  Starting Dosage Begin with 1 U/cat if blood glucose less than 360 mg/dl (20 mmol/L) and 2 U/cat if 360 mg/dl (20 mmol/L) or greater. 2.  Indications for Increasing Dosage Assess response for 5 to 7 days after each dosage increase, before increasing dosage again; ideally, assess with daily home blood glucose monitoring, but if this is not possible, use clinical data such as water drunk, urine glucose monitoring, and presence or absence of clinical signs of hypoglycemia as a guide to response to therapy as well as weekly blood glucose curves generated during weekly veterinary checks. • If preinsulin glucose concentration is 216 mg/dl (12 mmol/L) or greater, provided that nadir glucose is not less than 72 mg/dl (4 mmol/L), increase dosage by 0.25 to 1 U/ injection, depending on the degree of hyperglycemia   and if on a high (≥3 U/cat) or low dosage of insulin. • If nadir (lowest) glucose concentration is 126 mg/dl (7 mmol/L) or greater, increase dosage by 0.25 to 1 U/ injection, depending on the degree of hyperglycemia   and if on a high (≥3 U/cat) or low dosage of insulin. • After several weeks of therapy, aim for a nadir (lowest glucose) in the normal range (e.g., 72-126 mg/dl [4-7 mmol/L]). 3.  Indications for Maintaining Same Dosage • If pre-insulin glucose concentration is 180 to less than 216 mg/dl (10 to 126 to 180 mg/dl (7 to 10 mmol/L), although this may result in subsequent hyperglycemia. • For cats with a normal blood glucose, 60 to 126 mg/dl   (3.5 to 7 mmol/L), at the time of the next insulin injection, initially test which of the alternative methods is best suited   to the individual cat: 1. Feed the cat and reduce the dosage by 0.25 to 0.5 IU depending on if the cat is on a low (25 U/cat BID) to control blood glucose concentration. For cats on a high dosage of insulin (>5 U BID), screening for acromegaly should be done by measuring insulin-like growth factor-α; brain imaging may also be required (see Chapter 49). In cats with signs of other specific types of diabetes in which the underlying disease is potentially reversible, such as hyperadrenocorticism, acromegaly, or pancreatitis, one should not delay insulin therapy and wait to determine if blood glucose normalizes after instituting specific therapy for the underlying condition that is contributing to insulin resistance or loss of β-cell function. If blood glucose concentrations are elevated (≥270 mg/dl [15 mmol/L]), insulin therapy should be instituted immediately to preserve β cells and not be delayed until after other specific therapy.

Determining if Diabetic Remission Is Present Many cats achieve diabetic remission within 2 to 8 weeks. It is strongly recommended that insulin therapy not be withdrawn prematurely. Cats with almost normal β-cell function can tolerate 0.5 to 1 U once or twice daily and rarely develop clinical hypoglycemia. If insulin therapy is stopped prematurely and hyperglycemia recurs, it can take weeks or months to achieve the same level of glycemic control once insulin is reinstituted. It is recommended that insulin therapy continue for a minimum of 2 to 4 weeks after initiating treatment to facilitate β-cell recovery from glucotoxicity. Insulin dosage should be decreased gradually based on dosing guidelines in Box 48-1. When preinsulin blood glucose concentration is less than 180 mg/dl (10 mmol/L) and total dosage is decreased to 0.5 U twice daily, the dosing frequency can be reduced to once daily. If after 1 to 2 weeks preinsulin blood glucose is still less than 180 mg/dl (10 mmol/L) and nadir glucose concentration is not above the normal range (72 to 126 mg/dl [4 to 7 mmol/L]), insulin therapy can be discontinued, and blood glucose concentration should be monitored during the day. If blood glucose increases to greater than 180 mg/ dl (10 mmol/L) within 12 to 24 hours, insulin should be

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immediately reinstituted at 1 U once or twice daily, and one should wait a minimum of 2 weeks before attempting withdrawal of insulin again. If blood glucose concentration is less than 180 mg/dl (10 mmol/L), one should continue to withhold insulin, checking blood glucose every 3 to 7 days for several weeks, and carefully monitor the cat for signs of hyperglycemia (increasing thirst and glycosuria). Owners should monitor glucose concentrations once a week, but if this is not possible, they should measure water drunk and monitor urine glucose concentration because increased thirst or glycosuria likely indicates relapse. If blood glucose is 180 mg/dl (10 mmol/L) or greater, insulin therapy should be reinstituted immediately. Some cats regain substantial β-cell function but require 0.5 to 1 U of insulin every 2 to 3 days to maintain normoglycemia. Generally, blood glucose concentration following glargine or detemir administration does not change as quickly as with shorter acting insulins such as Lente; measuring blood glucose concentration every 4 hours is usually adequate. Critical time points to monitor are the blood glucose concentration just before each insulin injection (i.e., the preinsulin morning and evening glucose concentrations) when using glargine or detemir. For many cats treated with glargine or detemir, the evening blood glucose concentration is lower than the morning concentration and is often the nadir glucose concentration. Occasionally, blood glucose concentration can change rapidly, especially during the night, and can increase from 54 mg/dl to 324 mg/dl (3 mmol/L to 18 mmol/L) in 2 hours. It is unclear whether this rapid increase in blood glucose is mediated by counterregulatory hormones (Somogyi phenomenon) or reflects marked hepatic gluconeogenesis associated with negligible insulin concentrations. A rapid increase in blood glucose is more common when glargine is given once daily. Cats with low normal glucose concentration when last monitored in the evening may have very high blood glucose concentrations the next morning. In some cats, decreasing the dosage of insulin decreases morning blood glucose concentration, suggesting that the morning hyperglycemia may be the result of a Somogyi response. The Somogyi phenomenon appears to be very rare in cats treated with glargine or detemir compared with shorter acting insulins such as Lente insulin. However, cats treated with glargine appear quite susceptible to stress-induced hyperglycemia associated with hospital monitoring of blood glucose. If marked hyperglycemia occurs in the hospital, it is critical that information be obtained on glycemic control at home before the hyperglycemia is attributed to treatment failure. Home monitoring of blood glucose concentration helps to clarify the level of glycemic control. If home monitoring of blood glucose concentration is not possible, owners should measure water drunk and urine glucose concentration.

Biochemical Hypoglycemia Cats treated with glargine or detemir often have biochemical hypoglycemia without clinical signs of hypoglycemia. Humans treated with glargine have significantly

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lower frequency of clinical hypoglycemia compared with humans treated with NPH insulin. In cats, clinical hypoglycemia also appears to be less common with glargine or detemir than when Lente insulin is used. Biochemical hypoglycemia, with or without mild to moderate clinical signs, can usually be managed at home by feeding the cat, preferably a higher carbohydrate meal such as a dry maintenance feline diet. If a cat displays severe clinical signs such as seizures, glucose syrup or honey must be promptly rubbed into the gums, and veterinary attention should be sought immediately. Most cats showing signs of clinical hypoglycemia with glargine or detemir are in diabetic remission or achieve remission within a few weeks. If biochemical hypoglycemia without clinical signs is present at the time of an insulin injection, one should wait until blood glucose concentration is greater than 126 mg/dl (7 mmol/L) and then reduce the dosage by 0.25 to 0.5 U/cat depending on whether the insulin dosage is greater than or less than 3 U and the degree of hypoglycemia.

Monitoring Glycemic Control Home blood glucose monitoring two to five times daily provides superior glycemic monitoring to weekly or less frequent glucose monitoring by the veterinarian. However, in the absence of daily home glucose monitoring, measurement of water drunk and urine glucose concentration are invaluable indicators of glycemic control. Diabetic cats with exemplary glycemic control drink volumes similar to nondiabetic cats (9 µg/dl). The dose should then be decreased from the previous amount and/or frequency. Occasionally there may be evidence of hyperkalemia and hyponatremia. If these occur, an ACTH stimulation test should be performed; post-ACTH cortisol would be expected to be less than 20 nmol/L (50% of cases HTG and HCH can range from mild to marked; present in >75% of cases HTG and HCH can range from mild to marked

Pancreatitis*

HTG and/or HCH

Both HTG and HCH are typically mild if other causes of hyperlipidemia are not present; present in ~30% of cases

Obesity*

HTG and/or HCH

HTG and HCH can range from mild to marked; present in >25% of cases

Protein-losing nephropathy*

HCH

HCH is part of the nephrotic syndrome; HCH is usually mild

Cholestasis*

HTG and/or HCH

Increases are usually mild

Hepatic insufficiency*

HTG and/or HCH

Increases are usually mild

Lymphoma

HTG with or without HCH

Hyperlipidemia might persist despite treatment

Leishmania infantum infection

HTG and HCH

Increases are typically mild if present

Parvoviral enteritis

HTG

HTG is typically mild if present

Hypernatremia?

HTG and HCH

Based on a case report and evidence from human medicine

Drugs*   Glucocorticoids   Phenobarbital   Estrogen/progesterone?

HTG and/or HCH HTG HTG and/or HCH

Increases can range from mild to marked HTG can range from mild to marked; present in >30% of cases Anecdotal

Miniature schnauzer*

HTG with or without HCH

HTG can range from mild to marked; HCH may be mild to moderate; present in >30% of all dogs in the United States; prevalence increases with age

Beagle*

HTG and/or HCH

Increases are usually mild to moderate

Shetland sheepdog*

HCH with or without HTG

HCH might be marked; HTG is typically mild; present in >40% of dogs in Japan

Doberman pinscher

HCH

HCH is usually mild

Rottweiler

HCH

HCH is usually mild

Briard

HCH

HCH in briards has only been reported in the United Kingdom

Rough-coated collie

HCH

Reported in a single family in the United Kingdom

Pyrenees mountain dog

HCH

HCH is usually mild

Secondary Hyperlipidemia

Primary Hyperlipidemia

*Indicates common causes. HTG, Hypertriglyceridemia; HCH, hypercholesterolemia; ?, this cause is not well documented or is questionable.

evidence of insulin resistance in one study (Xenoulis et al, 2011a). This might have an implication on glycemic control in dogs with hypertriglyceridemia and concurrent diabetes mellitus or other diseases that cause insulin resistance. Finally, several other conditions have been reported  or suspected to be consequences of hyperlipidemia in  dogs. These include atherosclerosis, ocular disease (e.g., lipemia retinalis, lipemic aqueous, lipid keratopathy,

solid intraocular xanthogranuloma), seizures, and cutaneous xanthomata or lipomas.

Diagnostic Approach to Canine Hyperlipidemia Hyperlipidemia is typically diagnosed by measuring fasting serum triglyceride and cholesterol concentrations. Because hyperlipidemia is an important diagnostic clue

CHAPTER  58  Approach to Canine Hyperlipidemia

TABLE 58-2  Possible Consequences and Complications   of Hyperlipidemia Disorder

Type of Lipid Abnormality Responsible

Pancreatitis

HTG

Hepatobiliary disease   Vacuolar hepatopathy   Lipidosis   Biliary mucocele

HTG HTG HTG/HCH

Insulin resistance

HTG

Ocular disease   Lipemia retinalis   Lipemic aqueous   Lipid keratopathy   Intraocular xanthogranuloma   Arcus lipoides corneae

HTG HTG HTG HTG HTG/HCH

Seizures

HTG

Lipomas

HTG

Atherosclerosis

HCH

HTG, Hypertriglyceridemia; HCH, hypercholesterolemia.

for dogs with secondary hyperlipidemia and often the only abnormality in dogs with primary hyperlipidemia, measurement of serum triglyceride and cholesterol concentrations should be part of every routine chemistry panel. Moderate and severe hypertriglyceridemia (but not mild hypertriglyceridemia or hypercholesterolemia) can be diagnosed on the basis of inspection of serum or plasma that has turbid or lactescent appearance. However, even in those cases, measurement of serum triglyceride and cholesterol concentration is mandatory in order to get an accurate picture of the severity and spectrum of hyperlipidemia. After hyperlipidemia has been diagnosed, it must be determined whether the patient has a primary or a secondary lipid disorder. If hyperlipidemia is secondary, the specific condition responsible for causing hyperlipidemia should be diagnosed and treated. Thus specific diagnostic investigations should be performed in order to diagnose or rule out specific diseases that can cause secondary hyperlipidemia. If secondary hyperlipidemia is excluded, a tentative diagnosis of a primary lipid disorder can be made. In the diagnostic effort, a detailed history should be obtained and physical examination performed first. This is crucial because dogs with secondary hyperlipidemia typically show clinical signs of the primary disease (e.g., obesity, polyuria and polydipsia in dogs with diabetes mellitus or hyperadrenocorticism, hypoactivity and hair loss in dogs with hypothyroidism), which can prioritize the selection of diagnostic tests and lead the way toward an appropriate diagnostic plan. Dogs with primary

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hyperlipidemia may or may not have clinical signs; as mentioned earlier, primary hyperlipidemia per se is unlikely to cause any clinical signs, and therefore many dogs with hyperlipidemia are asymptomatic. However, diseases that develop as a result of hyperlipidemia can lead to various clinical signs (see the section on Clinical Importance of Hyperlipidemia in Dogs). Dogs with hyperlipidemia should have at least a complete blood count (CBC), chemistry panel, and urinalysis performed. Additional tests that aid in the diagnostic investigation of dogs with hyperlipidemia include measurement of serum total and free thyroxine concentrations, serum thyroidstimulating hormone (TSH) concentration, serum glucose concentration and urine glucose (if not previously performed), serum pancreatic-lipase immunoreactivity concentration, serum bile-acid concentrations, urine protein : creatinine ratio, and low-dose dexamethasone suppression test. The selection of tests to be performed is based on information from the history and clinical signs present and is tailored to each individual case. A more general and wide selection of tests might be necessary for patients that have vague or no clinical signs. Ideally, an appropriate selection of the aforementioned tests should be used in every dog with hyperlipidemia as part of the diagnostic investigation of the condition. One possible exception is the miniature schnauzer, in which primary hyperlipidemia is well documented and more common than secondary hyperlipidemia. A detailed diagnostic investigation of hyperlipidemia might not be necessary in this breed in the absence of clinical signs, unless hypercholesterolemia seems to be the main abnormality (without or with only mild hypertriglyceridemia) because in this case it is more likely that the dog has some form of secondary hyperlipidemia. Also, all miniature schnauzers in the United States (and potentially other dog breeds that commonly develop primary hyperlipidemia) should be evaluated for hypertriglyceridemia on multiple occasions (to incorporate the possibility of age-related lipid metabolism disorders) while they are healthy because  this information may help prevent misinterpretation of increased serum triglyceride concentrations when the dogs are presented for a clinical illness. In addition, by knowing the serum triglyceride status of the dog, the veterinarian might consider switching the affected dog  to a low-fat diet to avoid possible complications of hypertriglyceridemia. When an appropriate diagnostic investigation suggests a primary lipid disorder leading to hyperlipidemia is present, there is little more that can be done to diagnose the exact cause of hyperlipidemia. In the majority of cases the exact cause cannot be identified and such an investigation is usually only of academic and not therapeutic importance. Tests or methods that have been used to further characterize or investigate the cause of primary hyperlipidemia in dogs include the chylomicron test, lipoprotein electrophoresis, ultracentrifugation, and assessment of lipoprotein lipase activity. None of these tests or methods is used routinely in clinical cases and their availability is limited. Genetic testing for specific lipid disorders related to mutations of genes involved in lipid metabolism is currently not available.

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Treatment of Canine Hyperlipidemia Treatment of secondary hyperlipidemia relies on the successful treatment of the underlying disorder after which hyperlipidemia usually resolves. Resolution of secondary hyperlipidemia after treatment of the cause should always be confirmed by laboratory testing (typically 4 to 6 weeks after control of the primary disease). If hyperlipidemia has not resolved, an incorrect diagnosis, ineffective treatment, or concurrent primary or secondary hyperlipidemia due to other causes should be considered. In some dogs with secondary hyperlipidemia, especially those with hyperlipidemia due to diabetes mellitus, it might be difficult to optimally control their primary disease, and therefore hyperlipidemia might persist despite treatment. If persistent hyperlipidemia in such cases is severe, it may be necessary to take measures for its control. The management of persistent secondary hyperlipidemia relies on the same principles as for primary hyperlipidemia (see later). It has been traditionally recommended that hypertriglyceridemia should be treated only when serum concentrations of triglycerides exceed 500 mg/dl or even 1000 mg/ dl. However, recent studies have shown that insulin resistance, hepatobiliary disease, and possibly other complications of hypertriglyceridemia can exist even with serum triglyceride concentrations below 500 mg/dl. Therefore it is the author’s opinion that even mild hypertriglyceridemia (i.e., serum triglyceride concentrations above 200 mg/ dl) should be treated, at least with dietary management, to keep serum triglyceride concentrations as low as possible and reduce the risk for complications. The initial treatment goal for severe hypertriglyceridemia should be to keep fasting serum triglyceride concentration below 500 mg/dl. Attempts to reach this goal should start with dietary management, while drug therapy can be initiated at a later point if deemed necessary. After this initial goal has been achieved, further reduction or even normalization of serum triglyceride concentration (typically with the addition of lipid-lowering drugs) should be considered on the basis of a risk-to-benefit ratio calculation for each individual case. Dogs with hyperlipidemia in which treatment does not seem necessary (e.g., when serum triglycerides or cholesterol are borderline above the reference range) or has been declined by the owner should be monitored periodically for potential worsening of hyperlipidemia. Although the management of hypercholesterolemia seems to be of less clinical importance than that of hypertriglyceridemia in dogs, hypercholesterolemia should be treated appropriately at least with dietary management. Drug therapy should be considered in cases in which hypercholesterolemia is resistant to dietary therapy and exceeds 500 mg/dl. The following sections focus mainly on the treatment of hypertriglyceridemia unless otherwise indicated.

Dietary Management The first step in the management of primary or persistent secondary hyperlipidemia is dietary modification. Dogs with primary hyperlipidemia should be offered a low-fat diet throughout their lives, while dogs with persistent

secondary hyperlipidemia should be offered low-fat diets on the basis of repeated testing and the effectiveness of control of the primary disease. Diets that contain less than 25 g of total fat per 1000 kcal are generally recommended. Many commercially available diets are labeled “low-fat” but their fat content can vary widely. In addition, although many diets have low total fat content and in theory should be effective in the management of hyperlipidemia, several dietary aspects that might affect the response of dogs to specific diets are unknown. Published studies investigating the efficacy of low-fat diets in dogs with hyperlipidemia are lacking. Therefore the selection of the most effective low-fat diet for the treatment of hyperlipidemia is uncertain and quite challenging. In a recent unpublished study (Xenoulis et al, 2011c), miniature schnauzers with primary hyperlipidemia were put on the Royal Canin Gastrointestinal Low Fat diet for 8 weeks. By the end of the treatment period, there was a significant reduction in both serum triglyceride and cholesterol concentrations. Serum cholesterol concentrations returned to normal in all dogs, while serum triglyceride concentrations returned to normal in about 30% of dogs. However, all dogs that had serum triglyceride concentrations above 500 mg/dl at the beginning of the study had serum triglyceride concentrations below 500 mg/dl by the end of the trial. Homemade low-fat diets are also suitable for the management of canine hyperlipidemia, but care should be taken to make sure that these diets are balanced, especially when used for long periods. Some of these diets (e.g., boiled lean turkey breast without the skin and rice) have even lower fat content than most commercially available low-fat diets and may be more effective in lowering serum lipid concentrations in dogs. Therefore, in dogs that do not sufficiently respond to commercially available low-fat diets, an ultralow-fat home-prepared diet can be offered or medical treatment can be initiated. Treats and table scraps should be avoided unless they are low in fat. Fruits and vegetables typically constitute ideal treats for hyperlipidemic dogs. Serum lipid concentrations should be reevaluated after feeding a low-fat diet for about 4 to 6 weeks. If the serum triglyceride concentration in hypertriglyceridemic dogs has decreased to below 500 mg/dl, dietary therapy should be continued and serum triglyceride concentrations should be reevaluated every 6 months. If serum triglyceride concentration remains above 500 mg/dl or if additional reduction of serum triglyceride concentration is desired, additional dietary modifications (if possible) or medical treatment should be considered.

Medical Management Some dogs with primary hyperlipidemia do not respond sufficiently to being fed a low- or ultra-low-fat diet alone. In these cases, medical treatment is required in addition to the low-fat diet in an effort to effectively reduce serum lipid concentrations. Many lipid-lowering drugs are available and have been widely used in human medicine for decades. However, no studies have evaluated the efficacy and safety of lipid-lowering drugs in dogs, and there­ fore evidence-based recommendations cannot be made. Instead, recommendations in this chapter are based on clinical experience and extrapolation from human

CHAPTER  58  Approach to Canine Hyperlipidemia medicine. Also, lipid-lowering drugs are not approved for use in dogs and therefore owner consent is recommended when these drugs are used. The order of the discussion of the following drugs reflects the author’s preferred order of medical treatment of hyperlipidemia in dogs. Omega-3 Fatty Acids (Fish Oils) Polyunsaturated fatty acids of the n-3 series (omega-3 fatty acids; eicosapentaenoic acid [EPA] and docosahexaenoic acid [DHA]) are abundant in marine fish. Omega-3 fatty acid supplementation has been shown to lower serum triglyceride concentrations in experimental animals, normal humans, and humans with primary hypertriglyceridemia. Specifically, omega-3 fatty acids have been shown to reduce serum triglyceride concentrations by up to 50% when used at high doses in humans with hypertriglyceridemia. The mechanisms of the lipid-lowering action of omega-3 fatty acids include reduced lipogenesis, increased β-oxidation, and activation of lipoprotein lipase. In a study of healthy dogs, fish oil supplementation led to a significant reduction of serum triglyceride concentrations, suggesting that this supplement may be helpful in the treatment of canine hypertriglyceridemia. No major side effects have been observed in humans or in dogs receiving omega-3 fatty acids, even when administered at high doses. However, studies evaluating the efficacy and safety of omega-3 fatty acid supplementation in dogs with hyperlipidemia are lacking and clinical experience is limited. Because serious side effects are rarely reported and because omega-3 fatty acids are likely effective in lowering serum triglyceride concentrations, omega-3 fatty acid  supplementation is recommended as a second-line therapy in dogs with primary hypertriglyceridemia that do not respond to a low-fat diet alone. The formulation of omega-3 fatty acids with the highest purity currently is Lovaza, which is FDA approved for use in humans as a lipidlowering agent. Care should be taken to select products low in mercury because high concentrations of mercury and other environmental toxins may be present in fish oil products. Omega-3 fatty acids are used in dogs at doses ranging from 200 mg/kg to 300 mg/kg PO once a day, and their effect on serum triglyceride concentrations is dosedependent. Their lipid-lowering effect typically requires doses at the high end of the recommended dose for dogs. An upper daily limit of 4 to 5 grams might be recommended. Periodic retesting of serum triglyceride concentrations is recommended during the treatment period. Fibrates (Fibric Acid Derivatives) Fibrates are weak agonists of peroxisome proliferatoractivated receptor α (PPARα), a nuclear transcription factor that regulates lipid and lipoprotein synthesis and catabolism. Fibrates suppress fatty acid synthesis, stimulate fatty acid oxidation, activate lipoprotein lipase, and inhibit noncompetitively the enzyme diacylglycerol acyltransferase (the enzyme that catalyzes the conversion of diglycerides to triglycerides), therefore leading to an overall reduction in serum triglyceride concentration. In humans, fibrates typically reduce serum triglyceride concentrations by 25% to 50%. Fibrate use in humans is associated with a low incidence of myotoxicity and increases in serum liver enzyme activities.

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Gemfibrozil is the most commonly used fibrate in humans and has also been used anecdotally in dogs with hypertriglyceridemia. It can be administered at 7.5 mg/ kg q12h oral for dogs and cats. No side effects have been observed in dogs, although no studies have evaluated its safety in this species. Gemfibrozil may be recommended in dogs in which dietary modification and omega-3 fatty acids have failed to effectively reduce serum triglyceride concentrations. Periodic testing of serum triglyceride concentration and liver enzyme activities is recommended. Niacin (Nicotinic Acid) Niacin, a form of vitamin B3, has been used successfully for the treatment of hyperlipidemia in humans for years. When used in pharmacologic doses, niacin is a broadspectrum lipid-modifying drug and, in humans, it reduces both low-density lipoprotein (LDL)-cholesterol and serum triglyceride concentrations. The mechanism of action of niacin is complex and incompletely understood but includes inhibition of hormone-sensitive lipase and the enzyme diacylglycerol acyltransferase, both of which actions eventually lead to reduced triglyceride biosynthesis. In dogs, niacin treatment has been reported in very few patients with primary hypertriglyceridemia. In these patients, niacin reduced serum triglyceride concentrations for several months without causing any side effects. However, large clinical trials regarding the efficacy and safety of niacin in dogs with primary hypertriglyceridemia are lacking. As is often the case in humans, niacin administration in dogs is potentially associated with side effects such as erythema and pruritus, which usually require discontinuation of therapy. Long-term risk for myotoxicity and hepatotoxicity may also exist. Niacin ER (extended release) has been recommended as the preferred choice of niacin in humans due to its purity, tolerability, and lower incidence of side effects. Niacin is usually administered to dogs at a dose of 50 to 200 mg/day. Both the therapeutic and side effects of niacin are dose dependent and it is therefore recommended that niacin is started at a low dose and slowly titrated upward (every 4 weeks) based on the results of follow-up lipid panels. It should be used with caution in diabetic patients because it can increase blood glucose concentration (especially when used at higher doses), and serum liver enzyme activities should be monitored with long-term use of niacin. Other Drugs A large number of other drug classes are available for use in humans with hyperlipidemia. However, the use of most of these drugs is currently not recommended in dogs. Statins (HMG-CoA reductase inhibitors) are among the most potent and commonly used lipid-lowering drugs in humans. They are reversible inhibitors of the enzyme HMG-CoA reductase, which is the rate-limiting step for cholesterol biosynthesis. Therefore statins are mainly cholesterol-lowering drugs with less potent effects on triglyceride metabolism. This makes them less than ideal drug choices when hypertriglyceridemia is the main lipid abnormality. Statin use has been associated with myopathy, rhabdomyolysis, and hepatotoxicity in humans, and there are anecdotal reports of hepatotoxicity in dogs. The

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potential for hepatotoxicity is probably higher when hepatic steatosis is present, a condition that likely occurs in at least a portion of dogs with severe hypertriglyceridemia (especially miniature schnauzers). When collectively considering the potential side effects of statins, the fact that hypercholesterolemia rarely needs to be treated medically in dogs, and the fact that statins are unlikely to be very effective in the treatment of canine hypertriglyceridemia, the routine use of statins is not recommended in hyperlipidemic dogs. If statins are to be used in dogs, it should be kept in mind that the pharmacokinetic profiles of the various statins are unknown in this species and therefore the dose and frequency of administration of these drugs can currently only be extrapolated from human medicine. Serum liver enzyme activities should be periodically monitored for potential hepatotoxicity. Concurrent administration of statins and fibrates (e.g., gemfibrozil) should be avoided because the latter has been shown to affect the pharmacokinetics of statins, leading to increased risk for toxicity. Combination Drug Therapy Some dogs, especially those with primary hypertriglyceridemia, can manifest serum triglyceride concentrations in the thousands. Serum triglyceride concentration in many of these dogs cannot be controlled with diet alone or monotherapy with lipid-lowering drugs, and a combination of more than one lipid-lowering medication and

ultra-low-fat diet may be required. Experience with combination therapy is very limited in dogs. The author’s preferred order of treatment trials in dogs with severe hypertriglyceridemia is the administration of a low- or ultra-low-fat diet, followed by the addition of omega-3 fatty acids, followed by gemfibrozil, and finally the addition of niacin if necessary. Statins may also be used when other medications have proven ineffective.

References and Suggested Reading Toth PP: Drug treatment of hyperlipidemia: a guide to the rational use of lipid-lowering drugs, Drugs 70:1363-1379, 2010. Xenoulis PG et al: Serum liver enzyme activities in healthy Miniature Schnauzers with and without hypertriglyceridemia,  J Am Vet Med Assoc 232:63-67, 2008. Xenoulis PG, Steiner JM: Lipid metabolism and hyperlipidemia in dogs, Vet J 183:12-21, 2010. Xenoulis PG et al: Association between serum triglyceride and canine pancreatic lipase immunoreactivity concentrations in miniature schnauzers, J Am Anim Hosp Assoc 46:229-234, 2010. Xenoulis PG et al: Association of hypertriglyceridemia with insulin resistance in healthy Miniature Schnauzers, J Am Vet Med Assoc 15:238:1011-1016, 2011a. Xenoulis PG et al: Serum triglyceride concentrations in Miniature Schnauzers with and without a history of probable pancreatitis, J Vet Intern Med 25:20-25, 2011b. Xenoulis PG et al: Effect of a low-fat diet on serum triglyceride, cholesterol, and pancreatic lipase immunoreactivity concentrations in Miniature Schnauzers with hypertriglyceridemia,  J Vet Intern Med 25:687, 2011c.

WEB CHAPTER 

11 

Hypercalcemia and Primary Hyperparathyroidism in Dogs EDWARD C. FELDMAN, Davis, California

Differential Diagnosis and Diagnostic Approach to Hypercalcemia Differential Diagnosis Hypercalcemia is an abnormality that is usually seren­ dipitously identified on serum biochemical analysis. Disorders associated with hypercalcemia in dogs, in approximate order of incidence at the University of Cali­ fornia, include lymphosarcoma, acute and chronic renal failure, primary hyperparathyroidism (PHP), hypoadreno­ corticism, vitamin D toxicosis, apocrine gland carcinoma of the anal sac, multiple myeloma, uncommonly in asso­ ciation with a variety of carcinomas (lung, mammary, nasal, pancreas, thymus, thyroid, vaginal, and testicular), and uncommonly in association with certain granuloma­ tous diseases (blastomycosis, histoplasmosis, schistoso­ miasis). History, physical examination, complete blood count (CBC), urinalysis, serum biochemistry analysis, thoracic and abdominal radiographs, abdominal ultra­ sound, and examination of cytology and biopsy speci­ mens usually provide adequate information to establish a diagnosis in dogs.

History and Physical Examination Since hypercalcemia is almost always unsuspected, it is not a mistake to obtain a second blood sample to rule out laboratory error, although in our experience laboratory error is extremely rare. Once hypercalcemia is identified, the veterinarian should review the signalment and history with the owner to identify any clues to a definitive diag­ nosis that may not have been noted initially. From the history, one can attempt to identify a tentative explana­ tion for the hypercalcemia, such as possible exposure to toxins containing vitamin D (e.g., rodenticides, inappro­ priate supplementation of food), evidence of pain due to a lytic bone lesion (multiple myeloma or mammary tumor), difficulty eating due to oral lesions associated with renal failure, or a waxing/waning course of illness sometimes noted with hypoadrenocorticism. The physical examination should also be repeated in an attempt to identify a tentative explanation for hyper­ calcemia. The spine, ribs, and long bones should be pal­ pated to identify bone pain due to a lytic lesion, while the mammary chain should be evaluated for neoplasia, the oral cavity for “rubber jaw” or lesions consistent with renal failure, the rectal and perineal area for apocrine gland carcinoma of the anal sac or other tumor, the heart

rate (slow) and pulse quality (poor) for abnormalities con­ sistent with hypoadrenocorticism, and the peripheral lymph nodes for enlargement suggestive of lymphoma (most dogs with hypercalcemic lymphoma have a medi­ astinal mass and unremarkable peripheral nodes). Dogs with PHP commonly have a physical examination that does not contribute to a diagnosis (parathyroid masses are almost never palpable).

Routine “Database” A thorough review of the CBC, serum biochemistry profile, and urinalysis should be completed. The urine specific gravity is commonly less than 1.020 in hypercal­ cemic dogs with renal disease, hypoadrenocorticism, and PHP. Urinary tract infection is common in these disor­ ders. The CBC may demonstrate a normocytic, normo­ chromic, nonregenerative anemia, which is relatively common in renal failure; hypoadrenocorticism; and various neoplasias. The serum biochemistry profile should also be reviewed to assess the blood urea nitrogen (BUN), creatinine, and serum phosphate for increases consistent with renal failure or vitamin D toxicosis; hyperkalemia and hyponatremia suggestive of hypoadrenocorticism; hyperglobulinemia consistent with myeloma; and hypo­ phosphatemia consistent with PHP. To this point, the only “new” expense would be the repeated serum calcium concentration (if obtained), since the recommendation is to talk with the owner, repeat a physical examination, and review the laboratory results that were already obtained in order to identify the hypercalcemia in the first place.

Radiographs and Ultrasonography Assuming the review of the history, physical examina­ tion, and database has not defined the cause for hyper­ calcemia, thoracic radiographs are an important next step. The primary purpose for this study is to assess the cranial mediastinum for a mass consistent with lymphoma. If present, fine-needle aspiration or tissue obtained via biopsy should be evaluated. Radiographs also provide an opportunity to evaluate the perihilar area and lungs for neoplasia or systemic mycoses, the spine and ribs for lytic lesions caused by neoplasia, and the heart for microcardia of hypoadrenocorticism. Ab­­ dominal radiographs can also be assessed, although ultrasound examination of the abdomen is preferred. The size and consistency of the liver, spleen, e69

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and mesenteric and sublumbar lymph nodes can be evaluated for abnormalities suggestive of malignancy (lymphoma) or other conditions. Diagnostic imaging to evaluate for malignancy (lymphoma) applies to a variety of tumors located in other organs, but tumors other than lymphoma are less common causes of hypercalce­ mia. When possible, abnormal areas should be aspirated or biopsied to determine the presence or absence of neo­ plasia. The size and consistency of the kidneys can be assessed, although renal failure should have been ruled in or out on the initial blood test results. The kidneys, ureters, bladder, and urethra should be evaluated for the presence of calculi, which develop in about 30% of dogs with PHP and could develop in any hypercalcemic dog. If these assessments fail to confirm or suggest a diagnosis other than PHP, suspicion for PHP increases. Until a specific cause for hypercalcemia is confirmed, however, lymphoma should never be ruled out. Cervical ultrasonography (discussed in a later section) has become an extremely valuable screening test in dogs with hypercalcemia.

Signalment, History, and Physical Examination in Dogs with Primary Hyperparathyroidism Dogs with PHP are usually 6 years of age or older. The mean age from our series of 335 dogs with PHP was 10.7 years. Dogs of both genders are almost equally affected, about 14% of affected dogs are Keeshonds, but a huge number of breeds have been represented. The mean body weight of the 335 dogs was 24 kg. Dogs with PHP, unlike those afflicted with most other diseases that cause hypercalcemia, are usually not ill or not as ill. Owners of 124 of 335 PHP dogs (37%) had observed no hypercalcemia-related abnormalities in their pet. Blood had been obtained from these dogs usually for a routine geriatric evaluation, as part of a preanesthesia screen prior to a dental procedure, or for an unrelated condition. The most common owner-observed abnormalities in dogs with PHP were polyuria and polydipsia (57% of dogs), lethargy/weakness/decreased activity (43%), decreased appetite (30%), weight loss or muscle wasting (10%), shivering or trembling (7%), and vomiting (5%). However, even when clinical signs are observed, they are often relatively mild. When signs were observed, they had been present for as little as a few days to more than 2 years. Only about 5% of the PHP dogs with urolithiasis or urinary tract infection had appropriate clinical signs (i.e., straining to urinate, increased frequency of urina­ tion, and hematuria). Since more than 90% of the dogs identified as having both PHP and cystic calculi were asymptomatic for their stones, the indication for abdomi­ nal imaging in any hypercalcemic dog is emphasized. In 254 of 335 dogs with PHP (76%), the medical record stated that no abnormalities relative to the diagnosis of PHP were noted on physical examination. When noted, abnormalities included muscle wasting, the dog being slow to rise, and obesity in some dogs and thin body condition in others. Each of these problems was seen in fewer than 10% of dogs with PHP.

Clinicopathologic Abnormalities in Dogs with Primary Hyperparathyroidism Hypercalcemia (i.e., serum total calcium concentrations >12 mg/dl; reference range of 9.9 to 11.6 mg/dl) was identified in all 335 dogs with PHP in our series. This “sensitivity” (100%) may be misleading since we do not evaluate dogs for hypercalcemia unless this criterion is met. The mean serum total calcium concentration was 14.4 mg/dl, with a range of 12.1 to 24.2 mg/dl. About 50% of dogs with PHP had serum total calcium concen­ trations higher than 12 and below 14 mg/dl; about 33% had values higher than 14 and below 16 mg/dl; about 10% had values higher than 16 and below 18 mg/dl; and slightly more than 5% had values higher than 18 mg/dl. The mean plasma ionized calcium concentration in the 335 dogs with PHP was 1.77 mmol/L (range 1.22 to 2.58; normal reference range 1.12 to 1.41 mmol/L). Just under 4% of the dogs with PHP had a serum ionized calcium concentration within the reference range, almost 33% had values between 1.42 and 1.65 mmol/L, and almost 50% had concentrations between 1.66 and 1.90 mmol/L, with the remaining having concentrations higher than 1.91 mmol/L. A common reason for referral of dogs ultimately diag­ nosed with PHP is the referring veterinarian’s concern that if not treated, hypercalcemia would place dogs at risk for developing renal failure. However, this is not the case. The mean BUN concentration in 335 dogs with PHP (~18 mg/dl) was at the low end of the refer­ ence range of 18 to 28 mg/dl, the mean serum creati­ nine concentration (0.9 mg/dl) was well within the reference range (0.5 to 1.6 mg/dl), and the mean serum phosphate concentration (2.7 mg/dl) was less than the reference range (3.0 to 6.5 mg/dl). All these values were significantly less than values from 200 dogs of similar ages that were randomly reviewed from our hospital population. In other words, dogs with PHP seem pro­ tected from renal failure rather than predisposed to this condition. Duration of hypercalcemia was also not a factor, since some dogs with PHP went years without treatment. Owner-observed polyuria and polydipsia were well supported by finding a mean urine specific gravity of 1.012 in 335 dogs with PHP. About 30% of these dogs had urinary tract infections and about 30% had cystic calculi; some had both. Although renal failure is rare and not a reason for treating a dog that has PHP, infection and calculi are common and cer­ tainly should be among the reasons for recommending therapy.

Confirmation of Primary Hyperparathyroidism (Use of Serum Parathyroid Hormone and Parathyroid Hormone–Related Protein Concentrations) Are Parathyroid Hormone Assay Results Vital? The differential diagnosis for hypercalcemia is relatively short and veterinarians should be able to rule in or out most conditions using the diagnostic approach

WEB CHAPTER  11  Hypercalcemia and Primary Hyperparathyroidism in Dogs recommended earlier in this chapter. Sophisticated and relatively expensive studies, such as assaying serum parathyroid hormone (PTH) and parathyroid hormonerelated protein (PTHrP) concentrations, are less impor­ tant in this context. Serum PTH concentrations have been assessed on a large number of dogs with PHP that we have treated since the early 1980s. However, a majority of these results were available days to weeks after treatment had been completed. In other words, diagnosis and treatment were completed without these assay results because employing a logical approach in determining the cause of hypercalcemia was successful. This is not to suggest that the assays have no value, but rather that in many dogs the assay results are not vital.

Serum Parathyroid Hormone Concentrations Serum PTH concentrations are commercially available, and normal-to-increased concentrations confirm the diagnosis of PHP in non–renal failure hypercalcemic dogs. Dogs with renal failure may also have increased serum PTH concentrations; however, within the context of the renal parameters, the serum phosphate concen­ tration, ionized serum calcium concentration, and other pertinent information, dogs with PHP can usually be readily distinguished from those with renal failure. As serum calcium concentrations rise in healthy dogs, serum PTH concentrations should become undetectable. Therefore the term normal range can be misleading, since the average dog with PHP has a serum PTH con­ centration that is “normal.” This seems counterintui­ tive, whereas the term reference range provides better understanding of the condition. Increasing serum calcium concentrations should decrease serum PTH con­ centration below the reference range while values within the reference range would be physiologically abnormal. Using a reference range for serum PTH con­ centrations of 2 to 13 pmol/L, 198 of 335 dogs with PHP (~60%) had serum PTH concentrations within that range; 36% had results of 2.3 to 7.9 pmol/L, 24% had results of 8.0 to 13.0 pmol/L, 16% had results between 13 and 20 pmol/L, and 24% had results higher than 20 pmol/L.

Serum Parathyroid Hormone–Related Protein Concentrations Increased serum PTHrP concentrations in hypercalcemic dogs would be most consistent with lymphoma or apocrine gland carcinoma of the anal sac. If a specific explanation for hypercalcemia remains elusive, but malignancy remains possible, “response to treatment” should be a last resort. Before any medication is given, aspiration or biopsy of lymph nodes, spleen, and/or liver should be considered in an attempt to establish a diagnosis of malignancy, including lymphoma. Lym­ phoma is emphasized because it is a common condi­ tion; occasionally it can be a difficult diagnosis to confirm, especially after glucocorticoids have been administered.

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Localizing Parathyroid Tissue Causing Hyperparathyroidism Cervical Ultrasound Ultrasound examination of the cervical area is generally available, noninvasive, and relatively cost efficient. However, ultrasound value, as much as any diagnostic tool used in veterinary medicine, is operator dependent. The skill of the individual performing the examination is a major factor in assessing the value of this diagnostic aid. Parathyroid tumors are typically round-to-oval hypoechoic masses that measure 4 to 8 mm in greatest length and are closely associated with a thyroid lobe; some are as large as 20 mm in greatest diameter. Most masses are 4 to 6 mm in greatest diameter. Cervical ultrasound was per­ formed in 255 of the dogs with PHP in our series. In 221 of these dogs, a solitary parathyroid mass was visualized. In 218 of these 221 dogs, the diagnosis was correct. In 15 of these 221 dogs, the diagnosis of a solitary parathyroid mass and a single (or multiple) thyroid mass was correct. At the time of diagnosis, one dog had two parathyroid masses identified and removed at surgery, although only one mass had been reported on the ultrasound examina­ tion. In each of two dogs, ultrasound diagnosis reported both solitary thyroid and parathyroid masses; this was later discovered to be two parathyroid adenomas. About 5% of the dogs with PHP in our series had thyroid cysts, adenomas, or carcinomas at the time of PHP diagnosis. Ultrasound examination suggested that each of 12 dogs had two parathyroid masses; this was actually true for nine of the dogs. One dog had only one parathyroid mass and two dogs each had a solitary parathyroid and a solitary thyroid mass. Ultrasound examination failed to identify a parathyroid mass in five dogs, each of which had a solitary parathyroid tumor removed at surgery. Each of 31 dogs (9% of the 335) had two parathyroid masses correctly identified via ultrasonography at the time that PHP was diagnosed. Cervical ultrasonography has become a routine com­ ponent of evaluating hypercalcemic dogs. Failure to iden­ tify at least one enlarged parathyroid gland in a dog suspected of having PHP would not eliminate that diag­ nosis. However, failure to visualize a mass is reason to reconsider the diagnosis.

Other Tests Abnormal parathyroid tissue has been localized in humans by using technetium 99 (Tc99) sestamibi nuclear scintig­ raphy. Results in dogs with PHP have been inconsistent at best and the procedure is not recommended. Recent attempts to localize abnormal parathyroid tissue using selective venous sampling to measure the serum concen­ trations of PTH were not satisfactory.

Treatment of Primary Hyperparathyroidism Pretreatment Considerations: Candidates for Percutaneous Versus Surgical Treatment Treatment options for PHP include surgical removal and percutaneous heat or ethanol ablation. Several

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SECTION  III  Endocrine and Metabolic Diseases

factors should be considered prior to suggesting a treat­ ment recommendation. If a male dog has cystic or ure­ thral calculi, surgery or retrograde urohydropulsion is recommended to remove all calculi. The decision to perform surgery on dogs with renal or ureteral calculi must be considered on an individual basis. Dogs with evidence of both a parathyroid mass and a thyroid mass should probably undergo surgery. Dogs undergo­ ing surgery for calculi in the urinary tract should have their parathyroid mass removed during the same anesthesia. Candidates for ultrasound-guided ablation treatment must not have a mass too closely associated with one of the carotid arteries nor can the mass be too small to con­ fidently have a needle placed percutaneously. Masses larger than 12 to 15 mm in greatest diameter are not common and are often managed surgically. For dogs with two contralateral parathyroid masses, surgery is rec­ ommended or the percutaneous treatment should be “staged” at least 30 days apart to avoid any possibility of iatrogenic laryngeal paralysis, an uncommon but possi­ ble problem.

Pretreatment Considerations: Serum Calcium Concentrations Dogs are not at risk for developing hypocalcemia in the first 48 hours after surgical or percutaneous therapy, regardless of the pretreatment serum calcium concentra­ tion or duration of PHP. If the pretreatment serum calcium concentration is between 12 and 14 mg/dl, vitamin D therapy is usually withheld. In these dogs, serum calcium or ionized calcium concentrations are monitored once or twice daily for 5 to 7 days after treat­ ment. Vitamin D therapy is only instituted if the serum calcium concentration decreases below 9 mg/dl, the ionized calcium decreases below 0.95 mmol/L, or clinical signs of tetany are observed. Observation of any such response, while relatively uncommon, usually takes 3 to 7 days. If the serum calcium concentration prior to therapy is 15 mg/dl or higher or if a dog has more than one parathyroid mass, the incidence of postsurgical hypocal­ cemia is greater. In these patients, vitamin D therapy is usually initiated the morning of the treatment (cal­ citriol, 10 to 15 ng/kg q12h for first 3 to 4 days and then 2.5 to 5 ng/kg q12h). The decision regarding vitamin D therapy in dogs with a pretreatment calcium of 14 to 15 mg/dl is open. Whenever vitamin D therapy is used, monitoring of serum calcium is carried forth as described and parenteral calcium is only administered if tetany occurs or is thought to be imminent. Vitamin D is then tapered to ever-decreasing dosages over a 2- to 6-month period. Once the serum calcium concentra­ tions plateau at a safe concentration (usually >9.5 mg/ dl), the dog should be returned to the owner. Serum calcium concentrations can be checked frequently ini­ tially and then usually every 2 weeks to support any scheduled dose reduction. Dose reduction is usually by 50% every 2 weeks.

Percutaneous Ultrasound-Guided Heat Ablation Approximately 55% of the dogs we diagnose as having PHP have surgery and about 45% undergo percutaneous ultrasound-guided ablation. Both procedures have been used with excellent results. Dogs that meet the inclusion criteria for percutaneous therapy are placed under anes­ thesia and, with ultrasound guidance, have an insulated needle placed into the parathyroid mass. The needle is attached to a radiofrequency unit (radiofrequency waves are naturally converted to heat at the needle tip). The wattage is started at a low level and increased based on observing a “bubbling” appearance to the tissue. The needle tip is repositioned several times to ensure, as much as possible, that the entire parathyroid mass has been ablated. Percutaneous ultrasound-guided heat ablation requires 15 to 30 minutes of anesthesia and is usually less expensive. Post–heat ablation management of the dog is identical to the management following surgical removal of a parathyroid mass.

Percutaneous Ultrasound-Guided Ethanol Ablation Percutaneous ultrasound-guided ethanol ablation is no longer recommended. The procedure used resembled that for percutaneous ultrasound-guided heat ablation except the needle was connected to a syringe containing a volume of ethanol similar to the calculated volume of the parathyroid nodule. Ethanol was infused slowly in an effort to expose it to all tissue, with the needle tip repo­ sitioned several times to aid in accomplishing this goal. Unfortunately, leakage of this caustic material invariably occurred following the procedure. Such leakage could cause nerve damage and secondary laryngeal paralysis.

Surgery Complete exploratory surgery of both thyroid lobe areas, with both ventral and dorsal surfaces of the thyroid lobes examined, is recommended for dogs with PHP. In most of these dogs, the abnormal parathyroid tissue is solitary, off-color, and larger than normal parathyroid tissue, easily recognized and easily extirpated. Only abnormal parathyroid tissue is removed if possible, although when a parathyroid tumor lies within a thyroid lobe, that thyroid lobe is usually removed. If no parathyroid mass is observed and the diagnosis is thought to be correct, one thyroid/parathyroid complex should be removed and examined histologically. If two abnormal parathyroids are observed, both should be removed.

Posttreatment Care Dogs are kept in-hospital for 5 to 7 days after treatment to monitor serum calcium concentrations and, more importantly, to keep the dog quiet. Since most dogs are quiet in-hospital, the quiet hypocalcemic dog is less prone to clinical tetany than would be the case if the dog is active. Dogs that are unusually active in-hospital are

WEB CHAPTER  12  Clinical Use of the Vasopressin Analog Desmopressin for the Diagnosis sent home. We usually monitor serum total calcium con­ centrations twice daily until release from the hospital.

Histology Parathyroid tumors have been histologically classified as adenoma, hyperplasia, or carcinoma. These classifications have not had use clinically, since all parathyroid masses act biologically similar. We have not experienced a dog with local tumor invasion nor with distant metastasis. Recurrence rate is about 10% regardless of the histology.

WEB CHAPTER 

e73

References and Suggested Reading Feldman EC et al: Pretreatment clinical and laboratory findings in dogs with primary hyperparathyroidism: 210 cases (19872004), J Am Vet Med Assoc 227:756, 2005. Long CD et al: Percutaneous ultrasound-guided chemical para­ thyroid ablation for treatment of primary hyperparathyroid­ ism in dogs, J Am Vet Med Assoc 215:217, 1999. Pollard RE et al: Percutaneous ultrasonographically guided heat ablation for treatment of primary hyperparathyroidism in dogs, J Am Vet Med Assoc 218:1106, 2001. Wisner ER et al: High-resolution parathyroid sonography, Vet Radiol Ultrasound 38:462, 1997.

12 

Clinical Use of the Vasopressin Analog Desmopressin for the Diagnosis and Treatment of Diabetes Insipidus RHETT NICHOLS, New York, New York MARK E. PETERSON, New York, New York

Background Primary disorders of water balance such as central diabetes insipidus, primary nephrogenic diabetes insipidus, and primary polydipsia, although uncommon, should always be considered in the differential diagnosis of polyuria and polydipsia. The water deprivation test is generally considered the best diagnostic tool for differentiating between these disorders. However, the test is labor intensive, difficult to perform correctly, and unpleasant for the animal; relies heavily on repeated emptying of the bladder; and can lead to untoward complications and misdiagnosis in some animals. As an alternative to water deprivation testing, a simpler and more practical method of diagnosis is evaluation of the clinical response to a closely monitored therapeutic trial with desmopressin (DDAVP, Stimate, Minirin). Desmopressin is a synthetic analog of the natural antidiuretic hormone arginine vasopressin (ADH), which has increased antidiuretic activity, prolonged duration of action, decreased pressor actions, and fewer side effects than the natural hormone. Historically, if a diagnosis of central diabetes insipidus was confirmed, ADH tannate in oil, an extract of natural antidiuretic hormone prepared from bovine and porcine

pituitary glands, was administered every 2 to 3 days as needed to control polyuria and polydipsia. Because the product is no longer available, desmopressin has become the drug of choice for the treatment of central diabetes insipidus in dogs and cats.

Desmopressin Preparations Desmopressin is available in proprietary, generic, and compounded preparations for intranasal, ophthalmic, parenteral (injectable), or oral administration.

Nasal and Ophthalmic Solutions of Desmopressin The nasal formulations are supplied by two different delivery systems: via either a spray pump or a rhinal tube, with the desmopressin sprayed or “blown” into the nose, respectively. Obviously, most dogs and cats will not tolerate either of these intranasal delivery methods. Drops placed in the conjunctival sac provide a more suitable alternative for animals. With the rhinal tube delivery formulation (DDAVP Rhinal Tube), the desmopressin is packaged with a small,

e74

SECTION  III  Endocrine and Metabolic Diseases

calibrated plastic catheter so that exact amounts of the drug can be measured and administered. The calibrated rhinal tube has four graduation marks that measure amounts of 0.05 ml, 0.1 ml, 0.15 ml, and 0.2 ml and thereby can deliver doses of 5 to 20 µg of desmopressin. Although this system allows for accurate dosing, it is awkward to use. In addition, because this rhinal tube delivery system is not available as a generic product, this formulation is quite expensive. The most common intranasal formulations of desmopressin are marketed as nasal sprays or solutions equipped with a compression pump that delivers 10 µg of drug with each spray. For dogs and cats, this spray bottle is opened (pliers may be necessary to break the seal) and the desmopressin solution is transferred to a sterile vial; this dispensing vial then allows one to place the desmopressin drops into the animal’s conjunctival sac. These intranasal preparations of desmopressin are generally supplied as a concentration of 100 µg/ml; depending on drop size, one drop of nasal solution corresponds to 1.5 to 4 µg of desmopressin. One highly concentrated nasal solution (1.5 mg/ml) is marketed for use in type I von Willebrand’s disease and hemophilia, but it should not be used to treat animals with diabetes insipidus because of the strong likelihood of overdose. In most cats and small dogs, 1 to 2 drops of the intranasal preparation administered once or twice daily are sufficient to control polyuria and polydipsia. Larger dogs may require up to 4 to 5 drops twice daily. Use of a tuberculin or insulin syringe allows for more accurate dosing. As an alternative to the intranasal preparation, some compounding pharmacies offer a sterile ophthalmic solution (100 µg/ml) that costs considerably less than the intranasal product. In addition to its cost and convenience, the ophthalmic solution is buffered to a neutral pH, whereas the intranasal form is acidic and may cause local irritation. However, even without issues of local irritation, some animals may object to the daily eyedrops, making this route of administration ineffective.

Oral Desmopressin Tablets, Flavored Chews and Suspensions The proprietary and generic oral preparations of desmopressin are available both as a sublingual dissolve melt tablet and as 0.1 mg and 0.2 mg tablets. In addition, flavored oral chews and suspensions are available from compounding pharmacies. Each 0.1 mg (100 µg) tablet or chew is roughly comparable to 5 to 10 µg (1 to 2 large drops) of the nasal or ophthalmic solutions; the concentration of the flavored suspensions may vary. When comparing the cost of the proprietary forms of desmopressin, the tablet form is a more cost-prohibitive alternative compared with the conjunctival or subcutaneous routes of administration. The cost of daily oral desmopressin in animals is roughly 2.5 times that of conjunctival drops and roughly 6 times that of subcutaneous injections of desmopressin. By comparison, the cost of generic tablets and compounded flavored chews and suspensions is roughly equal to the cost of compounded ophthalmic and injectable preparations. For some pet owners a tablet, chew, or suspension may prove to be a more convenient, or the only possible, route of administration.

Injectable Desmopressin Solutions for Subcutaneous or Intravenous Use An injectable sterile solution of desmopressin (4 µg/ml) marketed for intravenous use is available and can be used in animals with diabetes insipidus. However, the cost is approximately 7 to 15 times higher per microgram than the intranasal preparation, making this formulation costprohibitive for use in most dogs and cats. To circumvent this cost issue, the intranasal form of desmopressin— although not designed for parenteral use—can be given subcutaneously to dogs and cats with excellent results. Because the nasal forms of desmopressin are not considered sterile, it is best to first sterilize the product by passing the nasal solution through a 0.2 µm bacteriostatic syringe filter. A less costly and more practical alternative to manually preparing the intranasal product for subcutaneous administration is a recently available “already prepared” injectable sterile solution of desmopressin (100 µg/ml). This preparation is a compounded form of desmopressin that can be obtained from many compounding pharmacies; it is virtually identical to the compounded ophthalmic solution but is supplied in a vial suitable for multiple injections. Clinically the nasal and injectable preparations of desmopressin induce indistinguishable responses when administered subcutaneously. To make dosing easier, the desmopressin is best administered with a U-100 low-dose insulin syringe (1 U is equivalent to 1 µg of the 100 µg/ml intranasal or injectable formulation). The solution can be diluted in sterile physiologic saline to make dosing easier. The subcutaneous route of desmopressin administration has many advantages over the other routes of administration, including the following: • The drug appears to be most effective when administered via the subcutaneous route. • The duration of action is longer after subcutaneous injection than when administered orally or via the conjunctival sac. • Because of the smaller subcutaneous doses required to control signs (about 15% and 40% of the oral and conjunctival doses, respectively), the cost of treatment is greatly reduced. • Many animals (especially cats) seem to prefer long-term subcutaneous injections to the chronic use of eyedrops or oral medication.

Therapeutic Trial with Desmopression as a Diagnostic Test Therapeutic trial with desmopressin as a diagnostic test is less complicated and time consuming than the water deprivation test and is certainly easier on cats and small dogs. The cost of the two approaches varies according to circumstances but is often comparable. However, before a desmopressin trial is initiated, it is extremely important to rule out all other common causes of polyuria and polydipsia, limiting the differential diagnosis to central diabetes insipidus, primary nephrogenic diabetes insipidus, and primary (psychogenic) polydipsia.

WEB CHAPTER  12  Clinical Use of the Vasopressin Analog Desmopressin for the Diagnosis To perform the test, the owner should first measure the animal’s 24-hour water intake for 2 to 3 days before desmopressin is initiated, allowing free-choice water intake. The dog or cat is then treated with therapeutic dosages of desmopressin. For the purposes of this test, the desmopressin ideally is administered at the dosage of 1.0 to 5.0 µg SC (or 1 to 5 U using a U-100 insulin syringe) twice daily for a period of 5 to 7 days. If subcutaneous injections cannot be given, administration of desmopressin by the conjunctival (1 to 5 drops twice daily) or oral route (0.05 to 2.0 mg twice daily) can be used instead. During this treatment period, the owner should continue to measure the animal’s daily water intake and monitor the degree of urine output. A dramatic reduction in water intake (>50% of pretreatment measurements) and polyuria strongly suggests a diagnosis of central diabetes insipidus, whereas a lack of any reduction in polydipsia and polyuria is most consistent with primary nephrogenic diabetes insipidus. With more prolonged treatment, water consumption and urine output should completely normalize in dogs and cats with central diabetes insipidus. In any older dog or cat that develops diabetes insipidus, one should consider pituitary imaging with computerized tomography or magnetic resonance imaging to exclude a pituitary mass. This is especially true if the affected animal has associated neurologic signs.

Treatment of Central Diabetes Insipidus with Desmopressin Once a diagnosis of diabetes insipidus has been confirmed, the next step is to start replacement treatment with desmopressin.

Initial Treatment with Desmopressin Recommended initial doses of desmopressin vary depending on the route of administration. In most cats and small dogs, 1 to 2 drops of the intranasal or ophthalmic preparation administered once or twice daily are sufficient to control polyuria and polydipsia. Larger dogs may require up to 4 to 5 drops twice daily. Use of a tuberculin or insulin syringe allows for more accurate dosing. Application of desmopressin into the conjunctival sac may cause local irritation because the solution is acidic (the ophthalmic preparation may alleviate this potential side effect). However, even without local irritation, some animals may object to the daily eyedrops, making this route of administration ineffective. With the subcutaneous route of administration, the initial recommended dose is 1.0 to 5.0 µg once or twice daily, depending on the size of the animal. If the nasal solution (100 µg/ml) is used for this purpose, only 0.01 to 0.05 ml (or 1 to 5 U using a U-100 insulin syringe) is injected. With the oral tablets or flavored chews and suspensions, a starting dose of 0.05 mg to 0.2 mg (50 to 100 µg) once or twice daily is initiated.

Desmopressin Dose Adjustments In dogs and cats with central diabetes insipidus, daily administration of desmopressin may completely

e75

eliminate polyuria and polydipsia. However, because of individual differences in absorption and metabolism, the dose required to achieve complete, around-the-clock control varies from patient to patient. The maximal effect of desmopressin occurs from 2 to 8 hours after administration, and the duration of action varies from 8 to 24 hours. Larger doses of the drug appear to both increase its antidiuretic effects and prolong its duration of action; however, cost can become a limiting factor for some owners. No matter what route of administration is used, the daily dose should be gradually adjusted as needed to control signs of polydipsia and polyuria. The morning and evening doses can be adjusted separately if needed.

Adverse Effects of Desmopressin Desmopressin is relatively safe for use in animals with central diabetes insipidus. Adverse effects are uncommon, but overdose can lead to fluid retention, hyponatremia, and decreased plasma osmolality. Although extremely rare, water intoxication associated with desmopressin overdosage can lead to central nervous system (CNS) disturbances including depression, increased salivation, vomiting, ataxia, muscle tremors, coma, and convulsions. In such instances, furosemide can be given to induce diuresis. To avoid the potential problem of overdose, animals should not be allowed free access to water immediately after each dose of desmopressin, especially if severe polydipsia and polyuria have redeveloped. Without short-term (1 to 2 hours) water restriction, the animal may consume excessive amounts of water that cannot be subsequently excreted because of the peak antidiuretic effects of desmopressin that may occur shortly after administration.

Cost of Desmopressin The principal drawback for any of the desmopressin preparations in the treatment of central diabetes insipidus is the drug’s considerable expense, although the compounded products are more reasonably priced. The oral route of administration is the most expensive, whereas the subcutaneous route of administration (using the sterilized nasal or injectable solutions) is generally the most cost-effective.

References and Suggested Reading Feldman EC, Nelson RW: Water metabolism and diabetes insipidus. In Feldman EC, Nelson RW, editors: Canine and feline endocrinology and reproduction, ed 3, Philadelphia, 2004, WB Saunders, pp 2-44. Nichols R: Clinical use of the vasopressin analogue DDAVP for diagnosis and treatment of diabetes insipidus. In Bonagura JD, editor: Kirk’s current veterinary therapy XIII: small animal practice, Philadelphia, 2000, WB Saunders, pp 325-326. Peterson ME, Nichols R: Investigation of polyuria and polydipsia. In Mooney CT, Peterson ME, editors: BSAVA manual of canine and feline endocrinology, ed 3, Glouscester, 2004, BSAVA, pp 16-25.

WEB CHAPTER 

13 

Complicated Diabetes Mellitus DEBORAH S. GRECO, New York, New York

C

omplications arising from the diabetic state are the most common reason for mortality from dia­ betes mellitus; the majority of diabetic animals die of renal failure, infections, or hepatic or pancreatic disease rather than from diabetes mellitus itself. Frequently there is an underlying stressful event that precipitates the shift from diabetes mellitus to diabetic ketoacidosis (DKA) or hyperosmolar nonketotic diabetes mellitus (HONKDM). The precipitating event may be a urinary tract infection; other viral or bacterial infections; or an inflammatory disorder such as pancreatitis, pyelonephritis, cholangio­ hepatitis, inflammatory bowel disease (IBD), eosinophilic granuloma complex, prostatitis, pyometra, upper respira­ tory infection, or pneumonia. Other concurrent diseases may include renal insufficiency or failure, hepatic lipido­ sis, neoplasia, or congestive heart failure. Recent drug therapy may also precipitate a crisis, especially adminis­ tration of glucocorticoids or progestagens. Thorough diagnostic testing of a diabetic patient that presents in a crisis is essential and should include a complete blood count, urinalysis with culture, serum chemistry profile, and pancreatic function tests. Abdominal radi­ ography and/or ultrasonography, as well as thoracic radi­ ography and/or echocardiography, may be indicated. Additional testing for concurrent endocrine diseases such as hyperthyroidism, hypoadrenocorticism, hypothyroid­ ism, and hyperadrenocorticism may be indicated, depend­ ing on history, physical examination, and preliminary testing. Concurrent conditions may be difficult to distinguish from complications of diabetes mellitus. Generally dia­ betic complications fall into nine major categories: (1) diabetic nephropathy, (2) diabetic neuropathy (peripheral and autonomic), (3) infections (e.g., urinary, pulmonary), (4) hepatic disorders, (5) pancreatic disease, (6) diabetic ocular problems (cataracts), (7) hypoglycemic complications, (8) ketoacidosis, and (9) hyperosmolar coma.

Diabetic Nephropathy Diabetic nephropathy occurs in approximately 40% to 50% of insulin-dependent humans with diabetes; however, it develops over a long period, often as long as 20 years. Although dogs may suffer from diabetic nephropathy, as evidenced by proteinuria and systemic hypertension, cats are more likely to suffer the long-term consequences of diabetic nephropathy because of a longer life span. The exact incidence of diabetic nephropathy in cats remains unknown; however, diabetic nephropathy, like other diabetic complications, is associated with poor glucose regulation. e76

The earliest sign of diabetic nephropathy is microalbu­ minuria followed by increases in the urine protein-tocreatinine ratio; the reference interval for the ratio is lower in cats than in dogs. Systemic hypertension, caused by activation of the renin-angiotensin system, may con­ tribute to glomerulosclerosis and further renal damage. Azotemia is a late consequence of diabetic nephropathy but may be partially or completely reversible with dia­ betic remission. Hyperglycemia increases glomerular fil­ tration rate and renal plasma flow and may increase binding of plasma proteins to glomerular basement membranes. Elevation of tissue polyol concentrations, a sequela of hyperglycemia, contributes to renal dysfunc­ tion via increased oxidative stress. Thickening of the glomerular basement membranes and glomerular hyper­ tension may also contribute to proteinuria and secondary renal damage. Early identification of diabetic nephropa­ thy may result in reversal of glomerular damage if glyce­ mic control improves. Diabetic nephropathy occurs in cats with type 2 diabetes mellitus. In a study of diabetic cats compared with age-matched nondiabetic controls, 70% of the dia­ betic cats exhibited microalbuminuria compared with only 20% of the normal control cats. Poorly regulated diabetic cats were more likely to exhibit proteinuria (100%) than well-regulated diabetic cats (50%). Further­ more, a significant relationship between systolic pressure and microalbuminuria has been noted (Al-Ghazlat et al, 2011). Early identification of diabetic nephropathy may allow for proper treatment and potential reversal of glomerular damage. Improvement of glycemic control is the key therapeutic intervention; however, wide swings in blood glucose should be avoided. Equally as important in con­ trolling hyperglycemia is minimization of the insulin dosage or eliminating insulin therapy altogether by inducing a remission. Large fluctuations in blood glucose contribute to glycosylation of tissues, including glomeru­ lar tissue. Proper treatment of type 2 diabetes mellitus in cats using a low-carbohydrate diet, oral hypoglycemic agents, and basal insulin (e.g., glargine) may help prevent progression of diabetic nephropathy. Canned renal prepa­ rations are preferred to avoid dehydration from renal disease and to lower the carb content to aid in diabetes mellitus regulation.

Diabetic Neuropathy Because of the difficulty in achieving adequate glycemic control with insulin therapy in cats with type 2 diabetes mellitus, diabetic neuropathy is a common attending condition in diabetic cats. Most diabetic cats suffer from

WEB CHAPTER  13  Complicated Diabetes Mellitus a clinical or subclinical form of diabetic neuropathy, as can be detected via neurologic examination, impaired motor and sensory peripheral nerve studies, and nerve biopsy (e.g., myelin degeneration in Schwann cells) (Mizisin et al, 1998, 2002). Clinical signs include severe manifestations such as plantigrade stance when standing and walking. Cats are unable to communicate sensory deficits or abnormalities; however, sensorimotor neuropathy, characterized by con­ duction deficits and increased F wave and cord dorsum potential latencies in both pelvic and thoracic limbs, has been documented in diabetic cats (Mizisin et al, 2002). Furthermore, nerve structural abnormalities such as split­ ting and ballooning of myelin and demyelination, indica­ tive of Schwann cell injury, are common in cats with neuropathy (Mizisin et al, 1998, 2002). Axonal degenera­ tion is less common, developing in severely affected cats. The pathogenesis of diabetic neuropathy is similar to that proposed for diabetic retinopathy and cataracts. Flux through the polyol pathway via the enzyme aldose reductase is hypothesized to promote reduction of glucose to sorbitol and then to fructose by sorbitol dehydroge­ nase. Species differences in tissue activity of these enzymes may explain the development of cataracts in dogs and the development of neuropathy in cats. Cats accumulate fructose in nerves rather than sorbitol as in humans, which contributes to the production of advanced glyca­ tion end products (Mizisin et al, 2002). The only treat­ ment that seems to work is to induce a diabetic remission using a low-carbohydrate, high-protein diet and insulin or oral hypoglycemic agents. Cats that were able to dis­ continue insulin therapy were more likely to resolve the neuropathy clinically, even though the structural abnor­ malities in the nerve itself may not have completely resolved.

Infection Impaired immune function secondary to diabetes melli­ tus increases the risk of infections. In one study, 50% of diabetic dogs had occult urinary tract infections without evidence of pyuria (Forrester et al, 1999). Urine from dia­ betic animals should always be cultured to determine the presence or absence of infection. If infections are detected, a long course (i.e., 6 to 8 weeks) of an appropriate bacte­ ricidal antibiotic is indicated. Good choices for antibiotic therapy that penetrate the urinary tract include the penicillins, cephalosporins, quinolones, and potentiated sulfas. The latter two antibiotics should be used in male dogs to ensure penetration into the prostate. Other common sites of infection in diabetic animals include the liver (e.g., infectious cholangiohepatitis); lungs, skin, and ears (e.g., yeast and bacterial infections); small intestine (e.g., bacterial overgrowth); and teeth (e.g., dental abscesses). In cats and dogs the stress of a condition as common as dental disease can lead to the release of counterregulatory factors. With resolution of the disease, insulin requirements may decline to the point at which the patient is no longer diabetic. Therefore dental prophylaxis should be considered standard treat­ ment in diabetic dogs and cats.

e77

Hepatic Disease Concurrent gastrointestinal disease is very common in those with diabetes, particularly cats. In a study by Crenshaw and Peterson (1996) 39 of 42 cats presented for DKA had concurrent diseases, including hepatic lipidosis, cholangiohepatitis, pancreatitis, chronic renal failure, urinary tract infection, or neoplasia. In another survey of concurrent disorders in 221 diabetic dogs, over 70% had elevated liver enzymes (Hess and Ward, 2000). Alanine aminotransferase and aspartate aminotransferase activities are most commonly increased, secondary to hypovolemia, poor hepatic blood flow, and subsequent hepatocellular damage. Greater increases in serum alka­ line phosphatase activity may occur if pancreatitis and secondary cholestasis ensue. Patient evaluation is compli­ cated by the effect of both the diabetes mellitus and DKA on liver enzymes and liver function tests. Ultrasonogra­ phy and biopsy may help differentiate primary hepatic disease from secondary diabetic complications such as hepatic lipidosis and cholangiohepatitis.

Pancreatic Disease Pancreatitis is a common concurrent disease with diabe­ tes mellitus (see Chapters 137 and 138). As such, it is not necessarily a complication of diabetes, but the two occur concurrently in about 40% of dogs and 50% of cats. Cats and dogs with acute necrotizing pancreatitis usually present with vomiting, abdominal pain, and con­ current DKA. Physical examination findings include icterus, cranial abdominal pain, and abdominal effusion. Radiographs may reveal a “ground glass” appearance of the abdomen, and abdominal ultrasound usually shows pancreatic enlargement and hypoechogenicity. Diagnos­ tic peritoneal lavage is usually necessary to demonstrate inflammatory, nonseptic peritonitis; abdominal lipase activity is usually increased dramatically in affected cats and dogs. If serum amylase and lipase are obtained on presentation, they may be elevated in pancreatitis or in the absence of pancreatitis, secondary to severe dehydra­ tion, or renal insufficiency. Therefore demonstration of a high circulating concentration of pancreatic lipase immunoreactivity (PLI) may be a more reliable means of diagnosis and is generally abnormal in cases having pancreatitis. Pancreatic insufficiency is another common but under­ diagnosed concurrent disease in dogs and some cats with diabetes. In the author’s experience as many as 25% of diabetic dogs and 10% of diabetic cats have exocrine pancreatic insufficiency (EPI), perhaps as a result of chronic recurrent pancreatitis. Clinical signs of EPI may be occult. Overt diarrhea and steatorrhea are uncommon in the author’s experience. More often, animals with EPI present with intermittent periods of anorexia, vomiting, weight loss, and hypoglycemia. Thus routine assessment of trypsin-like immunoreactivity (TLI) should be part of the minimum database for a diabetic dog if gastrointesti­ nal signs are present. Bacterial overgrowth and cobalamin deficiency should be considered in diabetic cats as well, particularly those over 10 years of age. Thus serum folate

e78

SECTION  III  Endocrine and Metabolic Diseases

and cobalamin concentrations should be measured at diagnosis.

Ocular Complications of Diabetes The classical ocular complication of diabetes mellitus in dogs is formation of diabetic cataracts. The incidence of cataracts in newly diagnosed diabetic dogs is about 40%; however, after a year of insulin therapy, the incidence of cataracts rises to about 80%. In contrast, cataracts are rare in cats with diabetes. Polyol pathways in the eyes rapidly convert glucose to sorbitol via aldose reductase and slowly to fructose via polyol dehydrogenase. In dogs, accumula­ tion of sorbitol within the lens fibers may lead to imbib­ ing of water and eventual lens swelling and opacity. Cats have lower aldose reductase activity in their lenses and higher levels in nerve sheaths. This may explain the lack of cataracts in most diabetic cats compared with diabetic dogs and fewer cases of neuropathy in dogs com­ pared with cats. Other complications of diabetes, more common in dogs than cats, include decreased corneal sensitivity, lens-induced uveitis, and keratoconjunctivitis sicca (Bashor and Roberts, 1995).

Hypoglycemia Recent studies have suggested that as many as 25% of diabetic cats and approximately 10% of diabetic dogs experience hypoglycemic episodes that require hospital­ ization. The dose of insulin prescribed for a newly diag­ nosed diabetic patient should be conservative (270

0.9% NaCl

Up to 90 ml/kg/hr to rehydrate

IV

PCV, TS, Na, K, osmolality

q4h

216-270

0.45% NaCl plus 2.5% dextrose

Up to 90 ml/kg/hr to rehydrate

IV

PCV, TS, Na, K, osmolality

q4h

145-215

0.45% NaCl plus 2.5% dextrose

Up to 90 ml/kg/hr to rehydrate

IV

CVP, urine output

q2h

108-144

0.45% NaCl plus 2.5% dextrose

Up to 90 ml/kg/hr to rehydrate

IV

CVP, urine output

q2h

270

10 ml/hr

IV

1.1 (C) 2.2 (D)

Blood glucose

q1-2h

216-270

7 ml/hr

IV

1.1 (C) 2.2 (D)

Blood glucose

q1-2h

145-215

5 ml/hr

IV

1.1 (C) 2.2 (D)

Blood glucose

q4h

108-144

5 ml/hr

IV

1.1 (C) 2.2 (D)

Blood glucose

q4h

270

Initial dose q1h

IM IM

0.2 0.1

Blood glucose Blood glucose

q1h q1h

50%) glossectomies.

The use of adjuvant chemotherapy in the treatment of oral tumors depends largely on tumor type, grade, local control, and goals of therapy. The use of systemic chemotherapy to treat gross disease and distant metastasis is of limited value in most cases and is considered palliative. In one study of dogs treated with carboplatin for oral melanoma, an objective response rate of 28% was reported. The responses were short-lived in most cases, with a median response duration of 165 days (Rassnick et al, 2001).

this category is the nonsteroidal antiinflammatory drug (NSAID) piroxicam. Expression of cyclooxygenase-2 has been identified in SCC in both dogs and cats. As a single agent, piroxicam (0.3 mg/kg q24h or q48h PO) has had limited efficacy in the treatment of SCC in dogs and cats (Schmidt et al, 2001). Caution is necessary in the use of NSAIDs in animals with renal insufficiency or renal failure. Increased toxicity has been seen when piroxicam is used in combination with chemotherapy agents such as cisplatin. Toceranib phosphate, a multitargeted tyrosine kinase inhibitor, has been approved by the Food and Drug Administration for use in the treatment of canine mast cell tumors. The phase I trial of this drug included several dogs with oral melanoma (n = 3) and SCC (n = 2). Although no objective tumor responses were seen, stable disease was achieved for a period of time in two of the three dogs with oral melanoma and one of the two dogs with SCC, which indicates a possible role for this drug in the treatment of oral tumors (London et al, 2003). The use of toceranib in cats, alone or in combination with RT, currently is being investigated.

Radiation Therapy

Immunotherapy

The role of RT in the treatment of oral tumors depends on the species and histologic features of the tumor. It also depends on the goal of therapy. RT can be used alone as a primary therapy, the goal of which is either cure or palliation of clinical signs, or it can be used as an adjunctive therapy to surgery when a tumor is resected incompletely. The goals and course of therapy depend on the histologic characteristics of the tumor, the extent of local disease, the stage of disease, and the wishes of the owner. Dogs and cats not expected to live longer than 6 months, even with treatment, often are treated using palliative protocols, whereas those with a better prognosis are treated with curative-intent protocols to avoid unacceptable and life-threatening adverse effects. The most significant acute effect associated with RT is mucositis, or inflammation of the mucous membranes. Although this tends to be worse with definitive protocols, it generally is well tolerated and resolves within a week or two of finishing a course of RT. Late effects, which can occur months to years after completion of a course of RT, occur more commonly with palliative protocols and can be life threatening. Because of the risk of late effects, particularly the increased risk of radiation-induced bone necrosis and fracture, any tooth extractions done in a previously irradiated area should be performed as atraumatically as possible with the alveolar bone smoothed. Other late effects of concern in dogs or cats that have undergone RT include necrosis of mucosal tissues and secondary tumor formation in the radiation field. It generally is recommended that a complete oral examination be performed and that any required dental work be done before RT is begun.

The use of immunotherapy for oral tumors is evolving rapidly. To date, immunotherapy has been limited largely to the treatment of malignant melanoma, although it  is being investigated for treatment of other tumor  types. In melanoma, multiple therapeutic vaccine strategies have been pursued and both preclinical and clinical trials have been reported (Grosenbaugh et al, 2011). Recently the U.S. Department of Agriculture has approved a xenogeneic plasmid DNA vaccine encoding the human tyrosinase gene for use in dogs with locally controlled stage I or II oral melanoma. Currently it is available  only for use by board-certified oncologists, and full efficacy data for this vaccine in canine oral melanoma treatment still are pending; however, this vaccine may  prove useful in at least a subset of dogs diagnosed with malignant melanoma. There have been anecdotal reports of the use of this vaccine in cats, but no efficacy data are available.

Chemotherapy

Targeted Therapy The use of targeted therapies is growing in veterinary oncology. Probably the most studied and oldest drug in

Specific Tumor Types Oral Melanoma Oral melanomas in dogs are highly aggressive. They can be pigmented, variably pigmented, or amelanotic in appearance. They are locally aggressive, invade underlying bone, and have a high metastatic rate, with local lymph nodes and the lungs being the most common sites of metastasis. Treatment for local control can include surgery and RT. The size of the tumor is important for prognosis, and tumors of less than 2 cm in diameter have a better prognosis. The reported median survival time for dogs with oral melanoma treated with surgery alone is 17 months for T1 tumors and approximately 5 months for T2 and T3 tumors. Most RT protocols are hypofractionated (palliative) protocols and are good at achieving  local control, with 80% to 100% response rates for gross

CHAPTER  81  Oral Tumors disease and reported median survival times of 5 to 12 months; most dogs die of metastatic disease (Proulx et al, 2003). The most commonly implemented chemotherapy protocols use carboplatin, although its efficacy in the adjuvant setting has not been well evaluated. Immunotherapy (see earlier) also has shown some promise as an adjuvant therapy to treat presumptive microscopic metastatic disease. In the cat, oral melanoma also appears to be highly aggressive, although less has been published on this subject. There is a single published case series of five cats treated with RT for gross disease. Three of the five cats experienced at least a partial response to treatment, and median survival time was 146 days.

Squamous Cell Carcinoma Nontonsillar oral SCC in dogs is a locally aggressive neoplasm that often invades bone. These lesions can appear as masses or areas of ulceration, most commonly over  the gingiva. Although regional metastasis to local lymph nodes is relatively uncommon (roughly 10%), the reported pulmonary metastatic rates range from less than 5%  to 36%. Surgery alone, RT alone, and surgery combined with RT all have been described in the treatment of  this disease. With surgery alone, the reported local recurrence rates range from 8% to 29%. RT often is used as a single modality when surgery is not possible or when owners are resistant to having the pet undergo a mandibulectomy or maxillectomy. Median progression-free intervals of approximately 1 year have been reported, with dogs with smaller tumors doing better than those with larger tumors. In cases in which excision is incomplete, RT can be used as a successful adjuvant therapy, with reported median local control times of 36 months. The role of chemotherapy in this disease remains undefined. Tonsillar SCC is a more aggressive and metastatic variant of this disease, with a higher rate of metastasis to local lymph nodes (>40%). Bilateral disease is relatively common, and treatment, such as tonsillectomy, can be performed bilaterally. Animals that receive combinations of surgery and RT seem to have superior outcomes, although there are limited numbers of reported cases in the literature. Median survival times with aggressive therapy range from 7 to 9 months. As with nontonsillar SCC, the role of chemotherapy in this disease remains undefined. The use of NSAIDs may have some benefit. In cats SCC presents most commonly along the base of the tongue and next most commonly over the mandibular or maxillary mucosa. When SCC is present over bone, it is common to find bone invasion. Usually these tumors are diagnosed when they are already invasive  and the cats are clinically affected. This tumor type is  very locally invasive but is slow to metastasize, with regional lymph node metastasis reported in fewer than 10% of cases and pulmonary metastasis uncommon at presentation. One study reported a median survival time of about 1.5 months with supportive care alone. There are few reported effective treatments. Surgery and palliative RT may have roles in select cases. If the tumor is small

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and localized to the rostral mandible, partial mandibulectomy may be an effective treatment. Although these tumors often initially respond to RT, recurrence usually is rapid; median survival times in most reports range from 3 to 5 months, with very few cats living beyond 1 year. To date, chemotherapy has limited utility. NSAIDs may have a role in the treatment of feline oral SCC for control of pain, but they also may have some antitumor effect (see earlier).

Fibrosarcoma Fibrosarcomas in dogs are locally invasive tumors that often affect underlying bone. The reported metastatic  rate has been variable, ranging from 24% to 57%, with regional lymph nodes and lungs being the most commonly reported sites. There appear to be several histologic variants of this disease, with a histologically low-grade but biologically high-grade variant reported. Surgery alone has resulted in reported median survival times  of 7 to 34 months depending on the study. The role of RT in the treatment of this tumor type has not been completely investigated. In the setting of gross disease, reported survival times of 7 to more than 26 months  have been reported with RT. RT also may be used as an  adjuvant therapy to surgery; one study reported a median survival of 18 months and another study 19 months  after a definitive course of RT (Forrest et al, 2000; Frazier et al, 2011). Although oral fibrosarcoma is the second most commonly reported oral cavity tumor in the cat, little clinical information is available. This tumor type is thought to have a low metastatic rate, although this may be because adequate treatment is lacking and local disease may cause patient death before the tumor has a chance to metastasize. In one study of cats that underwent mandibulectomy for mandibular fibrosarcoma, the 1- and 2-year survival rates were reported as 83%, although four of these six cats did have local recurrence.

Acanthomatous Ameloblastoma Although acanthomatous ameloblastoma (previously known as acanthomatous epulis) can be a locally aggressive tumor with a component of bone invasion, metastasis has not been reported. Both wide surgical excision (requiring bone removal) and RT have been reported to be effective and curative treatments for this disease.

References and Suggested Reading Arzi B, Verstraete FJ: Mandibular rim excision in seven dogs,  Vet Surg 39:226, 2010. Dvorak LD et al: Major glossectomy in dogs: a case series and proposed classification system, J Am Anim Hosp Assoc 40:331, 2004. Forrest LJ et al: Postoperative radiotherapy for canine soft tissue sarcomas, J Vet Intern Med 14:578, 2000. Fazier SA et al: Outcome of dogs with surgically resected oral fibrosarcoma (1997-2008), Vet Comp Oncol 10:33, 2012. Epub May 2, 2011. Grosenbaugh DA et al: Safety and efficacy of a xenogeneic  DNA vaccine encoding for human tyrosinase as adjunctive treatment for oral malignant melanoma in dogs following

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surgical excision of the primary tumor, Am J Vet Res 72:1631, 2011. Liptak JM, Withrow SJ: Cancers of the gastrointestinal tract:  oral tumors. In Withrow SJ, Vail DM, editors: Withrow and MacEwen’s small animal clinical oncology, ed 4, St Louis, 2007, Saunders, p 455. London CA et al: Phase I dose-escalating study of SU11654, a small molecule receptor tyrosine kinase inhibitor, in dogs with spontaneous malignancies, Clin Cancer Res 9:2755, 2003. Murray RL, Aitken ML, Gottfried SD: The use of rim excision as a treatment for canine acanthomatous ameloblastoma, J Am Anim Hosp Assoc 46:91, 2010.

CHAPTER 

Proulx DR et al: A retrospective analysis of 140 dogs with oral melanoma treated with external beam radiation, Vet Radiol Ultrasound 44:352, 2003. Rassnick KM et al: Use of carboplatin for treatment of dogs with malignant melanoma: 27 cases (1989-2000), J Am Vet Med Assoc 218:1444, 2001. Schmidt BR et al: Evaluation of piroxicam for the treatment of oral squamous cell carcinoma in dogs, J Am Vet Med Assoc 218:1783, 2001.

82 

Perineal Tumors MICHELLE M. TUREK, Athens, Georgia

M

any types of neoplasia can affect the perineum of dogs and cats. These include tumors whose development is not specific to this area, including mast cell tumors, soft tissue sarcomas, lymphoma, and benign masses such as lipomas and sebaceous gland adenomas. Although these must be considered as differential diagnoses when a dog or cat has a perineal mass, this chapter focuses on the three tumor types that arise from specialized glandular tissue in the perineum. The perianal glands are modified sebaceous glands that are abundant in the skin around the anus. They often are referred to as circumanal glands owing to the ring pattern that they form around the anus. They also can be found scattered on the prepuce, tail, and hind legs. Perianal glands are unique to the dog (absent in the cat), and their development is androgen dependent. Tumors that arise from these structures can be benign or malignant and are referred to as perianal gland adenomas and adenocarcinomas, respectively. The apocrine glands of the anal sac are embedded within the stroma that lies between the internal and external anal sphincters. The anal sacs represent cutaneous diverticula at the 4- and 8-o’clock positions around the anus that are lined by squamous epithelium originating at the anocutaneous junction. The anal sacs serve as reservoirs for the secretions produced by their associated apocrine glands. Tumors affecting the apocrine glands of the anal sac are almost always malignant. Unlike perianal tumors, which occur only in dogs, anal sac apocrine gland carcinomas can affect both dogs and cats. Of the three perineal neoplasms described here, the perianal adenoma is the most common in the dog. Of the

two malignant tumors, anal sac apocrine gland carcinoma occurs more frequently than perianal adenocarcinoma.

Perianal Gland Tumors Clinical Signs and Diagnosis Perianal adenoma, the benign form of perianal gland neoplasia, is common in older intact male dogs because of its sex hormone dependence. Dogs usually have a slowgrowing mass on the hairless skin around the anus. The tumor can also arise at the tail base, on the prepuce, or on the hind limbs. Perianal adenoma usually occurs as a single and well-circumscribed mass but can be multiple or appear as generalized hypertrophy of the perianal region. The tumors generally are nonpainful and asymptomatic. Rarely, large adenomas can become ulcerated and infected. Although it is unusual, perianal adenomas can affect females or castrated males. Androgen secretion from the adrenal glands in dogs with hyperadrenocorticism and lack of estrogen in ovariohysterectomized females are possible causes of perianal adenoma development in these dogs. Perianal adenocarcinoma should be considered as a differential diagnosis in these cases. Contrary to its benign counterpart, perianal adenocarcinoma is less common and is not androgen dependent. It can develop in any sex and is characterized by faster tumor growth and clinical signs. Perianal adenocarcinoma is more invasive and adherent to underlying tissues. It may occur as one or multiple masses. Dogs typically are brought to the veterinarian because of the presence of a mass, which may be

CHAPTER  82  Perineal Tumors ulcerated, or discomfort in the perianal region. Dyschezia and tenesmus can occur with large tumors. Cytologic analysis of a fine-needle aspirate of a perianal mass should be performed before a treatment plan is formulated. Differentiation between perianal adenoma and adenocarcinoma can be difficult by cytologic examination, but other conditions can be ruled out. A tissue biopsy is often needed to confirm malignancy, which greatly impacts the treatment approach. Because of their morphologic resemblance to hepatocytes, perianal adenomas are sometimes referred to as hepatoid tumors. Cats do not have perianal glands and therefore are not affected by these tumors.

Biologic Behavior and Staging Perianal adenoma has a benign clinical course. Metastasis does not occur. Removal of hormonal stimulation, combined with local therapy if needed to hasten relief of clinical signs, almost always is curative. Thoracic radiography and abdominal imaging for tumor staging are  not cost effective unless needed to assess non–tumorrelated problems before treatment. For cases in which perianal adenocarcinoma is high on the differential diagnosis list, such as in neutered males and females, tumor staging should be considered before a treatment plan is formulated. Perianal adenocarcinoma is a more locally invasive tumor, and it grows at a faster rate. The risk of metastasis is low early in the course of disease (15%). When metastasis does occur, it progresses via the lymphatic system to regional lymph nodes (sacral, hypogastric, and iliac) and then to lungs, liver, spleen, bone, and other organs. Tumor staging should begin with a thorough rectal examination. It is important to identify the gross tumor margins accurately for surgical planning. Palpation of the ventral aspect of the lumbar vertebral bodies during a rectal examination may reveal enlargement of sacral lymph nodes. Distant metastasis should be ruled out by thoracic radiography and abdominal imaging. Abdominal ultrasonography is more sensitive than radiography for less advanced lymph node metastasis and allows for a thorough evaluation of other organs. Lymph nodes within the pelvic canal are not well visualized with ultrasonography, so rectal palpation remains important, and radiography may be helpful to show pelvic lymphadenopathy in large dogs. Although the likelihood of metastasis at diagnosis is low for this tumor type, complete staging is recommended so that an accurate prognosis and effective treatment plan can be formulated for each patient. Clinicians should keep in mind that the presence of lymph node enlargement or splenic or hepatic nodules is not specific for metastasis. Tissue sampling with cytologic analysis is necessary to rule out a reactive or hyperplastic process.

Treatment and Prognosis Castration is the treatment of choice for perianal adenoma in intact male dogs. Most tumors regress, and recurrence is rare in the absence of androgenic stimulus. For ulcerated tumors, surgical excision can be considered to hasten

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relief. If surgical resection would be associated with a high risk of fecal incontinence, castration is recommended first, followed by surgery when the adenoma regresses  to a more manageable size. When females or neutered  males are affected, surgery is the treatment of choice. The surgical approach need not provide wide margins of normal tissue because these benign tumors are not highly invasive. Perianal adenocarcinoma requires a more aggressive therapeutic approach. Tumor growth is more invasive and independent of hormonal influences, so castration is not effective. Surgical excision should include a margin of normal tissue to remove microscopic cancer cells that extend beyond the gross tumor margin. Completeness of excision should be reported in the histopathology report. In the author’s practice, adjuvant radiotherapy (RT) is recommended when the microscopic margin of normal tissue is less than 5 to 10 mm and additional surgery is not possible. Incomplete or marginal tumor resections are common given the difficulty of surgery in this location. Local RT, targeting only the primary tumor bed, is justified for this tumor, which is associated with a low incidence of metastasis. The adjuvant radiation prescription used by the author is 2.7 Gy delivered daily (Monday through Friday) for 18 treatments. Information is lacking about the efficacy of RT, and variations on this prescription are common. Acute adverse effects related to RT  with curative intent are self-limiting and include moist desquamation of the perianal region within the RT field. The benefit of chemotherapy is not known; often it is  not recommended if RT is available since the risk of metastasis is low. For rare cases in which metastasis  has occurred, chemotherapy is a logical treatment recommendation. Although efficacy information is lacking, doxorubicin and platinum-based protocols are reasonable to consider (see later for dosing information). Tumor recurrence often can be managed with multiple palliative surgeries; however, each recurrence generally is more difficult to resect. Early diagnosis followed by an aggressive first surgery is the best therapeutic approach. The reported median disease-free interval is approximately 2 years for dogs with tumors smaller than 5 cm treated with surgical resection. Prognosis worsens with more advanced disease, including larger tumors or metastasis. For dogs with nonresectable tumors associated with dyschezia, discomfort, or tumor ulceration, palliative RT using a coarse-fraction radiation prescription is reasonable to consider. Common protocols include 6 to 8 Gy delivered once weekly for four treatments, or 4 Gy delivered daily for five treatments. Although the efficacy of RT in this setting has not been documented, responses have been observed anecdotally by the author, and acute adverse effects are minimal.

Tumors of the Apocrine Gland of the Anal Sac Clinical Signs and Diagnosis Anal sac apocrine gland adenocarcinoma (ASAC) occurs most commonly in older dogs (9 to 11 years), although dogs as young as 5 years can be affected. There appears

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to be no sex predilection. Cocker spaniels may be at increased risk. Dogs may be brought to the veterinarian because of perianal discomfort or because the owner detected a mass. In many animals, the primary tumor is small, does not protrude through the perineum, and is detectable only by rectal examination. In these cases, the presenting clinical signs are related to indirect effects of the primary tumor, such as the presence of regional lymph node metastasis that causes obstipation (dyschezia, tenesmus) or paraneoplastic hypercalcemia (associated with polyuria, polydipsia, or lethargy). Tumors also are found incidentally in asymptomatic dogs. This speaks to the importance of including a rectal examination as part of the routine physical examination. The presence of a firm subcutaneous mass palpable through the rectum at the 4- or 8-o’clock position around the anus is typical for ASAC. Usually only one anal sac is affected, although bilateral tumors can occur. Tumors range in size from a few millimeters to several centimeters. Differential diagnoses for small to moderate-sized masses include anal sacculitis, abscesses, and inspissated anal sac contents. ASAC often can be diagnosed by cytologic analysis of a fine-needle aspirate. Cytologically, tumor cells are uniform in appearance and organized in clusters. Notably, they lack many of the features usually associated with malignancy. Cytology reports specifying benign anal sac tumors should be interpreted with caution because truly benign tumors are exceedingly rare. A serum biochemistry panel and urinalysis should be performed to screen for hypercalcemia (approximately 30% of dogs are affected) and to evaluate renal function in hypercalcemic dogs. ASAC is rare in the cat. Affected animals usually are older. Clinical signs and diagnostic procedures are similar to those described for the dog. Paraneoplastic hypercalcemia is not associated with this cancer in cats.

Biologic Behavior and Staging ASAC is associated with a high risk of metastasis early in the course of disease. Fifty percent or more of dogs have metastasis along the regional lymph node chain (sacral, hypogastric, and/or iliac lymph node) at the time of diagnosis. A small primary ASAC may be associated with a greatly enlarged metastatic lymph node. Distant metastasis to lungs, liver, spleen, bone, or other sites develops later. Most dogs that succumb to this cancer are euthanized because of progressive disease at the primary tumor site (causing discomfort, tumor ulceration, and dyschezia), regional lymph node enlargement that results in obstipation, or uncontrollable hypercalcemia. Tumor staging and treatment planning begin with a thorough rectal examination to assess the size and degree of fixation of the anal sac mass. Evaluation of the sacral lymph nodes located along the ventral aspect of the lumbar vertebrae should be performed. Affected lymph nodes can be millimeters in size or markedly enlarged. Asymmetry or narrowing of the pelvic canal usually represents severe lymph node involvement. Sublumbar lymph nodes, including the hypogastric and iliac nodes, may not be detected by digital palpation depending on the size of the dog. Abdominal imaging is used to assess lymph node size objectively. Ultrasonography is more

sensitive than radiography for less advanced disease and also provides the opportunity to evaluate other organs. Mild to moderate lymph node enlargement and hepatic or splenic nodules should be evaluated by cytologic examination of a fine-needle aspirate to distinguish a reactive process from metastasis. Thoracic radiographs are recommended to evaluate for gross pulmonary metastasis, although distant metastasis is rare at the time of diagnosis. The biologic behavior of this rare tumor type in cats has not been clearly defined. As in dogs, ASAC is locally invasive, and metastatic sites include regional lymph nodes and distant sites. The rate of metastasis reported  is variable, from low to high. The approach to tumor staging is similar to that used in dogs: rectal palpation, thoracic radiography, and abdominal imaging (preferably ultrasonography).

Treatment and Prognosis A treatment plan for ASAC should take into consideration (1) the invasive nature of the primary tumor, (2) the high risk of metastasis to regional lymph nodes that extend into the sublumbar region of the abdomen, and (3) the risk of distant metastasis later in the course of disease. The surgical approach for ASAC is similar to that for an anal sacculectomy and involves sharp dissection of the anal sac and the associated mass. Because en bloc resection is not performed, histopathology reports suggesting complete excision of an ASAC should be interpreted with caution. Most tumor excisions are marginal or incomplete. Although bilateral tumors can occur, they are rare. The author generally does not advocate prophylactic removal of an unaffected anal sac. Metastatic regional lymph nodes accessible via laparotomy should be excised if an aggressive treatment plan is elected. Removal of nodes can be difficult owing to their sometimes friable texture and the proximity to large vessels. Changing instruments before closure of the abdomen is good surgical practice that prevents seeding of cancer cells in unaffected areas. To facilitate adjuvant RT planning, hemoclips should be placed at the borders of the sublumbar surgical field to delineate the extent of disease and tissue handling. Surgical resection of gross disease achieves palliation for dogs with clinical signs related to the primary tumor, metastatic lymph nodes, or hypercalcemia. The risk of recurrence after surgery is high, so adjuvant therapy, including curative-intent RT and chemotherapy, is recommended. It must be acknowledged that the relative importance of chemotherapy versus RT in tumor control has not been defined. In the author’s practice, both modalities are offered—RT to target the primary tumor and lymph node beds, and chemotherapy to address the risk of distant metastasis. Chemotherapy also may potentiate the effect of RT. Adjuvant RT can begin once surgical wounds are healed, usually 2 weeks after surgery. Curative-intent RT protocols involve total radiation doses of 48 to 54 Gy delivered daily (Monday to Friday) over approximately 4 weeks. The RT field should target both the primary site and the lymph node bed extending from the perineum to the sublumbar region in the abdomen. Since the rectum and colon commonly are

CHAPTER  82  Perineal Tumors included in the field, acute effects include loose stool and tenesmus as well as perianal moist desquamation. The dose per radiation treatment has an important impact on the risk of late effects, in particular rectal stricture. Daily RT doses should not exceed 3 Gy to minimize this risk. Optimal RT treatment planning for ASAC is performed using a computerized treatment planning system. This allows optimization of dose heterogeneity across the  radiation field, ensuring adequate dosing to tumor targets and allowing for control of dose to normal tissues.  A computed tomographic scan of the area undergoing  treatment is required. Curative-intent RT may be considered if metastatic lymph nodes have not been excised. Although good tumor responses can occur, RT is most effective in treating microscopic disease. Until studies indicate that prior surgical excision is not beneficial, the most aggressive approach is to resect all gross disease including metastatic lymph nodes and follow with RT. Commonly used single-agent chemotherapy protocols include carboplatin (300 mg/m2 q21d IV), mitoxantrone (5 to 6 mg/m2 q21d IV), or, less commonly, melphalan (7 mg/m2 daily for 5 days repeated q21d PO). The relative biologic activity of these drugs is not known; however, carboplatin is favored anecdotally. In the author’s experience, concurrent administration of RT and chemotherapy using mitoxantrone or carboplatin is well tolerated. Some clinicians prefer to treat sequentially, using chemotherapy after RT. Recurrent or progressive disease can be managed with repeated surgeries (when possible), or alternate chemotherapy. Toceranib phosphate (Palladia), a novel tyrosine kinase inhibitor (see Chapter 79), also is used currently as a second-line therapy for progressive disease or when traditional therapies are declined by the owner. As safety and efficacy information becomes available, its use as a first-line treatment in combination with standard therapies may become more frequent. For dogs with nonresectable ASAC that have dyschezia or tumor ulceration, palliative RT is reasonable to  consider. Common protocols include 6 to 8 Gy delivered once weekly for four treatments or 4 Gy delivered  daily for five treatments. Although efficacy has not been documented, responses have been observed anecdotally by the author, and acute adverse effects are limited. Medical therapy, including toceranib, also may be useful in this setting. When surgical options, including partial debulking of gross disease, are not available to control paraneoplastic hypercalcemia, bisphosphonates such as pamidronate (1 to 2 mg/kg delivered in 250 ml 0.9% NaCl over 2 hours IV q21-28d) can be useful to manage chronic hypercalcemia. An accurate estimate of prognosis is difficult to establish in dogs with ASAC. Reported survival times range from 6 to 31 months with varying treatments. The longest survival time is reported with RT and chemotherapy (mitoxantrone). Based on favorable results with platinum drugs, the author’s approach to adjuvant therapy when aggressive treatment is elected is combination curativeintent RT and carboplatin as described earlier. Prognostic factors are not clearly defined. It appears that dogs with advanced-stage disease (large primary tumor and distant

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metastasis) and those that receive no treatment may have shorter survival times. Lymph node metastasis is controversial as a predictor of outcome and may not influence survival negatively. Clinical experience has led to the following two important observations. First, a subset of dogs will enjoy a long survival time without progressive disease following surgery alone. These dogs may not benefit from adjuvant therapies. Currently we do not have a way to identify these dogs at presentation, so adjuvant therapy is recommended for all patients. Second, distant metastasis often progresses slowly, so many dogs can live a long time with advanced disease. These two factors may contribute to the disparate outcome results in the literature. The author’s approach to this uncertainty is to educate pet owners about the limitations of the information available and to inform them that the best survival time is reported with surgery followed by combination RT and chemotherapy. The owner is told that additional therapies may be needed to manage tumor recurrence (surgery, chemotherapy, or toceranib) and that disease progression can be slow, which may contribute to a prolonged survival. For cases in which combination therapy is not feasible following surgery, RT alone (preferred by the author), chemotherapy alone, and toceranib alone also are options that may be considered if adjuvant therapy is desirable. In general, early diagnosis and treatment may favor the best possible outcome. Little information is available about treatment efficacy and prognosis of ASAC in cats. Estimates of prognosis range from poor to good. Because of the lack of information suggesting otherwise, the author’s clinical approach to ASAC in cats is similar to that in dogs.

References and Suggested Reading Arthur JJ et al: Characterization of normal tissue complications in 51 dogs undergoing definitive pelvic region irradiation, Vet Radiol Ultrasound 49:85, 2008. Bennett PF et al: Canine anal sac adenocarcinomas: clinical presentation and response to therapy, J Vet Intern Med 16:100, 2002. Elliott JW, Blackwood L: Treatment and outcome of four cats with apocrine gland carcinoma of the anal sac and review of the literature, J Feline Med Surg 13:712, 2011. Emms SG: Anal sac tumours of the dog and their response to cytoreductive surgery and chemotherapy, Aus Vet J 83:340, 2005. London C et al: Preliminary evidence for biologic activity of toceranib phosphate (Palladia®) in solid tumours, Vet Comp Oncol 10(3):194, 2012. Epub June 1, 2011. Polton GA, Brearley MJ: Clincial stage, therapy, and prognosis in canine anal sac gland carcinoma, J Vet Intern Med 21:274, 2007. Shoieb AM, Hanshaw DM: Anal sac gland carcinoma in 64 cats in the United Kingdom (1995-2007), Vet Pathol 46:677, 2009. Turek MM et al: Postoperative radiotherapy and mitoxantrone for anal sac adenocarcinoma in the dog: 15 cases (1991-2001), Vet Comp Oncol 1:94, 2003. Vail DM et al: Perianal adenocarcinoma in the canine male: a retrospective study of 41 cases, J Am Anim Hosp Assoc 26:329, 1990. Williams LE et al: Carcinoma of the apocrine glands of the anal sac in dogs: 113 cases (1985-1995), J Am Vet Med Assoc 223:825, 2003.

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83 

Urinary Bladder Cancer DEBORAH W. KNAPP, West Lafayette, Indiana

Canine Urinary Bladder Tumors Urinary bladder cancer comprises approximately 2% of all reported malignancies in the dog. With the pet dog population in the United States exceeding 70 million, this translates into several thousand cases of urinary bladder cancer annually. Transitional cell carcinoma (TCC) is the most common form of canine urinary bladder cancer (Knapp, 2006, 2007). The vast majority of dogs with TCC have papillary infiltrative cancer of intermediate to high grade. TCC most often is located in the trigone region of the bladder. Papillary lesions and bladder wall thickening can lead  to partial or complete urinary tract obstruction. In a  series of 102 dogs with TCC, the tumor involved the urethra (as well as the bladder) in 56% of dogs and  the prostate in 29% of male dogs (Knapp, 2007). TCC metastasizes to distant sites in approximately 50% of cases. Sites of metastasis include regional lymph nodes, lung, liver, spleen, and, less commonly, kidney, bone,  and other organs. The clinician should not assume that all bladder masses are TCC. Mass effects in the bladder can occur with polyps, other inflammatory lesions, and other tumor types. The latter can include squamous cell carcinoma, adenocarcinoma, undifferentiated carcinoma, lymphoma, rhabdomyosarcoma, hemangiosarcoma, fibroma, and other tumors.

Cause and Possible Prevention Strategies The cause of canine bladder cancer is multifactorial. Risk factors include exposure to older-generation flea-control products (dips, powders, sprays), herbicides, insecticides, and possibly cyclophosphamide; obesity; female gender (female : male ratio, 1.7 : 1 to 1.95 : 1); and breed (Knapp, 2006, 2007). Breeds with increased risk of TCC are listed in Table 83-1. Knowledge of the risk factors for TCC can be used  to take steps that can reduce TCC risk or allow earlier  detection if TCC develops. The owners of dogs in highrisk breeds should be informed of the risk and the  clinical signs of TCC (hematuria, stranguria, inappropriate urination) and encouraged to seek timely veterinary care should these signs occur. Although it would appear appropriate to perform some form of TCC screening in older at-risk dogs (e.g., periodic urinalysis with sediment examination, abdominal ultrasonography), the benefit of this has not yet been determined. There is evidence that limiting exposure to lawn chemicals and older types of flea products can be important in reducing TCC risk, 370

especially in dogs in high-risk breeds. A significant association between herbicide exposure and TCC was identified in a case-control study in 166 Scottish terriers (Knapp, 2007). TCC risk was sevenfold higher (odds ratio, 7.19; 95% confidence interval, 2.15 to 24.07; P < .001) in dogs exposed to lawns or gardens treated with herbicides and insecticides than in dogs not exposed to these chemicals. An earlier case-control study of dogs of several breeds demonstrated the risk of older types of flea-control products (e.g., flea and tick dips). In the highest-risk group (overweight female dogs), the risk of TCC was 28 times that in normal-weight male dogs not exposed to the insecticides. It is important to note that the newer spot-on types of flea-control products appear safer. In a casecontrol study in Scottish terriers, spot-on products containing fipronil were not associated with increased risk of TCC (Knapp, 2007). In addition to avoiding certain exposures, adding vegetables to the diet can reduce TCC risk. In a study in Scottish terriers, dogs that ate vegetables at least three times a week, along with their normal diet, had a 70% reduction in TCC risk (odds ratio, 0.30; 95% confidence interval, 0.01 to 0.97; P < .001) (Knapp, 2007). The specific types of vegetable with the most benefit could not be determined, but carrots, given as treats, were the most frequently fed vegetable in the study.

Presentation, Diagnosis, and Clinical Staging Typically, TCC is a disease of older dogs (median age at diagnosis, 11 years), with females affected more often than males. Common clinical signs include hematuria, dysuria, pollakiuria, and, less commonly, lameness caused by bone metastasis or hypertrophic osteopathy. It is important to note that the lower urinary tract signs observed with TCC are similar to those that occur with urinary tract infection or calculi. Factors that raise suspicion of TCC include persistent or recurrent lower urinary tract signs or infection, older age, and high-risk breed. The physical examination of a dog with possible TCC should include a thorough rectal examination. Findings depend on the dog’s size but could include a thickened urethra, an enlarged or irregular prostate, a trigonal mass, or enlarged lymph nodes. Bladder masses often are not detected on abdominal palpation. Normal physical examination findings do not rule out TCC. When TCC is suspected, the clinician should pursue testing to (1) make a definitive diagnosis, (2) determine the cancer stage, and (3) assess the overall health of the patient. These tests include complete blood count, serum biochemistry panel, urinalysis, urine culture, thoracic radiography, abdominal ultrasonography, and bladder

CHAPTER  83  Urinary Bladder Cancer

TABLE 83-1 

BOX 83-1 

Breed and Risk of Urinary Bladder Cancer in Pet Dogs (Summary Data From Veterinary Medical Database)* Breed Mixed breed

371

Odds Ratio

95% Confidence Interval

1.0†

All pure breeds

0.74

0.62-0.88

Scottish terrier

19.89

7.74-55.72

West Highland white terrier

5.31

2.51-11.63

Shetland sheepdog

4.46

2.48-8.03

Beagle

4.15

2.14-8.05

Wirehaired terrier

3.20

1.19-8.63

Miniature poodle

0.86

0.55-1.35

Miniature schnauzer

0.92

0.54-1.57

Doberman pinscher

0.51

0.30-0.87

Labrador retriever

0.46

0.30-0.69

Golden retriever

0.46

0.30-0.69

German shepherd

0.40

0.26-0.63

*Updated from results published previously (Knapp, 2007). †Reference category.

imaging. Urine should be obtained by free catch or catheter sample and not by cystocentesis, which has been associated with TCC seeding of the needle tract. A diagnosis of TCC requires histopathologic confirmation. Although neoplastic cells have been reported to be present in the urine of 30% of dogs with TCC, cancer cells often are indistinguishable from reactive epithelial cells associated with inflammation. Urine antigen tests have been found to be sensitive for TCC, but high numbers of false-positive results limit the value of these tests. It is essential to perform histopathologic examination of the abnormal tissues to determine if TCC is present. Methods of obtaining tissue for diagnosis include cystotomy, cystoscopy, and traumatic catheterization. If surgery is performed, great care must be taken to avoid TCC seeding. Similarly, percutaneous biopsy methods (e.g., transabdominal core biopsy or fine-needle aspiration) should be avoided because these can lead to tumor seeding. Cystoscopy, using either a rigid or a flexible cystoscope, provides a means to visualize the mucosal surface of the urinary bladder and urethra, to determine tumor location and involvement of the ureteral orifices and urethra, and to collect tissues for diagnosis. Placing tissue samples in a histology cassette before processing helps prevent loss of small samples. In a recent study involving 92 dogs, diagnostic samples reportedly were obtained by cystoscopy in 96% of female dogs and 65% of male dogs that ultimately had histopathologically diagnosed TCC (Childress et al, 2011). The recent introduction of a wire basket designed to capture stones during cystoscopy allows collection of larger tissue samples and is expected to increase the yield of diagnostic biopsy samples.

World Health Organization Clinical   Staging System (TNM) for Canine Urinary Bladder Cancer T: Primary tumor Tis: Carcinoma in situ • T0 No evidence of primary tumor • T1 Superficial papillary tumor • T2 Tumor invading the bladder wall, with induration • T3 Tumor invading neighboring organs (prostate, uterus, vagina, and pelvic canal) N: Regional lymph node (internal and external iliac lymph node) • N0 No regional lymph node involved • N1 Regional lymph node involved • N2 Regional lymph node and juxtaregional lymph node involved M: Distant metastases • M0 No evidence of metastasis • M1 Distant metastasis present

Traumatic catheterization to collect tissues for diagnosis also has been performed, but samples usually are small and of limited diagnostic value. Percutaneous biopsy methods can lead to tumor seeding and are best avoided. Thoracic radiography and abdominal ultrasonography are recommended to look for evidence of metastases. Lymph node and distant metastases were present in 16% and 14% of 102 dogs, respectively, at the time of diagnosis of TCC (Knapp, 2007). Distant metastases were detected in 50% of dogs at the time of death. Tumor stage can be assigned following the World Health Organization clinical staging system for canine bladder tumors (Box 83-1). Abdominal ultrasonography also is useful for detecting ureteral obstruction and hydronephrosis. Such findings could be an indication for the placement of one or more ureteral stents, especially if other therapies do not relieve the urinary obstruction (see Chapter 76). Bladder imaging is used to determine the location  of the tumor within the urinary tract and to obtain  baseline measurements of the TCC to monitor response  to subsequent therapy. Ultrasonography is the method most commonly used to image the bladder. Cystography is used less frequently because of the need for anesthesia, catheterization, and enemas to remove colonic contents that could obscure images of the bladder; risk of urinary perforation with catheterization; and production of inconsistent images when the bladder shifts in position or is imaged at different levels of distention. Computed tomography (CT) with intravesical and intravenous contrast provides the best images of bladder masses, but CT is pursued less commonly because of expense and the need for anesthesia and urinary catheterization. Ultrasonography is an important imaging modality for the bladder. The degree of distention is important when imaging the bladder. When the bladder is minimally  distended, it can be difficult to visualize some lesions accurately, and it is not possible to determine whether

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evident lesions are remote to the trigone (where surgical resection could be possible). When ultrasonography is used to measure bladder masses over the course of therapy, it is crucial to follow a consistent protocol from visit to visit with regard to bladder distention, patient positioning, and method of measuring masses and to have the same operator perform the examinations over the multiple visits.

Treatment Surgery Surgical excision of TCC should be considered for lesions in the bladder apex for which 3-cm margins of grossly normal bladder can be removed around the tumor mass. Unfortunately, most TCCs are trigonal and many involve the urethra, which precludes surgical excision. In addition, many dogs appear to develop multifocal TCC in the bladder. This is consistent with the proposed “field effect,” in which the entire bladder lining is thought to undergo malignant change in response to exposure to carcinogens in urine. In the limited number of cases in which TCC has been removed “completely,” local recurrence still is common. If TCC is removed surgically from the bladder, there is some evidence that cyclooxygenase (COX) inhibitor treatment can reduce risk of recurrence. In a pilot study conducted at Purdue University, adjuvant deracoxib (Deramaxx) was given to nine dogs following surgical removal of TCC (McMillan et al, 2011). Three dogs had tumor-free margins, and six dogs had microscopic TCC present in surgical margins. Deracoxib (3 mg/kg q24h PO) was instituted postoperatively. In four of the dogs with microscopic residual TCC after surgery, there was no evidence of relapse at 345, 749, 963, and 2057 days, respectively. The other two dogs with residual microscopic TCC had recurrence at 140 and 231 days, respectively. Of the three dogs with tumor-free margins, one dog was disease free at death at 1437 days, and the other two dogs had recurrence at 210 and 332 days, respectively. The median survival time of the nine dogs was 749 days (range, 231 to 2581 days). Without a randomized trial comparing deracoxib with placebo, the true benefit of deracoxib in this setting is not known, but results to date have been encouraging. Even if surgical removal of the TCC is not possible, surgery has a role as an emergency palliative procedure to bypass urinary obstruction through the placement of ureteral and urethral stents (see Chapter 76) and prepubic cystostomy tubes (Berent, 2011). Urethral stents, which can be placed nonsurgically with fluoroscopic guidance, are attractive because no external tubing or hardware is necessary (as is the case with cystostomy tubes). The use of ureteral and urethral stents has been very important in prolonging the life of some dogs with TCC. Transurethral resection of bladder and urethral TCC has been attempted in a small number of dogs but has been limited by complications of the procedure and local disease recurrence. Laser ablation of TCC combined with medical therapy also has been reported, but it is not yet known if this offers an advantage over traditional surgery and medical therapy.

Radiation Therapy Studies of the effects of radiation therapy (RT) on TCC are very limited. RT appears to kill TCC cells effectively, but complications (urinary incontinence, cystitis with accompanying pollakiuria and stranguria) have limited the use of traditional RT. In a report of RT in 10 dogs (Poirier et al, 2004), weekly coarse-fraction external beam RT plus mitoxantrone and piroxicam was tolerated, but results were no better than those with medical therapy alone. Recently, the use of intensity-modulated and image-guided radiation therapy for treatment of genitourinary carcinomas in dogs has been described with encouraging results (Nolan et al, 2012). Medical Treatment of Transitional Cell Carcinoma Medical management of TCC is indicated in dogs with nonresectable or metastatic tumors. Medical therapy for TCC consists of chemotherapy, COX inhibitors, and combinations of the two (Henry et al, 2003; Knapp, 2006, 2007, 2013). Regardless of the treatment pursued, basic concepts apply in tailoring the therapy to the individual dog with TCC. Complete staging of the TCC to define the extent of the disease and size of lesions should be performed before and after approximately 6 weeks of treatment. After 6 weeks of treatment, if the tumor is smaller or stable in size, and if the treatment is acceptable with regard to any adverse effects, the same treatment should be continued. Restaging should be performed at 6- to 8-week intervals, and therapy adjusted as appropriate. If cancer progression or unacceptable toxicity occurs, different therapy could be considered. COX Inhibitor Treatment.  COX inhibitors offer a simple oral treatment for TCC that is associated with relatively few side effects and lower costs than chemotherapy. Although COX inhibitors induce remission less often than standard chemotherapy for TCC, some pet owners elect to use COX inhibitor therapy for their pets. The nonselective COX inhibitor piroxicam (0.3 mg/kg q24h PO) has been used to treat dogs with TCC since the 1980s. The quality of life in most dogs receiving piroxicam has been excellent. In 62 dogs treated with piroxicam (Knapp, 2007), tumor responses included complete remission (complete resolution of all evidence of cancer) in 3%, partial remission (≥50% reduction in tumor volume) in 14%, stable disease (99

5 cm in diameter) having a poor response to chemotherapy and radiation therapy Some sarcomas are not included in the traditional STS classification because of more aggressive biologic behavior

WEB CHAPTER  27  Soft Tissue Sarcomas (e.g., higher metastatic rates) and different histologic features. These include osteosarcoma, chondrosarcoma, hemangiosarcoma (HSA), synovial cell sarcoma, histiocytic sarcoma, mesothelioma, and lymphangiosarcoma. Canine hemangiopericytoma (HEP) may be a nonspecific term, encompassing several neoplasms of different histologic origin. Canine perivascular wall tumors (c-PWT) have been described as a mixed group of distinct biologic entities comprising hemangiopericytomas, angioleiomyomas, myopericytomas, and most likely angiomyofibroblastomas and angiofibromas. PWT are distinguished from HEP on the basis of specific histologic growth patterns, cell shape, and immunohistochemistry (Avallone et al, 2007). In humans this is important because myopericytoma is generally benign compared with mostly malignant HEP. However, it is not yet clear whether this distinction between HEP and PWT is clinically important in dogs.

Incidence and Risk Factors STSs account for 15% and 7% of all skin and subcutaneous tissues in the dog and cat, respectively. The annual incidence of STS is 35 per 100,000 dogs and 17 per 100,000 cats. The etiology is generally unknown; however, in dogs sarcomas have been associated with radiation, trauma, foreign bodies, orthopedic implants, and the parasite Spirocerca lupi. In cats, sarcomas have been associated with feline sarcoma virus, vaccines and other subcutaneous injections, and trauma (e.g., intraocular sarcoma). This discussion is limited to spontaneous, non–vaccineassociated STSs in dogs and cats.

Clinical Features Most STSs are solitary and occur in middle-aged to older dogs and cats. They are more common in medium- to large-breed dogs but can occur in any age or breed. STSs often are a soft to firm, spherical, nonpainful subcutaneous mass over the trunk or extremities and can be fixed to the underlying tissue. They can originate in visceral and nonvisceral sites. They are generally slow growing, and clinical signs are related to the site of involvement and the degree of invasion.

Diagnosis and Clinical Workup The mass is palpated to give an idea of site, size, fixation to underlying or adjacent structures, and an initial assessment of the extent of local disease. The regional lymph nodes also should be palpated for enlargement and fixation to underlying tissues. Fine-needle aspirates (FNAs) are recommended to exclude other differential diagnoses but are often insufficient for obtaining a definitive diagnosis of STS. In one study in which FNAs were performed on STS from 40 dogs, 15% were diagnosed incorrectly, a further 23% were nondiagnostic, and only 62% were diagnosed correctly (Baker-Gabb et al, 2003). In another study of 44 dogs with STS, FNAs incorrectly diagnosed four cases as benign masses (Mallik et al, 2010). The difficulty in cytologic diagnosis of STS may be due to poor exfoliation, high

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degree of necrosis resulting in false negatives, and nonmalignant disease showing similar results. A definitive preoperative diagnosis of STSs requires a needle core, punch, or incisional biopsy. The biopsy should be planned so that the biopsy tract can be included in the curative-intent treatment, whether it be surgery and/or radiation therapy (RT), without increasing the surgical dose or size of the radiation field. Excisional biopsies are not recommended because they are rarely curative, and subsequent surgery required to achieve complete histologic margins is often more aggressive than surgery after core or incisional biopsies, resulting in additional morbidity and expense. Histopathologic grading (low, intermediate, high, or I, II, III) is ascertained from large biopsy specimens and always should be requested from the pathologist. One recent study compared histologic grading from pretreatment biopsies with definitive surgical samples. The two methods correlated 59% of the time, with pretreatment biopsies tending to underestimate grade. Additionally, the method of pretreatment biopsy (14-gauge needlecore, 4- to 8-mm punch, or a wedge biopsy with a mean sample width of 0.5 cm) did not significantly affect grade concordance (Perry et al, 2005). Tumor grade is predictive of behavior and prognosis and is critical to treatment planning. Less than 10% of grade I, 20% of grade II, and 50% of grade III STSs metastasize to the regional lymph node and lung. Higher grade lesions also tend to grow more rapidly and are more locally invasive. The tests performed for workup and clinical staging are dependent on the type and location of the STS, especially if atypical (e.g., HSA, histiocytic sarcoma, lymphangiosarcoma, and synovial cell sarcoma), but usually involves routine hematologic and serum biochemical blood tests, urinalysis, three-view thoracic radiographs, and potentially regional imaging of the STS. Blood tests are usually within the normal reference range for most dogs with STS; however, anemia and thrombocytopenia are relatively common in dogs with disseminated histiocytic sarcoma and HSA. Paraneoplastic hypoglycemia has been reported with intraabdominal leiomyosarcomas or leiomyomas. Further imaging of the local tumor may be required for planning the surgical approach or RT if the mass is very large, within a body cavity, fixed to underlying bone, or impinging on or in close proximity to vital structures. Three-dimensional imaging techniques, such as computed tomography (CT) and magnetic resonance imaging (MRI) scans, are particularly useful for staging the local tumor. The surgeon then may better assess the feasibility and more accurately plan an aggressive surgical resection. The most important diagnostic test for staging of metastatic disease is three-view thoracic radiographs because the lungs are the most common metastatic site for typical STS. Lymph node metastasis is uncommon with typical STS. Fine-needle aspiration or biopsy of regional lymph nodes should be performed in dogs with clinically abnormal lymph nodes or atypical STS with a high rate of metastasis to regional lymph nodes, such as HSA, histiocytic sarcoma, lymphangiosarcoma, synovial cell sarcoma, leiomyosarcoma, and possibly

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rhabdomyosarcoma. Abdominal imaging (e.g., ultrasonography or advanced imaging) also may be employed to assist in further staging in selected cases.

Treatment Options Treatment options are considered once clinical staging is complete. For nonmetastatic STS, local tumor control is the most important consideration for optimal management because of locally aggressive behavior. On gross examination, STSs appear to be well encapsulated. This is not the case because microscopically the pseudocapsule is composed of compressed tumor cells. These peripheral cells are thought to be more aggressive and responsible for the invasion into adjacent normal tissues. Shelling out the tumor leaves behind the potentially more aggressive subpopulation of peripheral, invasive cells. Consequently, recurrent lesions are often behaviorally more aggressive or of a higher grade than the initial lesion and may compromise the optimal treatment and long-term outcome for the animal. Incomplete surgical excision for canine STS has been reported to result in a probability of local recurrence of 60% within the first 12 months, increasing in subsequent years. In a study comparing local recurrence rates for canine STS treated with a variety of surgical margins, local recurrence occurred in 60% of cases overall, 100% of cases with dirty margins, 80% of cases with close margins, and 22% of cases with clean margins over a 24-month follow-up period (Scarpa et al, 2012). Margin classification was a significant predictor of the recurrence-free interval, and was 87% accurate. In another study, geriatric dogs (median age 10 years) treated in first opinion practice with a variety of surgeries (marginal to radical) to remove STS were followed for a median of 875.5 days postoperatively. Local tumor recurrence occurred in 28% overall, in 13 of 45 dogs with marginal resection, in 3 of 18 dogs with narrow resection, in 1 of 5 dogs with wide resection, and in no dogs treated with radical excision. Additionally, 22% of dogs in this study died as a result of their STS. This study again indicates the importance of wide clean margins in preventing local and distant tumor recurrence. In another study, 28% of dogs with incomplete surgical margins had local recurrence and were more than 10 times more likely to have local recurrence than dogs with completely excised STS. In a study of 55 c-PWT in which more than 90% of tumors were of low or intermediate grade in various locations, resection was performed with either clean (13%), clean but close (27%), or dirty (60%) margins (Stefanello et al, 2011). The overall tumor recurrence rate was 22% (20% local recurrence and 4% distant recurrence), with an average follow-up time of 665 days. These results compare similarly with the previously reported local recurrence rates for the larger STS classification group of low-to-intermediate grade treated with incomplete resection. Low-grade STS of the extremities in 35 dogs were treated by marginal excision in another study, resulting in an 11% local tumor recurrence rate, and 6% of these dogs died of tumor-related causes. The median age at diagnosis was 11 years and the median time to recurrence was 522 days. This study highlights that marginal resection of an extremity low-grade STS is a valid treatment option in a

geriatric dog because the median time to recurrence is prolonged and many dogs (37%) ultimately died of unrelated causes. However, in a younger cohort of dogs, the median time to recurrence is more likely to be reached, warranting a more curative-intent initial treatment approach. Dogs with higher-grade tumors also warrant a more curative-intent treatment approach, as local recurrence rates for STS were shown to be grade dependent in another study, with recurrence rates of 7%, 35%, and 75% for grade I, II, and III tumors, respectively. In dogs with incompletely resected STS, treatment options include observation (particularly for a grade I STS), staging recut, wide surgical excision, and adjuvant therapies such as RT, conventional chemotherapy, metronomic chemotherapy, and electrochemotherapy. In one study of 39 dogs with incompletely resected STS, early reexcision of the surgical scar with widest surgical margins possible (0.5 to 3.5 cm) resulted in 15% local recurrence and 10% distant metastatic rates, with a median follow-up time of 816 days. This study again highlights the importance of attaining clean histologic margins to prevent local recurrence.

Surgical Resection with Wide Margins Surgical resection with wide surgical margins provides the best chance for a cure for cats and dogs with STSs. Proper preoperative staging and diagnosis provide essential information to formulate a surgical plan. Excision of the STS, with associated biopsy tracts and any areas of fixation (e.g., bone, fascia), with wide margins is the recommended treatment. The minimum recommended surgical margins are 3 cm of grossly normal tissue lateral to the tumor and one fascial layer deep to the tumor. In two different studies, surgical resection with wide, histologically complete margins resulted in 90% to 100% local disease control and a 90% to 93% 1-year disease free survival. In these studies, resected specimens were processed and fixed to emulate their in situ dimensions as closely as possible, and surgical margins were evaluated using a standardized protocol. The deep margin was always the closest margin in cases of clean resection or the dirty margin in cases of incomplete resection and therefore more likely to be a site of treatment failure than either lateral margin. In all but one dog, tumors resected with deep margins more than 1 mm did not develop local recurrence, as all had a layer of fascia resected as part of the deep margin. These studies showed lateral surgical margins of 11 to 30 mm, which may be acceptable for grade I to II STSs, especially when a deep uninvolved fascial layer is removed en bloc with the lesion. Another study reported that canine STS removed with attempted wide margins, regardless of completeness of excision, had an 85% rate of local tumor control with a median time to recurrence of 368 days. In another study, 79% of canine STS resected with wide, complete histologic margins were controlled for 2 years. No recurrence occurred in 30 completely resected canine STSs in another study, irrespective of grade, for a follow-up period of 6 to 24 months. The dose of surgery was the only factor significantly associated with survival time in a series of 56 dogs with liposarcomas. Resection of liposarcomas with wide margins achieved a median survival time of

WEB CHAPTER  27  Soft Tissue Sarcomas 1188 days compared with 649 days for marginal excision and 183 days for incisional biopsy. Therefore wide surgical resection provides the optimal treatment and best chance of long-term control and survival for canine and feline spontaneous STS.

Marginal Resection and Adjuvant Radiation Therapy If the tumor or previous scar cannot be excised with wide margins, particularly for STSs of the extremity, marginal resection followed by adjuvant RT is recommended to prolong the disease-free interval (DFI) and preserve limb function. This approach ideally involves planning with a radiation oncologist before starting treatment, rather than employing RT as a salvage procedure after recurrence. In two studies, marginal resection followed with alternate-day megavoltage RT resulted in a 16% local recurrence rate with a median time to recurrence of 700 to more than 798 days. In another study in which 56 dogs with limb STS received marginal excision and an adjuvant coarse fractionated megavoltage radiation protocol (the total treatment dose of 32 to 36 Gy was delivered in 4 × 8 to 9 Gy fractions at 7-day intervals), 18% had local recurrence and 10% distant metastasis. The 1-, 3-, and 5-year recurrence rate estimates were 19%, 30%, and 35%, respectively. Delaying radiotherapy for more than 4 weeks had a positive impact on local disease control (Demetriou et al, 2012). The optimal fractionated and total doses for canine STS have not been determined, but cumulative doses more than 50 Gy are recommended and local tumor control is better with higher cumulative doses. In some cases, RT can be used before surgery because this may decrease tumor volume so that the tumor is more amenable to wide surgical excision. The use of RT ideally should involve a team approach with the surgical oncologist and the radiation oncologist.

Marginal Resection and Adjuvant Metronomic Chemotherapy Metronomic chemotherapy is the continuous administration of fixed, low doses of chemotherapeutic agents without prolonged breaks in treatment. Thirty dogs with incompletely excised STS were treated with piroxicam and cyclophosphamide metronomic chemotherapy. There were also 55 unrandomized control dogs that received surgery alone. All control dogs had local tumor recurrence with a median DFI of 211 days, whereas the median DFI for treated dogs was not reached. Some adverse effects to treatment were evident in 40% of dogs. Although these effects were generally mild, one dog was euthanized because of grade 4 hemorrhagic cystitis.

Radiation Therapy Alone RT alone achieves local control in 48% to 67% of tumors in the first 12 months, with higher cumulative radiation doses resulting in better control rates; however, this reduces to 20% to 33% at 2 years. Thus RT is not considered adequate as sole therapy and generally is considered palliative.

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Chemotherapy Situations in which postoperative chemotherapy should be considered include intraabdominal STS (e.g., splenic sarcoma and leiomyosarcoma), metastatic disease, and dogs with histologic subtypes with a higher rate of metastasis (e.g., histiocytic sarcoma, hypodermal HSA [stage II or III], synovial cell sarcoma, rhabdomyosarcoma, and lymphangiosarcoma), and incompletely resected canine STS, in which additional surgery or RT are not feasible. Grade III STSs are associated with an increased risk of metastasis (41% to 50%) and decreased survival times. Postoperative chemotherapy may have a role in these cases to delay or prevent the development of metastatic disease. However, metastasis usually occurs late in the course of disease (median time to metastasis of 365 days), and this may minimize the beneficial effects of postoperative chemotherapy in such cases. Three chemotherapy drugs are active in adult human STS: anthracyclines (doxorubicin [DOX] and epirubicin), ifosfamide, and dacarbazine. In dogs, DOX is considered the most active single agent to treat STS with overall response rates of up to 23% in dogs. Mitoxantrone has a variable effect in canine STS with a 0 to 33% response rate, and a response rate of 21% has been reported in cats with better responses in lower grade tumors. Ifosfamide showed a complete response rate of 15% in 13 dogs with sarcomas of skin, bladder, and spleen. In dogs, the combination of DOX with either ifosfamide or cyclophosphamide does not appear to be more efficacious than DOX alone. Chemotherapy responses are usually partial and of short duration. Studies investigating DOX-based protocols, singleagent ifosfamide and mitoxantrone, and dual-agent DOX-ifosfamide in canine STS have shown no difference in DFI or survival time when used postoperatively for high-grade STS. In humans, postoperative chemotherapy also does not affect overall survival time but may improve local tumor control. In one study, postoperative DOX was not beneficial in increasing the metastasis-free interval or overall survival time in dogs with high-grade STS of various locations, but there was a significant decrease in the rate of local tumor recurrence in dogs with incompletely resected tumors. The role of neoadjuvant (preoperative) chemotherapy in the management of cats and dogs with STS has not been investigated.

Intraoperative Chemotherapy Marginal resection with implantation of an intralesional biodegradable polymer of open cell polylactic acid containing cisplatin has been reported with a 31% local tumor recurrence rate and a median time to recurrence of 640 days. This product is not commercially available and local toxicity is common. Another study reported marginal resection with intralesional implantation of a biodegradable polymer solution, combined with cisplatin, which solidifies when injected in situ. Local recurrence occurred in 17% of dogs with a mean time to recurrence of 451 days. However, the wound complication rate was unacceptably high at 84%.

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Other Postoperative Therapies Studies have evaluated hyperthermia/RT combinations, orthovoltage RT plus low-dose weekly DOX, and bleomycin electrochemotherapy for postoperative treatment of incompletely resected canine and feline STS. None are as thoroughly researched, practical, or efficacious as complete excision or incomplete excision followed by RT.

Metastatic Disease Animals with metastatic disease should be managed palliatively rather than treated with more aggressive curative-intent techniques such as surgery and/or radiation therapy. Pulmonary metastasectomy has not been evaluated for metastatic STS.

Prognosis Prognostic Factors for Local Tumor Recurrence Prognostic factors for local tumor recurrence include size, location, grade, and completeness of surgical excision. Tumors more than 5  cm in diameter are more likely to recur. Site is also prognostic with STS located in superficial sites or the extremities having a better prognosis than tumors that are deep, truncal, invasive, or close to the spinal cord. This is probably because location can affect ability to achieve complete surgical resection. Dogs with incomplete resection are more than 10 times more likely to develop local recurrence. Tumor grade (low or intermediate grades are more favorable) and thickness of deep margin (>10  mm or at least one fascial plane nonadherent to the tumor) are prognostic factors for local recurrence. Tumors that are freely movable have a more favorable prognosis than those fixed to underlying tissues.

Prognostic Factors for Metastasis The absence of metastatic disease at presentation is a positive prognostic factor. Mitotic rate has been shown to be associated significantly with the development of metastasis at a distant site. In one study, dogs with at least 20 mitotic figures per 10 high-power fields were 5 times more likely to develop metastasis than dogs with less than 20 mitotic figures per 10 high-power fields. Mitotic rate, degree of differentiation, tumor grade, and histologic type significantly affected the likelihood of metastasis. Less than 10% of grade I STS, 20% of grade II, and 50% of grade III STS undergo metastasis to the regional lymph nodes and lungs.

Prognostic Factors for Survival Tumor-related deaths in animals with STS usually are caused by uncontrolled local disease. The median survival times for dogs with nonoral STS treated with wide surgical resection and marginal surgical resection combined with adjuvant megavoltage radiation are 1416 and 2270 days, respectively. Mitotic rate and percentage tumor necrosis

were significantly associated with survival time. Dogs with more than 10% necrosis are 2.8 times more likely to die of tumor-related causes than dogs with less than 10% necrosis. Dogs with at least 20 mitotic figures per 10 highpower fields were 2.6 times more likely to die of tumorrelated causes than dogs with less than 20 mitotic figures per 10 high-power fields. Other prognostic factors for overall survival include tumor size, completeness of surgical resection, degree of differentiation, histologic grade, and local tumor control.

References and Suggested Reading Avallone G et al: Spectrum of canine perivascular wall tumors: morphologic, phenotypic and clinical characterization, Vet Pathol 44:607, 2007. Bacon NJ et al: Evaluation of primary re-excision after recent inadequate resection of soft tissue sarcomas in dogs: 41 cases (1999-2004), J Am Vet Med Assoc 230:548, 2007. Baker-Gabb M, Hunt GB, France MP: Soft tissue sarcomas and mast cell tumours in dogs: clinical behaviour and response to surgery, Aust Vet J 81:732, 2003. Banks TA et al: Soft tissue sarcomas in dogs: a study assessing surgical margin, tumour grade and clinical outcome, Aust Vet Pract 34:142, 2004. Chase D et al: Outcome following removal of canine spindle cell tumours in first opinion practice: 104 cases, J Small Anim Pract 50:568, 2009. Demetriou JL et al: Intentional marginal excision of canine limb soft tissue sarcomas followed by radiotherapy, J Small Anim Pract 53:174, 2012. Dernell WS et al: Intracavitary treatment of soft tissue sarcomas in dogs using cisplatin in a biodegradable polymer, Anticancer Res 17:4499, 1997. Elmslie RE, Glawe P, Dow SW: Metronomic therapy with cyclophosphamide and piroxicam effectively delays tumor recurrence in dogs with incompletely resected soft tissue sarcomas, J Vet Intern Med 22:1373, 2008. Havlicek M et al: Intra-operative cisplatin for the treatment of canine extremity soft tissue sarcomas, Vet Comp Oncol 7:122, 2009. Kuntz CA et al: Prognostic factors for surgical treatment of softtissue sarcomas in dogs: 75 cases (1986-1996), J Am Vet Med Assoc 211:1147, 1997. Mallik MK et al: Grading of soft tissue sarcomas on fine-needle aspiration cytology smear, Diagn Cytopathol 38:109, 2010. McKnight JA et al: Radiation treatment for incompletely resected STS in dogs, J Am Vet Med Assoc 217:205, 2000. McSporran KD: Histologic grade predicts recurrence for marginally excised canine subcutaneous soft tissue sarcomas, Vet Pathol 46:928, 2009. Perry JA et al: Diagnostic accuracy of pre-treatment biopsy for grading soft tissue sarcomas in dogs, Vet Comp Oncol 2012. DOI: 10.1111/j.1476-5829.2012.00333.x Scarpa F et al: Use of histologic margin evaluation to predict recurrence of cutaneous malignant tumors in dogs and cats after surgical excision, J Am Vet Med Assoc,240:1181, 2012. Selting KA et al: Outcome of dogs with high-grade soft-tissue sarcomas treated with and without adjuvant doxorubicin chemotherapy: 39 cases (1996-2004), J Am Vet Med Assoc 227:1442, 2005. Stefanello D et al: Marginal excision of low-grade spindle cell sarcoma of canine extremities: 35 dogs (1996-2006), Vet Surg 37:461, 2008. Stefanello D et al: Canine cutaneous perivascular wall tumors at first presentation: clinical behavior and prognostic factors in 55 cases, J Vet Intern Med 25:1398, 2011.

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Collection of Specimens for Cytology KENITA S. ROGERS, College Station, Texas

T

he usefulness of cytology as a diagnostic tool is well established. Evaluation of high-quality cytology preparations can provide a definitive diagnosis in many cases and may at least provide powerful supportive evidence of a disease process in others. Cytology can play an important role in establishing a prognosis, as well as guiding further diagnostic and therapeutic decisions. Collection of representative cells from a lesion or organ remains the quality-limiting step of this important technique. Poor-quality samples even have the potential to be misleading in the diagnostic workup and can prompt inappropriate therapy. This chapter focuses on cellular collection techniques, necessary supplies, appropriate slide preparation methods, and problems that may arise during this process. Indications for cytologic evaluation include a palpable external mass, swelling, or ulceration; mass lesions arising from an internal organ; irregularity in an organ within the thoracic or abdominal cavity noted by physical examination or imaging techniques; organomegaly, including lymph nodes, liver, spleen, prostate, or kidneys; or fluid accumulation in body cavities, including joints, peritoneum, pleura, or pericardium. Cytology also can be used to assess for inflammation or tumor infiltration in organs that are grossly normal on examination. Because of its immediacy cytology can be used effectively to help with decision making in the intraoperative setting. The basic supplies required for sample collection are listed in Web Box 28-1. Whereas 1- to 11 2-inch needles are adequate for many clinical cases, longer spinal needles often are required for intracavitary aspirates to access deeper tissues. The recommended needle size varies with the tissue type and expected exfoliation. Large 18- to 20-gauge needles may be needed for lesions that are unlikely to exfoliate well, such as bone aspirates, whereas most lesions and organs can be aspirated adequately with 21- to 25-gauge needles. The recommended syringe size is typically between 6 and 12 ml, which provides adequate suction and also is a comfortable fit for the operator’s hands.

Methods of Cell Collection The technique recommended for collecting cytologic specimens varies, depending on lesion location, expected tissue characteristics, and patient restraint issues. No skin preparation is needed for external lesions or lymph nodes; however, if a body cavity is to be penetrated,

surgical preparation of the skin is required. The area penetrated by the needle is small; thus extensive shaving is not necessary.

Imprints The simplest method to collect cells is to directly imprint tissues onto a glass slide. This is an effective technique for biopsy specimens from organs or masses that exfoliate well. Blood and tissue fluid is blotted from the cut surface of the specimen, which subsequently is touched to the surface of a clean glass slide. Depending on the size of the specimen, several imprints may be made per slide. If the biopsy was retrieved as a small core, the specimen can be rolled gently down the slide with a small-gauge needle, avoiding crushing or fragmenting the biopsy. Imprinting also may be used to collect cells from discharges, typically from the nasal or vaginal cavities or external ulcers. Although easily accomplished, imprinting discharge fluid or an ulcerated surface often collects superficial inflammation, dysplastic cells, and contaminating bacteria, which may not be representative of the underlying disease process. For a superficial lesion or discharge, a glass slide is impressed directly to the lesion to collect material. If the material appears to be too thick, horizontal or vertical pull-apart smears can be made to ensure that some areas are thin enough for evaluation (see section on slide preparation later in the chapter). Swabs may be used to collect cells from fistulous tracts; ear canals; or the vaginal, nasal, or respiratory tracts. A sterile cotton swab or biopsy brush is used to collect cells from these sites and then is rolled down the length of the slide.

Fine-Needle Aspiration Fine-needle aspiration (FNA) is preferred for cell collection from mass lesions and organs. It avoids superficial contamination and is more likely than imprinted specimens to be representative because several adjacent areas can be aspirated. The classic method of cellular collection involves piercing a mass or organ with a needle (21- to 25-gauge) that is attached to an empty syringe (6 to 12 ml). A 4- to 8-ml amount of suction is placed on the syringe to create a pressure vacuum that encourages cells to dislodge and move into the needle. With pressure held, the needle can be moved in different directions within the mass. If the aspirated site is intraabdominal, the risk of hemorrhage may be increased slightly with repeated e153

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WEB BOX 28-1  List of Supplies Required for Basic Cytologic Collection Techniques Clean, dust-free glass slides 6- to 12-ml syringes Variety of 1- to 112-inch needles (20- to 25-gauge needles) 2 12 - to 3 12 -inch spinal needle with stylet Scalpel blades (nos. 10 and 11) Romanowsky-type stain: Diff-Quik Slide dryer Marker for identifying slides Ethylenediaminetetraacetic (EDTA) acid (purple top) and serum (red top) tubes

needle redirection, and it often is recommended that the area be examined with ultrasound after the procedure to note any evidence of continued bleeding from the site. Redirection of the needle is not recommended with lung aspirates because of the risk of developing clinically significant pneumothorax. When aspiration has been completed, pressure is released, and the needle and syringe are withdrawn from the lesion. The cells collected typically are within the needle, and there may be no visible material within the syringe. Indeed, if material or blood is noted within the syringe, suction should be released, and the aspiration technique stopped. The needle is disconnected from the syringe, which subsequently is filled with air. After reattaching the air-filled syringe to the needle and holding the tip close to the slide, air is expelled through the needle to push material onto an appropriate area of the glass slide. Aspiration is facilitated by immobilization of the mass while the aspiration occurs. One helpful method is to hold a palpable mass between the thumb and index finger of the left hand with the palm up (for the right-handed clinician). This leaves the remaining fingers and palm free to grasp the barrel of the syringe while the right hand is used to apply suction.

Coring Technique To avoid the cellular disruption that can be caused by the pressure of aspiration, the coring technique uses only a needle to collect cells. The needle is advanced through the mass or organ and is redirected several times for the purpose of dislodging cells and causing them to be driven into the hollow shaft of the needle. After the needle has been removed from the lesion, an air-filled syringe is used to expel the contents of the needle onto a slide similar to FNA. Alternatively, an air-filled syringe already can be attached to the needle, expediting the process. The coring technique diminishes blood contamination of the specimen in vascular tissues, and there is better control of needle placement, which is particularly useful for ultrasound-guided collections.

Scraping Although FNA and coring are excellent methods for collecting cells from masses that exfoliate well, some types

of tissue are compact and do not readily release cells by these techniques. In these situations a scalpel blade or spatula can be used on the lesion or biopsy specimen to scrape across the surface several times and remove a small portion of the tissue. This fragment is placed on the proximal end of the slide and then spread as thinly as possible over the remainder of the slide by the blade or a second slide. Some tissues, such as tumors of fibrous connective tissue origin, have cellular adhesion characteristics that do not allow the cells to be spread adequately over the slide for cytologic evaluation; for these specimens histopathology is required for definitive diagnosis. For superficial ulcerative lesions such as squamous cell carcinoma (SCC), a scraping may be used to collect cells below the ulcerated surface. In this case representative cells may have been difficult to collect with FNA because of the thin layer of tumor cells that characterizes some SCCs. Scraping collects a large amount of material; however, as with imprints, if the collected cells are too superficial, they may not be representative of the underlying disease process.

Intracavitary Collection FNA and the coring technique can be performed on mass lesions within the thoracic, peritoneal, or pericardial cavities. Differences in technique include the need to clip a small area of hair and perform a surgical preparation of the area. In addition, the animal must be well restrained, and in some cases sedation is necessary. Additional risks may be encountered with intracavitary aspirates. These include hemorrhage, which is usually minor and selflimiting, and the risk of rupturing an abscess or neoplasm that may spill into and contaminate a body cavity. Pneumothorax is an important potential complication when performing lung FNA. Use of small-gauge needles and appropriate patient selection can diminish this risk. Patients that are significantly tachypneic or in respiratory distress have a higher complication rate with this procedure, and fractious animals should be sedated to avoid unnecessary movement. The risk of pneumothorax is small when aspirating cranial mediastinal masses because the lungs are pushed caudally. Lung aspirates are most rewarding with diffuse infiltrative disease or large focal lesions. Many primary lung tumors have necrotic centers; thus recovery of only inflammatory material from a lung mass does not rule out neoplasia. Although intracavitary lesions can be aspirated based on triangulation techniques or mass palpation, ultrasound guidance improves the accuracy of cellular recovery. Blood contamination is a particularly common problem with joint aspirates. The use of small-gauge needles, gentle aspiration with no redirection of the needle, and patience as the viscous fluid is collected are helpful. If the disease process appears multifocal, multiple joints should be aspirated.

Slide Preparation The quality of the slide depends on the number of cells collected and the percentage of cells that remain intact and available for microscopic evaluation. Artifactual cell rupturing and cellular distribution on the slides can be

WEB CHAPTER  28  Collection of Specimens for Cytology

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Web Figure 28-1  Technique for making vertical pull-apart

Web Figure 28-2  Technique for making horizontal pull-apart

affected greatly by the techniques used in slide preparation. Smears should be made immediately after the material has been placed on the slide. If a large amount of material is collected, placing a portion on more than one slide helps avoid preparations that are too thick. Having too much material on a slide initially diminishes greatly the chance of spreading it into a monolayer that easily can be assessed microscopically. Making multiple slides increases the chance of obtaining a diagnostic sample. In addition, material that is placed near the end or edges of a slide may be difficult to bring into focus at different magnifications. The ultimate goal is to have a wellprepared slide with many intact, representative cells. A description of the two most common slide preparation techniques follows.

Most tissues have cells that can withstand some degree of shear force and trauma in preparation without causing widespread cellular disruption. These samples and materials collected by scraping or other thick preparations should be prepared by horizontal pull-apart techniques (Web Figure 28-2). In this case cells are pushed from the needle onto one end of the slide. The second slide is used to smear the cellular material along the length of the first slide in a continuous motion, with the flat surfaces of the slides remaining parallel to one another. In most cases the majority of the cellular material remains with the first slide. One form of a horizontal preparation is the technique used to make a blood smear. A small drop of thin fluid is placed at one end of the slide, while a second slide is pulled backward at a 45-degree angle to touch the drop, which spreads along the surface of contact. The second slide is advanced immediately, spreading the cellular material along the length of the first slide. The advantage of a horizontal preparation is that the cells are spread more thinly over the length of the slide and there is less confusion regarding the spatial relationship of the cells to one another. The most important disadvantage is a greater risk of cellular rupture. After collection of a fluid sample (pleural, pericardial, peritoneal, or joint effusions; transtracheal wash; bronchoalveolar lavage; peritoneal lavage; prostatic or bladder wash), aliquots should be placed immediately in ethylenediaminetetraacetic acid (EDTA) tubes to prevent clotting and appropriately collected for culture and sensitivity testing if indicated. Cytologic smears should be made quickly after fluid collection. Direct smears are made from well-mixed fluid or alternatively from the spun pellet of cells after centrifugation. The slide made from a drop of the fluid or sediment can be prepared vertically, horizontally, or similar to blood smear preparation.

slides. The stained specimen on the right represents a properly prepared vertical pull-apart slide.

Making Smears Cells from lesions or organs deemed fragile can best be prepared using the vertical pull-apart technique (Web Figure 28-1). The cells collected within the needle are pushed onto the center of the first slide. The center of the second slide is placed gently at right angles directly down on the cellular material, which then spreads between the slides. If the material is too thick, gentle compression of the slides may be necessary. With as little rotational motion or shear force as possible, the two slides should be separated vertically; the material is likely to be fairly evenly distributed between the two slides, providing mirror images of the cytology preparation. This technique often is required for fragile tissues such as lymph nodes, and it is particularly useful when lymphoma is suspected because malignant lymphocytes are often even more fragile than healthy normal lymphocytes. A potential negative outcome of preparing a vertical pull-apart slide is that cells are not allowed to separate as well as with other methods and many areas may be too thick to evaluate properly. This can result in particular difficulty in differentiating cells that are truly clustering (epithelial origin) from cells that are simply close together because of the method of slide preparation, thereby leading to confusion regarding the type of tumor represented on the slide.

slides. The stained specimen on the right represents a properly prepared horizontal pull-apart slide.

Fixation and Staining Ideally, when several slides are made, a few should remain unstained in the event that special procedures are required at a later time. The most common cytologic stains used in the practice setting are Romanowsky-type stains such as Diff-Quik and occasionally new methylene blue.

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Although new methylene blue provides wonderful nuclear detail, the visual aesthetics, practicality, and permanence of the Romanowsky-type stains make them the most useful agents for routine cytology. They are inexpensive, easily obtained, and simple to use. These polychromatic stains highlight organisms and cytoplasm well, and nuclear and nucleolar detail is usually adequate for assessing inflammation, neoplasia, and characteristics of malignancy. Smears must first be air dried, which allows the cells to adhere to the slide. With most staining kits there are typically four individual steps. The first is fixation of the cells; lipid droplets from ruptured lipocytes often dissolve in this step. The red and blue stains follow, and then the slides are rinsed. Each manufacturer recommends specific staining procedures, but in general the thinner the smear and the lower the total protein concentration on the slide, the less time required for staining. Conversely, the thicker the preparation and the higher the total protein concentration, the more time the slide needs to remain in contact with the stain. Therefore, based on the perceived cellularity and thickness of the preparation, the clinician must adjust the amount of time used in the staining procedure. Drying the slides is important before evaluating them microscopically with oil immersion lenses. A nail dryer can be modified for use if several slides need to dry simultaneously. The patient and the site of cell collection should be identified clearly on all slides. If cytology specimens are submitted to an outside laboratory, all glass slides should be packaged in such a way that breakage is avoided. Steps should be taken to prevent motion of the slides, even within commercially available slide holders; a box within a box is a common approach. If cytology slides are packaged with samples for histopathology, formalin fumes can inhibit the cells from adequately taking up stain. Ideally two to three air-dried, unfixed slides and two to three stained slides should be submitted to the cytologist for evaluation.

of the sample, making diagnosis more difficult. Using smaller-gauge needles, less aggressive aspiration, or the coring technique can help diminish blood contamination. Poorly stained specimens can result from inadequate staining times or weakened stain from overuse or dilution. The stains may have to be changed at different intervals based on frequency of use and thickness of the specimens. In addition, the stains should be changed when unexpected contaminating organisms or cells appear on slides. It is helpful to have two separate sets of stain available, one for cytology and one for “contaminated” samples, such as ear or fecal swabs. Typically the blue stain and the rinse must be changed most frequently. If a slide must be restained, the clinician should skip the fixative step, dip the slide a few more times in the red and blue stains, and then rinse again. One criticism of Diff-Quik stain is that, because it does not undergo the metachromatic reaction, granules from some mast cell tumors do not stain. The author has found this to be a problem only rarely in the clinical setting. However, if mast cell tumor is suspected, new methylene blue or Giemsa stain can be used to demonstrate the presence of mast cell granules. Cellular collection and slide preparation are the first steps in using cytology as a diagnostic tool; the ability to interpret accurately what is on the slide becomes the next limiting factor. Many clinicians are extremely capable of slide interpretation, and with practice every clinician can continue to improve. One simple method of practicing these skills is to make a cytology preparation each time a biopsy specimen is submitted to the laboratory. When the histopathology report returns, results are compared, and the cytology slide reviewed again. If most cytologies are sent to a diagnostic laboratory for interpretation, developing a good working relationship with the cytologist is critical. The clinician’s role is to provide high-quality specimens with accurate clinical information so that the cytologist has every opportunity to be an effective part of the diagnostic team.

Commonly Encountered Problems The clinician must feel comfortable that the submitted material is representative of the disease process, thus it is important for the individual collecting the material to look at slides before submission to ensure that adequate, representative material has been collected before the patient leaves the hospital. Otherwise, a slide may not contain adequate diagnostic material. Some lesions, particularly mesenchymal tumors, typically do not exfoliate well; the needle can miss the lesion, or an area of central necrosis within a tumor can be aspirated. Making several slides from multiple locations can be helpful in obtaining a representative diagnostic specimen. Excessive blood contamination can dilute tissue cells and cause clotting

References and Suggested Reading Meyer DJ: The acquisition and management of cytology specimens. In Raskin RE, Meyer DJ, editors: Atlas of canine and feline cytology, Philadelphia, 2001, WB Saunders, p 1. Meyer DJ: The essentials of diagnostic cytology in clinical oncology. In Withrow SJ, MacEwen EG, editors: Small animal clinical oncology, ed 3, Philadelphia, 2001, WB Saunders, p 54. Morrison WB, editor: Cancer in dogs and cats: medical and surgical management, Jackson, Wyo, 2002, Teton New Media. Rogers KS, Barton CL, Habron JM: Cytology during surgery, Compend Cont Educ Pract Vet 18:153, 1996. Tyler RD et al: Introduction. In Cowell RL, Tyler RD, Meinkoth JH, editors: Diagnostic cytology and hematology of the dog and cat, St Louis, 1999, Mosby, p 1.

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Nasal Tumors LISA J. FORREST, Madison, Wisconsin

Pathology and Clinical Presentation Tumors of the nasal passage and paranasal sinuses in dogs account for approximately 1% to 2% of all canine neoplasms; the majority are carcinoma (60%) and sarcoma (30%) histologies. Further breakdown of histology includes adenocarcinoma, squamous cell carcinoma, fibrosarcoma, chondrosarcoma, and osteosarcoma. Dolichocephalic breeds and dogs with exposure to indoor coal or kerosene heaters are at increased risk for development of nasal tumors. Most dogs with nasal tumors are middle to older age, with reported median ages of 7.6 to 11.3 years. Nasal tumors generally are locally invasive and slow to metastasize but can metastasize to local lymph nodes (mandibular/retropharyngeal and less often to lung, abdominal organs, bone, and brain). Clinical signs in dogs with nasal tumors include nasal obstruction/ respiratory stridor, sneezing, reverse sneezing, epistaxis, facial deformity, and exophthalmos. Initially signs may respond partially to antibiotics or antiinflammatory treatments because of concurrent inflammation and secondary bacterial infection that are inevitably present. These tumors often are advanced locally when diagnosed, and occasionally patients can present with neurologic signs (seizures, altered mentation, behavior change) secondary to destruction of the cribriform plate and extension into the brain.

Staging and Diagnosis Imaging Thoracic radiographs to evaluate for pulmonary metastases and as a general cardiac and geriatric evaluation should be obtained. Nasal radiographs can be used to image animals with nasal disease and should include the following: 1. Straight lateral to medial view 2. Open-mouth ventrodorsal maxillary view, angled 10 degrees rostral-caudal 3. Intraoral dorsoventral maxillary view 4. Frontal sinus view (rostral-caudal oblique) However, cross-sectional imaging is preferred. Computed tomography (CT) is the most commonly used imaging modality for evaluating dogs and cats with nasal disease, but magnetic resonance imaging (MRI) also is used. Both imaging modalities have advantages and disadvantages in the imaging of nasal disease in cats and dogs. Bone destruction is easier to identify on CT (Web Figure 29-1), and soft tissue changes are delineated better

on MRI. Generally MRI studies are more expensive, and imaging time is longer than CT studies. Because computerbased radiation therapy (RT) plans are generated commonly using CT images, CT may be the preferred imaging modality if RT is contemplated.

Biopsy Biopsy and histology of the nasal tumor are needed for definitive diagnosis. Before the biopsy procedure, additional evaluation should include complete blood count and blood chemistry along with a clotting profile. Fineneedle aspiration cytology of mandibular lymph nodes also should be performed as part of tumor staging and sometimes can yield a diagnosis in cases with lymph node metastasis. A transnostril biopsy using a closed-suction technique, a bone curette, or cup-type biopsy forceps should be performed under general anesthesia to collect a sample. Whenever a transnostril biopsy technique is used, the biopsy instrument is measured and marked to penetrate no farther than the distance from the tip of the nose to the medial canthus of the eye. This prevents penetration of the cribriform plate. A minimally invasive diagnostic and potentially therapeutic high-pressure saline hydropulsion technique also has been proposed recently. Tumor tissue generally is white; mild-to-moderate hemorrhage is expected and usually subsides within a few minutes. Cytology of nasal swabs or expectorated material is rarely rewarding. Some large nasal tumors protrude into the nasopharynx and can be sampled using retrograde rhinoscopy. When obtaining biopsy samples with smaller endoscopic instruments, clinicians also risk sampling the surrounding inflammation instead of the tumor.

Treatment and Prognosis A variety of treatments for nasal tumors are reported in the literature, including RT, surgery, cryosurgery, chemotherapy, or a combination of these modalities. Unfortunately long-term survival for dogs with nasal tumors generally has been poor, with median survival times ranging from 5 to 23 months, depending on the treatment used. Generally surgery is considered ineffectual as a sole treatment modality. The median survival after diagnosis with no treatment is 3 to 6 months. A recent study retrospectively examined pretreatment CT scans of 94 dogs from four institutions treated with curative RT. Histology and a modified CT staging system were significantly prognostic for disease-free and overall survival times. Anaplastic, squamous cell, and undifferentiated e157

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L

Web Figure 29-1  Postcontrast computed tomographic (CT)

Web Figure 29-2  Postcontrast administration CT axial slice at

carcinoma histologies had a shorter survival time (4.4 months) as compared with all sarcomas (10.6 months). Regarding CT staging, dogs with unilateral intranasal involvement without bony destruction beyond the turbinates had the longest median survival (23.4 months) and dogs with CT evidence of cribriform plate lysis (Web Figure 29-2) had the shortest median survival (6.7 months). At this time, external-beam RT alone (see Chapter 74) or in combination with surgery or chemotherapy is the most effective treatment available. The clinician is encouraged to speak with a radiation oncologist or oncologist with experience in managing nasal tumors. The close proximity of the eyes to the nasal cavity has resulted in unavoidable acute and late toxicity of RT to ocular structures. Most dogs develop keratoconjunctivitis sicca (KCS) and cataracts in at least one eye. Dogs also may develop retinal hemorrhage and corneal ulcers. Chronic ocular toxicities are seen in approximately 45% of dogs. Lowerenergy orthovoltage RT has been used alone and after surgical exenteration of the nasal tumor with reported survival times of 7.4 to 23 months, respectively. Currently megavoltage external-beam RT, delivered via linear accelerator or cobalt machines, is used commonly to treat nasal tumors, with reported median survival times of 5.9 to 23 months. The course of treatment varies among institutions and practices; treatments can be delivered on a daily Monday-to-Friday schedule for 2 to 4 weeks or on a Monday, Wednesday, Friday schedule for 4 to 6 weeks. Increased survival times were recently reported in a retrospective, multiinstitutional study of dogs with intranasal sarcomas treated with curative intent using daily (Monday-Friday) treatment protocols.

Recent use of intensity-modulated radiation therapy (IMRT) available with modern linear accelerators and Helical TomoTherapy (HT) has resulted in decreased ocular side effects because of the ability to avoid ocular structures. With increased accuracy using IMRT, improved immobilization techniques and image-guided radiotherapy (IGRT) become essential. Use of megavoltage CT and cone-beam CT for IGRT has identified a need for rigid fixation of the head to accurately deliver repeated radiotherapy treatments to nasal tumors. Cisplatin and other chemotherapy agents have been used in some dogs with nasal tumors because of their radiosensitizing properties. A study of 51 dogs treated with external-beam RT in combination with slow-release cisplatin chemotherapy reported a median survival time of 15.8 months. A small study of eight dogs receiving chemotherapy alone reported a good outcome using a protocol of alternating doses of doxorubicin, carboplatin, and oral piroxicam. Use of an accelerated fractionated RT protocol (4.2 Gy × 10 fractions = 42 Gy) results in similar median survival times of 14 to 19 months, compared with more conventional fractionation schemes. Surgical exenteration after accelerated RT increased overall survival to 47.7 months in a small study of 13 dogs; however, the dogs reported in this study had significant morbidity associated with surgery; 69% of dogs had rhinitis, 31% had osteomyelitis, and 20% had significant hemorrhage during surgery that required a transfusion. Attempts at increasing the RT dose to the tumor by using a boost technique (additional dose delivered to a smaller tumor volume) resulted in increased normal tissue morbidity and no improvement in tumor

axial slice at the level of the eyes of an 8-year-old field spaniel dog with a right-sided nasal adenocarcinoma. Note the soft tissue attenuating material (tumor) in the right nasal cavity. Tumor destruction of the right maxilla (black arrow) with tumor extension into the right retrobulbar space is present.

the level of the rostral brain of the same dog as in Web Figure 29-1. Note the brain contrast enhancement of the right olfactory lobe (black arrow) and deviation of the falx cerebri to the left (black arrowhead). This indicates tumor mass extension into the brain, which is prognostic for a short disease-free interval and overall survival.

WEB CHAPTER  29  Nasal Tumors control. Increasing total tumor dose using advanced linear accelerator modalities may be possible without increasing normal tissue toxicity.

Feline Tumors Nasal lymphoma is the most common nasal tumor in the cat followed by carcinoma and least often sarcoma. Clinical signs in cats include nasal discharge, dyspnea, epistaxis, stertor, facial deformity, and anorexia. Nasal lymphoma often extends into the nasopharynx. Treatment approaches for cats with nasal lymphoma include external-beam RT alone, chemotherapy alone, or combination RT and chemotherapy; a recent study reported no difference in survival times among the three treatment options. As with dogs, treatment of choice for nasal carcinoma and sarcomas is external-beam RT. Many cats with nasal lymphoma eventually have systemic spread of disease, although long-term local disease control often is reported after local therapy alone.

Future Directions There is clearly room for advancement in the treatment of tumors of the nasal and paranasal sinuses. Use of CT and MRI has improved the ability to delineate tumors accurately. The use of three-dimensional computerized treatment plans also has increased the accuracy of delivered RT dose. More and more radiation oncology centers are installing linear accelerators with multileaf collimators, allowing the radiation oncologist to shape the treatment beam to the tumor and avoid critical ocular tissues. A multileaf collimator and appropriate software allow intensity-modulated radiotherapy (IMRT), in which the treatment beam intensity and the treatment field shape can be conformed. HT, which is image-guided IMRT, was used in a trial of 31 dogs in which the goal was to treat the nasal tumor and avoid ocular structures. None of the dogs experienced significant ocular side effects, and all dogs were visual with no signs of KCS or other uncomfortable ocular toxicity. Tumor response in the trial is similar

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to that previously reported. Currently, HT with the addition of a simultaneously integrated boost (SIB) to the gross tumor volume is being investigated. In addition, this study is using PET/CT molecular imaging of tumor proliferation and hypoxia (known markers of radioresistance) as potential regions for SIB to individualize RT protocols. These results indicate the future of treating canine nasal tumors lies with IMRT technology, early diagnosis, and potentially molecular imaging in the form of PET/CT.

References and Suggested Reading Adams WM et al: Prognostic significance of tumor histology and computed tomographic staging for radiation treatment response of canine nasal tumors, Vet Radiol Ultrasound 50:330, 2009. Ashbaugh EA et al: Nasal hydropulsion: a novel tumor biopsy technique, J Am Anim Hosp Assoc 47:312, 2011. Drees R, Forrest LJ, Chappell R: Comparison of computed tomography and magnetic resonance imaging for the evaluation of canine intranasal neoplasia, J Small Anim Pract 50:334, 2009. Gutiérrez AN et al: Radiobiological and treatment planning study of a simultaneously integrated boost for canine nasal tumors using helical tomotherapy, Vet Radiol Ultrasound 48:594, 2007. Haney SM et al: Survival analysis of 97 cats with nasal lymphoma: a multi-institutional retrospective study (1986-2006), J Vet Intern Med 23:287, 2009. Kubicek LN et al: Helical tomotherapy setup variations in canine nasal tumor patients immobilized with a bite block, Vet Radiol Ultrasound 53:474, 2012. Langova V et al: Treatment of eight dogs with nasal tumours with alternating doses of doxorubicin and carboplatin in conjunction with oral piroxicam, Aust Vet J 82:676, 2004. Lawrence JA et al: Proof of principle of ocular sparing in dogs with sinonasal tumors treated with intensity-modulated radiation therapy, Vet Radiol Ultrasound 51:561, 2010. Sones E et al: Survival times for canine intranasal sarcomas treated with radiation therapy: 86 cases (1996-2011), Vet Radiol Ultrasound 54:194, 2013. Turek MM, Lana SE: Tumors of the respiratory system—canine nasosinal tumors. In Withrow SJ, Vail DM, Page RL editors: Withrow & MacEwan’s small animal clinical oncology, ed 5, Philadelphia, 2013, Saunders, p 435.

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Nonregenerative Anemias DOUGLAS J. WEISS, St. Paul, Minnesota

Evaluation of Nonregenerative Anemias Nonregenerative anemias are caused by a variety of primary and secondary disease processes that must be differentiated before determining a prognosis or instituting a therapeutic plan. A diagnostic plan for evaluation of anemic disorders is outlined in Web Box 30-1. Initial evaluation of the animal should include a careful history to exclude drug or toxin exposure that may have caused the hematologic dyscrasia. Initial evaluation of the anemia should include a complete blood count, blood smear examination, and reticulocyte count. In addition, immune-mediated and infectious causes of anemia should be evaluated with appropriate diagnostic testing. Mild-to-moderate nonregenerative anemias (packed cell volume [PCV] 20% to 37% in dogs and 14% to 26% in cats) frequently occur secondary to inflammatory neoplastic, renal, hepatic, and certain endocrine disorders. Appropriate testing should be performed to detect these conditions. If a definitive diagnosis is not achieved based on the initial evaluation, bone marrow aspiration cytology and core biopsy are indicated. The combination of bone marrow aspiration cytology and core biopsy is essential to evaluate fully cytologic details and histopathologic alterations. Bone marrow evaluation may result in a clinical diagnosis (e.g., acute myelogenous leukemia, myelodysplastic syndrome). In these situations, treatment usually can be pursued without further diagnostic evaluation. Other bone marrow reports may provide only a pathologic diagnosis (e.g., aplastic anemia, myelofibrosis, myelonecrosis). Each of these pathologic diagnoses have multiple causes, and additional testing is needed to define the underlying cause and establish an approach to treatment and a prognosis. For example, myelofibrosis can be caused by immune-mediated hemolytic anemia, systemic bacterial infections, endotoxemia, drug-induced bone marrow toxicity, and malignant neoplasia.

Drug-Induced Hematologic Dyscrasias A growing number of drugs are associated with hematologic disorders in animals. Some drugs, most notably chemotherapeutic agents and oxidant compounds, cause dose-dependent hematologic disorders (type A adverse drug reactions) frequently at or near the therapeutic doses. Other drugs induce idiosyncratic hematologic dyscrasias (type B adverse drug reactions). The most frequent types of idiosyncratic hematologic drug reactions are immune-mediated hematologic reactions and toxic injury to bone marrow. Drugs most frequently reported to e160

induce hematologic dyscrasias include chemotherapeutic agents (dog, cat), estrogenic compounds (dogs), phenylbutazone (dog), acetaminophen (dog, cat), trimethoprim/ sulfadiazine (dog), phenobarbital (dogs), azathioprine (dog, cat), propylthiouracil (cats), methimazole (cats), and griseofulvin (cat). Other drugs associated with hematologic dyscrasias include phenacetin (dog), benzocaine (dog, cat), propofol (cat), methylene blue (dog, cat), diphenylhydrazine (dog) DL-methionine (cat), phenazopyridine (cat), cephalosporins (dog), carprofen (dog), chloramphenicol (dog), primidone (dog), naproxen (dog), phenytoin (dog), metronidazole (dog), levamisole (dog), albendazole (dog, cat), fenbendazole (dog), thiacetarsamide (dog), amiodarone (dog), captopril (dog), quinidine (dog), colchicine (dog), and mitotane (dog).

Hematologic Disorders Secondary to Other Disease Processes Inflammatory diseases are accompanied consistently by a mild-to-moderate normocytic, normochromic, nonregenerative anemia, a condition termed anemia of inflammatory disease (AID). The hematocrit drops within the first few days to weeks after onset of inflammation and then stabilizes. Anemia also frequently accompanies large or metastatic malignancies. Multiple causes of anemia may be involved, including AID and acute or chronic blood loss. Chronic blood loss can cause iron deficiency that further impairs erythropoiesis. Microangiopathic hemolytic anemia can result from damage to vascular endothelium or from fibrin deposition within the vessels. The hallmark of this process is the presence of schistocytes and keratocytes in the blood of affected animals. In most animals with AID the anemia is mild and does not require treatment. The anemia usually resolves with successful treatment of the underlying disease. The anemia is, however, responsive to erythropoietin (EPO) therapy. Chronic renal disease/renal failure consistently results in normocytic, normochromic, nonregenerative anemia. The anemia, although complex, is primarily the result of decreased EPO production by the kidney. Although the anemia is initially mild to moderate in severity, it can become severe in the late stages of the disease. AID associated with canine and feline chronic renal failure is responsive to EPO replacement therapy. A side effect of administration of recombinant human EPO is bone marrow erythroid hypoplasia or pure red cell aplasia due to development of antibodies against the recombinant EPO that neutralizes the animals’ own EPO. Speciesspecific recombinant EPO should be used if it is available.

WEB CHAPTER  30  Nonregenerative Anemias

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WEB BOX 30-1  Diagnostic Approach to Evaluation of Nonregenerative Anemias and Multiple Cytopenias Initial Evaluation Establish the presence and severity of anemia and provide some differential diagnoses 1. Complete blood count 2. Blood smear examination 3. Reticulocyte count Evaluate history for drug-induced hematologic disorders Test for diseases causing secondary suppression of erythropoiesis (based on clinical signs) 1. Infectious/inflammatory diseases (dog, cat) 2. Neoplasia (dog, cat) 3. Chronic renal disease (dog, cat) 4. Chronic liver disease (dog, cat) 5. Hypothyroidism (dog, cat) 6. Hypoadrenocorticism (dog, cat) Test for infectious diseases (choose tests appropriate to patient) 1. Ehrlichia canis (dog) 2. Anaplasma phagocytophilum (dog) 3. Parvovirus (dog, cat) 4. Feline leukemia virus (cat) 5. Feline immunodeficiency virus (cat) 6. Leishmania spp. (dog) Test for immune-mediated diseases (when indicated) 1. Direct Coombs’ test 2. Antinuclear antibody test

Infectious Diseases Ehrlichia and Anaplasma Species Infections Acute monocytic ehrlichiosis and granulocytic ehrlichiosis are well-recognized disease conditions in dogs but also have been identified in cats. In dogs, thrombocytopenia and mild to moderate nonregenerative anemia are the most consistent hematologic alterations. Although dogs with granulocytic ehrlichiosis readily respond to doxycycline therapy, dogs with monocytic ehrlichiosis frequently develop subclinical and chronic phases of the disease after an initial response to doxycycline. In chronic canine monocytic ehrlichiosis, pancytopenia is the result of decreased bone marrow production. In feline monocytic ehrlichiosis, nonregenerative anemia is a consistent finding, with neutropenia and thrombocytopenia present in some cats. Because some Ehrlichia-infected cats test

Secondary Evaluation Bone marrow aspirate and core biopsy: provides a pathologic diagnosis and possible causes and may provide a clinical diagnosis 1. Erythroid hypoplasia w/o polychromasia a. Nonregenerative IMHA (dog) 2. Erythroid maturation arrest a. Nonregenerative IMHA (dog) 3. Pure red cell aplasia a. Nonregenerative IMHA (dog, cat) b. FeLV (cat) 4. Myelonecrosis a. Drugs (dog, cat) b. Nonregenerative IMHA (dog, cat) c. Sepsis (dog, cat) d. Neoplasia (dog, cat) e. Myelodysplastic syndromes (cat) 5. Aplastic anemia a. Drugs (dog, cat) b. Parvovirus infection (dog, cat) c. Ehrlichia canis infection (dog) d. Idiopathic (dog, cat) 6. Myelofibrosis a. Nonregenerative IMHA (dog, cat) b. Neoplasia (dog, cat) c. Drugs (dog, cat) d. Myelodysplastic syndromes (cat) e. Infectious disease (cat) 7. Acute inflammation a. Nonregenerative IMHA (dog, cat) b. Sepsis/systemic fungal diseases (dog, cat) 8. Hemophagocytic syndrome a. Nonregenerative IMHA (dog) b. Infectious diseases (dog) c. Lymphoma/myelodysplastic syndromes (dog, cat) d. Idiopathic (dog) 9. Myelodysplastic syndromes (dog, cat) 10. Acute leukemia (dog, cat) 11. Chronic leukemia (dog, cat) 12. Lymphoma (dog, cat) 13. Multiple myeloma (dog, cat) 14. Malignant histiocytosis (dog, cat)

positive for antinuclear antibodies, feline ehrlichiosis can be confused with immune-mediated disease processes. A polymerase chain reaction test is available for detection of ehrlichiosis.

Parvovirus Infection Parvovirus invades and destroys rapidly proliferating cells, including intestinal epithelium and bone marrow precursor cells. This results in diarrhea and panleukopenia. Bone marrow injury also can occur secondary to septicemia or endotoxemia. The bone marrow is characterized by severe degenerative changes in hematopoietic precursor cells, multifocal areas of necrosis, and many phagocytic macrophages. Broad-spectrum antibiotic therapy and supportive care is essential to recovery. Hematologic recovery is usually rapid if the animals survive the secondary bacterial infection.

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Feline Leukemia Virus Infection In cats infected with feline leukemia virus (FeLV), anemia and granulocytopenia frequently develop early and predispose the animal to bacterial infections. The anemia is frequently macrocytic and nonregenerative. Either thrombocytosis with increased mean platelet volume or thrombocytopenia can be seen. Bone marrow of infected cats is characterized by granulocyte hypoplasia or by a maturation arrest at the myelocyte or metamyelocyte stage. Other hematologic dyscrasias documented in FeLV-infected cats include hemolytic anemia, pure red cell aplasia (PRCA), aplastic anemia, and myelofibrosis. Recombinant EPO has been used to treat severe nonregenerative anemias.

Feline Immunodeficiency Virus Infection Cats infected with feline immunodeficiency virus (FIV) have transient neutropenia and persistent lymphopenia. Thrombocytopenia is a less frequent finding. Bone marrow alterations in symptomatic cats include granulocyte and erythroid hyperplasia and dysplastic changes in erythroid and megakaryocyte cell lines. When coinfected with FeLV, FIV-infected cats are frequently anemic and leukopenic. Recombinant EPO has been used to treat severe nonregenerative anemias, but recombinant granulocyte colony-stimulating factor is not recommended because it leads to an increase in viral load.

Nonregenerative Immune-Mediated Anemias and Pure Red Cell Aplasia Several studies indicate that a high percentage of dogs and cats with immune-mediated hemolytic anemia (IMHA) have a nonregenerative anemia when initially diagnosed. Associated bone marrow changes vary considerably. Some dogs and cats have erythroid hyperplasia with few polychromatophilic erythrocytes, whereas others have erythroid maturation arrest, or pure red cell aplasia (PRCA). In addition, dysmyelopoiesis, myelofibrosis, myelonecrosis, or acute inflammation may be present. Plasma cell hyperplasia is a consistent finding in dog bone marrow, and lymphocytosis is a frequent finding in cat bone marrow. Diagnosis of nonregenerative IMHA can be problematic. If the diagnosis is restricted to detection of a positive direct Coombs’ test, spherocytosis, or autoagglutination, many cases of nonregenerative IMHA may be missed. Therefore IMHA sometimes becomes a diagnosis of exclusion. Differential diagnosis in cats includes FeLV and FIV infections, feline infectious peritonitis, feline infectious anemia, drugs/toxins, and myelodysplastic syndromes. In dogs, ehrlichiosis, babesiosis, leishmaniasis, and drugs or toxins should be excluded. Bone marrow evaluation provides important clues to the diagnosis of nonregenerative IMHA. Increased mature plasma cells in bone marrow of dogs and increased small lymphocytes in bone marrow of cats are consistently present. Erythroid hyperplasia without a corresponding increase in reticulocytes in bone marrow or a maturation arrest in the erythroid series also may be seen. Erythrophagocytosis is another clue of antibody-coated erythroid cells. Finally, pathologic changes in bone marrow, including

myelofibrosis, necrosis, acute inflammation, and hemorrhage may be seen. PRCA is defined as the presence of a severe nonregenerative, normocytic, normochromic anemia and a marked erythroid hypoplasia or aplasia in bone marrow. Total leukocyte and platelet counts are within or above reference intervals. It occurs in dogs and cats and is thought to result from an immune response that attacks early erythroid precursor cells in the bone marrow. However, in cats PRCA also can be caused by FeLV subgroup C infection. In cats the percentage of lymphocytes in bone marrow invariably is increased, and a slight lymphocytosis may be present in the blood. The approach to treatment of nonregenerative IMHA and PRCA is similar to that of regenerative IMHA. In the author’s experience, the response to treatment in dogs and cats is similar whether the initial anemia is regenerative or nonregenerative. The treatment response for dogs and cats with nonregenerative IMHA is not as good for those with underlying bone marrow pathology (i.e., myelofibrosis, necrosis, acute inflammation, hemorrhage) compared with those without bone marrow pathology. Prednisone (2.2 to 4.4 mg/kg q24h PO as a single or divided dose in dogs) has been the mainstay in treatment of IMHA. Because of the high rate of thromboembolism and evidence of circulating activated platelets in dogs, ultra-low–dose aspirin (0.5 mg/kg q24h PO) is recommended for all patients. In dogs, concurrent azathioprine therapy (2 mg/kg q24h PO tapering to 0.5 to 1 mg/kg q48h) has resulted in improved survival times).

Aplastic Anemia Aplastic anemia is defined as the presence of a bicytopenia or pancytopenia in the blood and a marrow in which more than 95% of the hematopoietic space is occupied by adipose tissue. Causes of aplastic anemia in dogs include infectious agents (Ehrlichia canis, parvovirus), drug toxicities (estrogen, phenylbutazone, trimethoprimsulfadiazine, quinidine, chemotherapeutic agents, thiacetarsemide, albendazole, captopril, griseofulvin), ionizing radiation, and idiopathic causes. Dogs with idiopathic aplastic anemia are usually less than 3 years old. The anemia is moderate to severe, and neutropenia and thrombocytopenia are usually severe. Although the prognosis for idiopathic aplastic anemia is guarded to poor, some dogs recover with supportive care. No specific therapy short of bone marrow transplantation is available at this time. Disease conditions associated with aplastic anemia in cats include chronic renal failure, FeLV infection, and methimazole and griseofulvin toxicities. Idiopathic aplastic anemia also occurs in cats. In some cats starvation may play a role in the development of marrow aplasia.

Myelonecrosis Myelonecrosis in the dog consists of focal or multifocal areas of coagulative necrosis or individual cell necrosis. In cats, individual cell necrosis is seen, but coagulative necrosis rarely is seen. Chronic necrosis frequently is accompanied by variable degrees of myelofibrosis. Associated disease conditions in dogs include sepsis, lymphoma,

WEB CHAPTER  30  Nonregenerative Anemias IMHA, systemic lupus erythematosus, and drug toxicities. Drug treatments associated with bone marrow necrosis include phenobarbital, carprofen, metronidazole, mitotane, cyclophosphamide, vincristine, colchicine, and fenbendazole. Although there is no specific treatment for canine myelonecrosis, the prognosis appears to be good, with complete hematologic recovery seen in most cases. Diseases associated with myelonecrosis in cats include nonregenerative IMHA, FeLV infection, myelodysplastic syndromes, and acute leukemia. The prognosis for myelonecrosis in cats depends on the associated disease process.

Secondary Myelofibrosis Myelofibrosis is defined as proliferation of fibroblasts, collagen, or reticulin fibers in bone marrow. Myelofibrosis (i.e., secondary myelofibrosis) occurs most frequently secondary to bone marrow injury. Therefore it is a frequent sequela of myelonecrosis. Myelofibrosis also occurs as a rare chronic myeloproliferative condition termed idiopathic myelofibrosis. In dogs secondary myelofibrosis is associated with IMHA; neoplasia; and drug treatments, including phenobarbital, phenytoin, phenylbutazone, and colchicine. Diseases associated with secondary myelofibrosis in cats include IMHA, myelodysplastic syndromes, and acute myelogenous leukemia. The most frequent hematologic finding in dogs and cats is moderate-tosevere nonregenerative anemia, with relatively few animals neutropenic or thrombocytopenic. Other frequent blood findings in dogs included ovalocytosis, dacryocytosis, and metarubricytosis. No specific treatment for myelofibrosis is available. Identifying and treating the underlying cause of the fibrosis is essential. Although the prognosis for secondary myelofibrosis is guarded, approximately half of affected dogs in one study recovered.

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histiocytosis). General criteria for diagnosis of hemophagocytic syndrome include the presence of bicytopenia or pancytopenia in the blood and greater than 2% benignappearing hemophagocytic macrophages in bone marrow. Cases that have concurrent myelonecrosis, myelofibrosis, or marrow inflammation should be excluded because the hemophagocytic macrophages are probably the result of these conditions and not a primary disorder. Disease conditions associated with hemophagocytic syndrome in dogs include IMHA, systemic lupus erythematosus, sepsis, E. canis infection, blastomycosis, lymphoma, and myelodysplastic syndromes. Approximately 20% of canine cases are idiopathic. These cases are characterized by acute onset of weakness, lethargy, fever, and splenomegaly. Survival appears to depend on the associated disease condition. Records from the University of Minnesota Veterinary Medical Center indicate that nine of nine dogs with immune-associated hemophagocytic syndrome died within 1 month, whereas four of five dogs with infectionassociated hemophagocytic syndrome survived. Therapy of hemophagocytic syndrome in dogs should be directed at treating associated disease conditions and administering immunosuppressive doses of prednisone (2.2 to 4.4 mg/kg q24h PO as a single or divided dose) to suppress macrophage activity.

Dysmyelopoiesis Dysmyelopoiesis is defined as a hematologic disorder characterized by the presence of morphologic abnormalities (i.e., dysplasia) in one or more hematologic cell lines in the blood or bone marrow. Dysmyelopoiesis has been classified in several ways but has been divided most recently into myelodysplastic syndromes (MDSs), secondary dysmyelopoiesis, and congenital dysmyelopoiesis. Myelodysplastic syndromes are discussed here.

Inflammation

Myelodysplastic Syndromes

Acute (i.e., purulent), pyogranulomatous, and granulomatous inflammation have been documented in bone marrow. Acute inflammatory lesions are the most frequent and have been associated with nonregenerative IMHA, bacterial sepsis, and feline infectious peritonitis. Some affected dogs have a history of acute onset of lameness or bone pain. Neutrophilia, left shift, and toxic change may be seen in the blood. Bone marrow core biopsies are characterized by dilation of sinusoids, fibrin deposits, multifocal accumulations of neutrophils, and necrosis. Affected dogs and cats tend to have moderateto-severe anemia. Pyogranulomatous inflammation has been observed in dogs and cats with disseminated histoplasmosis, and anemia may be prominent in some animals. Granulomatous inflammation has been seen in dogs with systemic fungal infections. Approach to treatment of inflammatory bone marrow disorders is based on treatment of the associated disease condition.

MDSs are acquired clonal proliferative disorders that result from genetic mutations in hematopoietic stem cells. Differentiating MDS from acute leukemia is based on the percentage of myeloblasts in the bone marrow. Under the current World Health Organization (WHO) classification system, leukemias are classified as having more than 20% myeloblasts, and MDS as fewer than 20% myeloblasts. In dogs, two major categories should be differentiated because they have therapeutic and prognostic significance. According to the WHO classification system these are termed refractory anemia and refractory anemia with excess blasts (other minor types of MDS are not discussed). Refractory anemia has less than 6% myeloblasts, whereas refractory anemia with excess blasts has 6% to 20% myeloblasts. Hematologic alterations in dogs with refractory anemia consist of moderate-to-severe normocytic, normochromic, nonregenerative anemia. Dysplastic features in bone marrow usually are restricted to the erythroid series. Dogs with refractory anemia tend to be less severely ill when initially evaluated, tend to have substantially better response to supportive therapy, and have much longer survival times when compared with refractory anemia with excess blasts. The anemia in dogs with refractory

Hemophagocytic Syndrome Hemophagocytic syndrome is a benign proliferative disorder of macrophages and must be differentiated from a malignant proliferation of histiocytes (i.e., malignant

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anemia frequently is responsive to EPO therapy (50 to 2000 units/kg subcutaneously three times/week). Dogs with refractory anemia with excess blasts have bicytopenia or pancytopenia. Bone marrow has dysplastic features in all cell lines and 6% to 20% myeloblasts. Survival time is usually short. Treatment is mostly supportive. Recombinant EPO and other hematopoietic growth factors have been used, but they do not appear to prolong survival. Chemotherapeutic agents, including hydroxyurea, low-dose cytosine arabinoside, and low-dose aclarubicin, have been tried with limited success. Major categories of MDS in cats include refractory cytopenia with multilineage dysplasia and refractory anemia with excess blasts. Cats with refractory cytopenias with multilineage dysplasia may have a macrocytic normochromic anemia, and many are pancytopenic. The presence of metarubricytosis and autoagglutination is a frequent finding in blood smears of these cats, making them easily confused with IMHA. Dysplastic features frequently are present in all cell lines in the bone marrow. Some cats respond to symptomatic therapy and have prolonged survival. Therapy usually involves steroidal and nonsteroidal immunosuppression (e.g., prednisone, cytarabine, cyclosporin A). Refractory anemia with excess blasts in cats is characterized by multiple cytopenias in the blood, dysplastic features in all cell lines, and 6% to 20% myeloblasts in bone marrow. Affected cats tend to be severely ill when initially presented, and survival presently varies from a few days to a few months. Therapeutic options are limited to supportive care and steroidal and nonsteroidal immunosuppressive therapy.

Bone Marrow Neoplasia Leukemia Most dogs and cats with acute and chronic leukemias have a nonregenerative anemia at the time of diagnosis, and some are thrombocytopenic. If leukemic cells extensively displace normal hematopoietic cells in the bone marrow (myelophthisis), pancytopenia can develop. Approximately half of acute leukemias diagnosed at the University of Minnesota are “aleukemic” (i.e., do not have circulating malignant cells); therefore bone marrow evaluation is critical to establish a diagnosis. Alternatively, chronic leukemias usually have moderate-tomarked leukocytosis at the time of diagnosis.

Lymphoma Unlike in cats, lymphoma is the most frequently diagnosed neoplastic condition in canine bone marrow. Disseminated lymphoma must be differentiated from acute lymphoblastic leukemia. Animals with lymphoma typically have lymphoblasts in multiple lymph nodes or organs, relatively low numbers of lymphoblasts in the blood, and lack of severe cytopenias. The most consistent hematologic finding in disseminated lymphosarcoma is a

mild-to-moderate nonregenerative anemia (see the previous edition of Current Veterinary Therapy, Chapter 72).

Multiple Myeloma Multiple myeloma is the second most frequently diagnosed neoplastic condition in the bone marrow of dogs and cats. Diagnosis of multiple myeloma depends on finding large numbers of atypical plasma cells in bone marrow with or without the presence of hypercalcemia, osteolytic lesions, monoclonal gammopathy, or lightchain proteinuria. Features most helpful in differentiating malignant plasma cells from reactive plasma cell hyperplasia include anisocytosis, anisokaryosis, high nuclearto-cytoplasmic ratio, binucleation, and clustering of plasma cells. These anaplastic features are important in differentiating multiple myeloma from plasma cell hyperplasia associated with immune-mediated diseases, ehrlichiosis, or feline infectious peritonitis infection. Dogs and cats with multiple myeloma frequently have a nonregenerative anemia and may be concurrently thrombocytopenic or neutropenic.

Malignant Histiocytosis Malignant histiocytosis (also called disseminated histiocytic sarcoma) appears to occur relatively frequently in dogs with distinct breed predilections but is diagnosed infrequently in cats. Organs frequently involved include the liver, spleen, lungs, and bone marrow. Affected dogs can have multiple cytopenias, whereas cats may be only anemic. Dogs and cats have large numbers of histiocytic cells in bone marrow, but features of malignancy are variable. Features of malignant histiocytosis that are useful in differentiating it from hemophagocytic syndrome include greater than 30% histiocytic cells in bone marrow, high nuclear-to-cytoplasmic ratio, and multinuclearity. In addition, malignant histiocytosis rarely is confined to the bone marrow. At present disease progression is usually rapid, and disease outcome is invariably fatal.

References and Suggested Reading Harvey JW: Canine bone marrow, normal hematopoiesis, biopsy techniques, and cell identification and evaluation, Compend Contin Educ Pract Vet 6:909, 1984. Kohn B et al: Primary immune-mediated hemolytic anemia in 19 cats: diagnosis, therapy, and outcome (1998-2004), J Vet Intern Med 20:159, 2006. Stokol T, Blue JT: Pure red cell aplasia in cats: 9 cases (1987-1997), J Am Vet Med Assoc 214:75, 1999. Stokol T, Blue JT, French TW: Idiopathic pure red cell aplasia and nonregenerative immune-mediated anemia in dogs: 43 cases (1988-1999), J Am Vet Med Assoc 216:1429, 2000. Weiss DJ: A retrospective study of the incidence and classification of bone marrow disorders in cats (1996-2004), Comp Clin Pathol 14:179, 2006. Weiss DJ: A retrospective study of the incidence and classification of canine bone marrow disorders (1996-2004), J Vet Intern Med 20:955, 2006. Weiss DJ: Bone marrow pathology in dogs and cats with nonregenerative immune-mediated haemolytic anaemia and pure red cell aplasia, J Compar Pathol 138:46, 2008.

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Pulmonary Neoplasia KEVIN A. HAHN, Topeka, Kansas SANDRA M. AXIAK-BECHTEL, Columbia, Missouri

Lung Pathology and Natural Behavior The incidence of primary lung tumors in the dog and cat is low. The majority of tumors are malignant, and the most frequently reported tumor type is adenocarcinoma in the dog and cat. The average age at presentation is 9 to 10 years in dogs and 11 to 12 years in cats. Primary lung tumor has no breed or sex predisposition and no proven cause. Clinical signs tend to occur late in disease and vary at presentation. Often a chronic nonproductive cough is present; however, lung tumors may be diagnosed incidentally during radiography for another indication. Other signs include lethargy, dyspnea, weight loss, and tachypnea. Lameness can be seen in cats with musculoskeletal metastasis (lung-digit syndrome seen with pulmonary adenocarcinoma, bronchial carcinoma, and squamous cell carcinoma), and in dogs with hypertrophic osteopathy (rare in the cat).

Diagnostic Approach Thoracic radiographs are the most important diagnostic test. Common findings are soft tissue density mass(es) (discrete or ill defined); lobar consolidation; and diffuse interstitial, alveolar, peribronchial, or mixed patterns. The appearance of pulmonary neoplasia in cats can vary dramatically, ranging from solitary, possibly cavitated lesions to diffuse mixed patterns. Differential diagnoses for discrete soft tissue opacity masses are abscess, hematoma, cyst, and granuloma; for other patterns they are pneumonia, metastasis, hemorrhage, edema, and fibrosis. Thoracic ultrasonography and cytologic examination of needle aspirates, pleural fluid, or bronchoalveolar lavage washes can aid in diagnosis. However, the sensitivity of detecting neoplasia in pleural effusions is as low as 60% in the dog and cat. Biopsy may be required for definitive diagnosis (Hirschberger et al, 1999). Computed tomography (CT) may be used to better determine the extent of disease before surgery if this information would alter the owner’s decision regarding treatment (Paoloni et al, 2006).

Treatment and Prognosis Surgical removal is the preferred treatment for primary lung tumors. Reported median survival times after lung lobectomy are in the 10- to 13-month range. Positive prognostic indicators are absence of clinical signs at

presentation, solitary nodule, peripheral location, and size of less than 5 cm in diameter. Negative prognostic indicators are lymph node involvement, more than one nodule, central location, size greater than 5 cm in diameter, and high histologic grade (Hahn and McEntee, 1998: McNiel et al, 1997). Small case series of chemotherapy with vindesine/cisplatin or vinorelbine have been reported in dogs, with antitumor activity observed with both protocols (Mehlhaff et al, 1984; Poirier et al, 2004). Radiation therapy for solitary lung masses has not been reported in veterinary medicine. Hypertrophic osteopathy in dogs, if present, usually resolves after removal of the primary mass. No information regarding the efficacy of postoperative chemotherapy for dogs or cats with lung tumors is available, although this treatment may be considered in patients with “high-risk” disease.

Pleural Space Pathology and Natural Behavior Primary cancer of the pleura is called mesothelioma. Exposure to asbestos, especially amphibole fibers (long and thin), is considered a risk factor in humans. The mechanism by which it causes malignant transformation is unknown. Mesothelioma is highly metastatic and can invade the diaphragm and implant on abdominal structures. Neoplastic differentials include metastatic tumors of the pleural space, which in dogs and cats most commonly occur from carcinomas. The most common clinical sign is respiratory distress caused by pleural effusion (pericardial effusion also can occur with mesothelioma of the pericardium). Reactive mesothelial cells may be interpreted as malignant mesotheliomas based on cytology. However, a true mesothelioma in veterinary medicine is rare.

Diagnostic Approach Fluid collected from the pleural space can range in appearance from hemorrhagic to chylous. Fine-needle aspiration can be obtained with ultrasound guidance, but cytologic diagnosis of pleural disease is problematic. Reactive mesothelial cells can appear malignant; thus cytology of fluid usually does not give a definitive diagnosis. Diagnosis usually requires a biopsy of the pleura via thoracotomy or thoracoscopy. Differentials include tumor seeding from cardiac hemangiosarcoma (HSA), chemodectoma, or metastatic carcinoma. Imaging of the thoracic and e165

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abdominal cavities is indicated to rule out primary tumors.

Treatment and Prognosis Prognosis is poor for primary mesothelioma or for disease metastatic to the pleura. Because no successful definitive treatments have been reported, the goal of treatment is palliation of clinical signs. Intracavitary chemotherapy for palliation of pleural effusions is discussed in Chapter 75. Systemic chemotherapy has not been effective in either dogs or cats. Cytoreductive surgery may be used for larger masses before intracavitary therapy. Similar therapeutic approaches may be considered for animals with pleural carcinomatosis.

A

L

Mediastinum Pathology and Natural Behavior The incidence of mediastinal masses is low in dogs and cats. The two most common differentials for a mediastinal mass are thymoma and lymphoma. Branchial cyst, ectopic thyroid carcinoma, and chemodectoma also can occur but are less common. The mean age at presentation is 9 years in dogs and 10 years in cats. Benign mediastinal cysts also are recognized in cats and carry a good prognosis with transthoracic needle drainage. Thymomas originate from thymic epithelium and are infiltrated with lymphocytes (making differentiation from lymphoma difficult). The epithelial portion of the thymic tissue is considered neoplastic. Benign thymomas are noninvasive and well encapsulated, whereas malignant thymomas are locally invasive and aggressive. Thymomas rarely metastasize. Lymphoma is considered a systemic disease in dogs and cats. Cats presenting with mediastinal lymphoma usually are young (mean age of 2 years) and positive for feline leukemia virus (FeLV). Clinical signs for mediastinal masses include coughing, tachypnea, dyspnea, caval syndrome (dependent edema of the head and neck, and/or forelimbs, owing to restricted lymphatic flow), muscle weakness, or megaesophagus caused by myasthenia gravis (a paraneoplastic syndrome associated with thymoma).

Diagnostic Approach History may include cough, respiratory distress, or signs of esophageal disease. Physical examination findings could include pitting edema of the head, neck, or forelimbs if precaval syndrome is present. Lung sounds may be decreased because of compression of lung lobes by the mass or associated pleural effusion. Infrequently, Horner’s syndrome is identified from compression of ascending sympathetic nerves. Peripheral lymphadenopathy may be present in dogs with lymphoma. Hypercalcemia in association with mediastinal lymphoma is common, with a 25% to 50% incidence rate in dogs; but it also has been reported with thymomas and thus cannot be used to distinguish between the two diseases. Thoracic radiographs reveal a cranial mediastinal mass, pleural effusion, and/or megaesophagus (Web Figure 31-1).

B Web Figure 31-1  Thoracic radiographs (left lateral) (A) and

ventrodorsal view (B) in an FeLV-positive cat with lymphoma, showing mild pleural effusion and large mediastinal mass. FeLV, Feline leukemia virus.

Ultrasonography of the mediastinal mass may be instructive and can help distinguish solid tumors from cysts (especially in older cats). Fine-needle aspiration and cytology of thymomas generally reveal mature lymphocytes and sometimes mast cells, whereas fine-needle aspiration of lymphoma often reveals lymphoblasts. These procedures are guided optimally by ultrasound or CT. Flow cytometry, performed on needle aspirates, often can provide information distinguishing lymphoma from thymoma (Lana et al, 2006); however, tissue biopsy remains the gold standard. A CT scan can provide information for staging and surgical removal of thymomas but cannot differentiate between tumor types.

Treatment and Prognosis Surgical excision is the preferred treatment for thymomas and can be curative. Radiation therapy is used if surgical incision is incomplete or not possible. With radiation therapy alone for the treatment of thymomas in dogs and cats the objective response rate is 75%, and the median survival time is 248 days in dogs and 720 days in cats

WEB CHAPTER  31  Pulmonary Neoplasia (Smith et al, 2001). The prognosis for surgically resected benign thymomas without myasthenia gravis is good, with an 83% 1-year survival reported in dogs and 2-year median survival reported in cats. Chemotherapy targeting the malignant (epithelial) component of thymoma has not proven effective in dogs or cats. Systemic combination chemotherapy is recommended for the treatment of mediastinal lymphoma, with radiation therapy if needed to alleviate clinical signs. With an aggressive chemotherapy protocol, median survival times range from 6 to 12 months for dogs and 6 to 9 months (if FeLV negative) or 3 to 6 months (if FeLV positive) for cats. See Chapter 85 for further discussion of lymphoma treatment.

Heart Pathology and Natural Behavior Primary myocardial tumors are rare in dogs and cats. The majority of tumor types are malignant. The most common tumor type in dogs is HSA; the German shepherd dog is predisposed (see Chapter 88). In cats, the most common primary heart tumor is lymphoma. Other differentials for the dog and cat include aortic body tumor (chemodectoma), ectopic thyroid carcinoma, and rhabdomyosarcoma. Dogs and cats are middle aged to older at presentation. Most cardiac masses are located intrapericardially (intracavitary heart masses are rare) and can cause pericardial effusion. Mesothelioma of the pericardium also can lead to pericardial effusion. Clinical signs vary and depend on tumor location and invasiveness. Clinical signs are variable. In acute intrapericardial hemorrhage, signs can be acute with collapse and features of hypotension and cardiogenic shock. Chronic pericardial effusion generally leads to congestive heart failure with jugular venous distension, ascites, and/ or pleural effusion. Syncope may be caused by cardiac arrhythmias, heart failure, obstruction to venous return, or ventricular outflow obstruction. Respiratory distress also may develop from pleural effusion, pulmonary thromboembolism, or metastatic lung disease. Acute death from tumor rupture and blood loss can occur. Major differentials for these clinical signs are idiopathic pericardial effusion, pericarditis, cardiomyopathy, congestive heart failure, and valvular insufficiency.

Diagnostic Approach Electrocardiographic (ECG) findings may correlate with the mass location or be secondary to myocardial ischemia or pericardial effusion. Possible abnormalities include low-amplitude QRS complexes, electrical alternans, ST-segment changes, and cardiac arrhythmias. Thoracic radiographs may show a globoid-shaped heart (as a result of pericardial effusion), cardiomegaly, heart base mass, or pulmonary metastasis. However, the cardiac silhouette may be enlarged only modestly, making recognition of pericardial effusion difficult. Cytology of pericardial fluid occasionally may help to distinguish between neoplastic and nonneoplastic causes, especially with lymphoma. Echocardiography is the preferred test to identify and

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determine tumor location and size, as well as the presence of pericardial effusion.

Treatment and Prognosis Medical treatment is aimed at palliating signs of heart failure and arrhythmias. Pericardiocentesis is the initial treatment of choice to stabilize patients with cardiac tamponade (see Chapter 182). Surgical resection of accessible masses can be successful in the hands of an experienced thoracic surgeon. Palliation of signs of pericardial effusion also can be achieved by a pericardial window or pericardiectomy. The prognosis depends largely on the tumor type. For example, the prognosis for atrial or pericardial HSA in dogs and cats is poor (see Chapter 88). Although surgical excision of right atrial HSA is feasible and associated with a relatively low rate of complication, metastasis generally occurs rapidly, and postoperative chemotherapy is indicated. The prognosis for most primary cardiac tumors is poor, and in general they do not respond well to medical management. Conversely, long-term survival exceeding 1 year is not uncommon with aortic body tumors (chemodectoma) palliated by a large pericardial window or pericardiectomy (see below). The outcomes with pericardial mesothelioma are variable, and some long-surviving cases likely have been misdiagnosed because of pronounced mesothelial reaction.

Major Vessels Pathology and Natural Behavior Tumors arising from the carotid or aortic body are most commonly chemodectomas (arising from the chemoreceptor organs). Chemoreceptor organs are part of the parasympathetic nervous system and initiate changes in blood pressure, respiration depth and rate, and heart rate. Chemodectomas are nonfunctional, and clinical signs are caused by space occupation and mechanical disturbances. These tumors are more common in the dog than in the cat. Other differentials for heart base masses include thymoma, HSA, ectopic thyroid carcinoma, abscess, and granuloma. Dogs are middle aged to older at presentation, with males at a higher risk for developing aortic body tumors. Brachycephalic breeds are at a higher risk of developing chemodectomas; this is thought to be caused by chronic hypoxia. Clinical signs are those associated with right-sided heart failure (aortic body mass, dyspnea, arrhythmia, ascites, pericardial or pleural effusion, coughing, cyanosis) or space-occupying mass in the neck (carotid body mass, dyspnea, Horner’s syndrome, laryngeal paralysis). Concurrent endocrine neoplasia (testicular, ovarian, thyroid, parathyroid, adrenal, pituitary, and pancreatic) is a common finding, with an incidence of up to 50% in dogs.

Diagnostic Approach Thoracic radiographs often show dorsal deviation of the trachea, a mass at the base of the heart, and right-sided heart enlargement. Metastasis also can be seen in some

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cases. ECG can be normal; or electrical alternans, lowamplitude QRS complexes, or arrhythmias (premature ventricular contractions or ventricular tachycardia) may be seen. Abdominal radiographs and ultrasound can be performed to check for involvement of the liver, spleen, or lymph nodes and the presence of ascites. Echocardiography can identify a mass at the base of the heart and pericardial effusion and also can aid in the determination of surgical resectability. Chemodectomas do not exfoliate well; thus cytology of pericardial or pleural fluid usually is not helpful. Definitive diagnosis requires histopathology from surgery or necropsy.

Treatment and Prognosis Early surgical excision is the preferred treatment. However, chemodectomas tend to be highly invasive and also have the moderate potential to metastasize. Pericardiectomy can be performed at the time of biopsy and has been shown to extend survival time (whether or not pericardial effusion is present). In dogs with aortic body tumors, those that have a pericardiectomy have a median survival time of 730 days, whereas those without a pericardectomy have a median survival time of 42 days (Ehrhart et al, 2002). Even when the mass is not respectable, pericardial windows may be beneficial to prevent accumulation of pericardial effusion. This treatment often may be accomplished using minimally invasive “mini”-thoracotomy approaches or thoracoscopic methods. Radiation therapy has not been well studied for chemodectomas in dogs and cats, although chemodectoma

WEB CHAPTER 

is considered a radiation-sensitive neoplasm in humans. The prognosis for dogs and cats is guarded because of the metastatic potential and locally aggressive nature. The median survival time for dogs after surgical resection is 25 months.

References and Suggested Reading Ehrhart N et al: Analysis of factors affecting survival in dogs with aortic body tumors, Vet Surg 31:44, 2002. Hahn KA, McEntee MF: Prognosis factors for survival in cats after removal of a primary lung tumor: 21 cases (1979-1994), Vet Surg 27:307, 1998. Hirschberger J et al: Sensitivity and specificity of cytologic evaluation in the diagnosis of neoplasia in body fluids from dogs and cats, Vet Clin Pathol 28:142, 1999. Lana S et al: Diagnosis of mediastinal masses in dogs by flow cytometry, J Vet Intern Med 20:1161, 2006. McNiel EA et al: Evaluation of prognostic factors for dogs with primary lung tumors: 67 cases (1985-1992), J Am Vet Med Assoc 211:1422, 1997. Mehlhaff CJ et al: Surgical treatment of pulmonary neoplasia in 15 dogs, J Am Anim Hosp Assoc 20:799, 1984. Paoloni MC et al: Comparison of results of computed tomography and radiography with histopathologic findings in tracheobronchial lymph nodes in dogs with primary lung tumors: 14 cases (1999-2002), J Am Vet Med Assoc 228:1718, 2006. Poirier VJ et al: Toxicity, dosage, and efficacy of vinorelbine (Navelbine) in dogs with spontaneous neoplasia, J Vet Intern Med 18:536, 2004. Smith AN et al: Radiation therapy in the treatment of canine and feline thymomas: a retrospective case study (1985-1999), J Am Anim Hosp Assoc 37:489, 2001.

32 

Surgical Oncology Principles JAMES P. FARESE, Rohnert Park, California

A

nimals with cancer often have advanced (locally invasive or metastatic) disease. Veterinarians con­ sulting with owners must have a strong knowledge base regarding the behavior of the tumors that commonly occur in dogs and cats. Insufficient knowledge may pre­ clude the appropriate diagnostic testing and procedures commonly performed by oncology specialists. Many tumors demand an aggressive surgical approach that requires an experienced operator. In these cases, referral to a specialist should be considered because the best chance to remove a tumor is the first attempt. In addition to knowing when tumor resection is possible, clinicians must realize when the extent of disease has become too

advanced to recommend surgical treatment. Veterinari­ ans always must be mindful of the impact of any inter­ vention on the quality of their patients’ lives. Convincing owners of the importance of quality of life can be a dif­ ficult task when owners struggle to accept the limitations of the therapies currently available.

Tumor Excision One fundamental of oncologic surgery is an under­ standing of the classification scheme that describes dif­ ferent types of tumor excision. This nomenclature, published by Enneking (1983), is an important means of

WEB CHAPTER  32  Surgical Oncology Principles

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communication between oncologists. It also helps the surgical oncologist categorize levels of tumor excision and have a clear goal for the amount of tissue that must be excised in the context of the overall treatment plan (e.g., when the combination of surgery and radiation therapy [RT] is being considered).

the tissue planes that act as natural barriers to tumor invasion). This technique often is used during limb amputations for appendicular osteosarcoma and mastec­ tomy for mammary neoplasia.

Intracapsular

All tumors are not created equal, and even within the benign and malignant categories tumor behavior varies. The surgeon must be familiar with the biologic behavior of the individual tumor types because tumor identity affects many aspects of case management. In general, carcinomas metastasize via the lymphatic system, and sarcomas via the hematogenous route. However, the two vascular systems are connected by lymphovenous com­ munications, and there are exceptions to these patterns. A strong knowledge base enables the surgeon to perform thorough physical examinations and educate the client about tumor behavior (e.g., degree of local invasion, pat­ terns of metastasis), important staging tests, the type of resection required for cure, and long-term prognosis. Perhaps the best example of the importance of under­ standing tumor behavior is illustrated by the behavior of appendicular osteosarcoma. In these cases the client must understand that, despite “clean” chest radiographs, dormant micrometastasis in the lungs likely is present and that the possibility of cure is extremely low. Under­ standing tumor behavior helps guide these preoperative staging evaluations.

The intracapsular approach involves piecemeal removal of a mass with the dissection plane interior to the tumor pseudocapsule. It is a debulking or cytoreductive surgery that leaves behind macroscopic disease, making local recurrence almost guaranteed if the tumor is malignant. This approach commonly is used to treat benign diseases, such as bone cysts, or select malignancies, such as infiltra­ tive lipomas, before RT.

Marginal A marginal excision is immediately outside the tumor pseudocapsule with the dissection plane through the reactive zone (a layer of reactive tissue consisting of pro­ liferating mesenchymal cells, inflammatory cells, and neovascularization). This technique generally is used for benign tumors (e.g., lipoma). When used for malignant tumors, it often results in residual microscopic disease and therefore often is combined with adjunctive RT. For example, a low- or intermediate-grade soft tissue sarcoma (STS) of the extremity could be removed with a marginal excision followed by postoperative RT to minimize the potential for local recurrence.

Wide A wide excision is removal of the mass, pseudocapsule, reactive zone, and an additional margin of normal tissue (e.g., 2 to 3 cm) or an anatomic mesodermal barrier to tumor cell migration such as fascia, cartilage, or bone. Because the entire tissue compartment (e.g., entire bone or muscle belly) is not removed, it is possible that “skip” metastases (satellite tumor colonies nearby but separate from the primary mass) could be left behind. Through the years, the 3-cm margin rule plus a deep fascial plane has been accepted by most surgeons for tumors such as mast cell tumors (MCTs) and STSs. More recently research­ ers suggested that 2-cm margins may be satisfactory for grade I and II MCTs (Simpson et al, 2004) and that the grade of a given STS may be important to determine margin width. For example, low-grade STSs may require smaller margins, whereas other tumors such as vaccineassociated sarcomas call for maximal margin width (e.g., 5-cm skin margins and two layers of fascia) because of the tumor extension along fascial planes.

Radical A radical excision is an en bloc removal (removal of the primary mass, draining lymphatic vessels, and lymph nodes [LNs] with a single incision) of a mass and the entire tissue compartment that contains it. The dissection plane is extracompartmental (the compartment refers to

Understanding Tumor Biology

Client Communication The surgeon must develop a good relationship with the client and communicate effectively. Owners of pets with cancer often are anxious and overwhelmed about the condition of their pets, which makes effective communi­ cation challenging. Given the aggressive nature of some surgical resections (e.g., nasal planum resection), sur­ geons should prepare clients for the expected postopera­ tive appearance of their pets. To do this, clinicians can create an image library depicting immediate postopera­ tive and follow-up appearance from other cases. Clients must have a good understanding about the patterns of the disease, the likelihood of local recurrence, and the overall prognosis. Almost as important as knowing when to recommend surgery is knowing when the disease state is too advanced to warrant surgery or will cause the patient to have a poor quality of life because of the extent of the resection. For example, resection of a large thyroid carcinoma that is fixed and invading underlying tissues likely would be incomplete and associated with significant hemorrhage and high morbidity. Furthermore, this surgery likely would not be curative because of local tumor thrombi and/or metastatic disease. The value of this determination cannot be overemphasized, and the ability to communi­ cate this effectively to clients is crucial. Reactions from clients vary greatly regarding their view of acceptable surgical procedures. Some clients may be comfortable with radical laryngectomy and a permanent tracheos­ tomy for a laryngeal neoplasm; others will not consider limb amputation because they cannot bear the thought

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of seeing their pet with such an altered appearance. Clients who initially are reluctant to have a certain pro­ cedure performed often change their minds once they have had a chance to reconsider the information or speak with another client whose pet was treated similarly. However, the surgeon must not impose a decision on clients who are undecided about surgery and make sure the client is comfortable with the plan. Many veterinary cancer centers use mental health professionals to assist with the surgeon-client communication and provide support to clients during the decision-making and/or treatment process.

Tumor Staging In the diagnostic approach, there are two important con­ siderations: (1) whether to obtain a preoperative biopsy and (2) the extent of preoperative staging. These ques­ tions are usually easy to answer in hindsight. Staging varies, depending on tumor type, but typically consists of thoracic radiographs and aspiration of regional LNs, with or without abdominal imaging. A lack of LN enlargement does not necessarily indicate the absence of nodal metastasis. Knowing the tumor identity before surgical excision is helpful because tumor behavior can influence case management in many ways: degree of local invasion, metastatic potential, and biologic activity (e.g., release of histamine, heparin with manipulation of an MCT). However, the decision of whether to obtain a preopera­ tive (versus postoperative) biopsy is not always straight­ forward. A major consideration is whether the information obtained will affect case management. A good example of this is the handling of oral tumors. The types of oral tumors vary widely in their behavior. For example, the treatment of a fibromatous epulis differs drastically from that of a fibrosarcoma. Aside from melanomas, many oral tumors have a similar gross appearance. Thus in this sce­ nario veterinarians must perform preoperative biopsy and properly stage the disease if they are to educate clients and help them make informed decisions. Regarding biopsy techniques for tumor diagnosis, con­ sideration also should be given to the invasiveness of the procedure and the potential for causing hemorrhage into a body cavity (e.g., a large, cavitated splenic mass) or the seeding of tumor cells into a body cavity or along a needle tract (e.g., a transitional cell carcinoma of the urinary bladder). If the need for surgery is clear (e.g., a stagedclean cavitated splenic mass that is hemorrhaging), fore­ going additional diagnostic efforts may be in the patient’s best interests. The surgeon must decide whether the risks of the diagnostic tests are justified.

Incisional versus Excisional Biopsy Incisional biopsy is the removal of a portion of a tumor by sharp incision. This technique usually is performed in cases in which knowing the specific behavior of a tumor may affect an owner’s willingness to treat the pet surgi­ cally or when knowing the identity of the tumor would alter the treatment plan. Common methods include the following:

• Wedge incision: Small, wedge-shaped section of tumor tissue removed with a scalpel blade or biopsy punch. For deeper subcutaneous tumors or those under superficial muscle bellies, a short skin incision is necessary to approach the mass. • Needle core biopsy: Large-bore needles used to sample deeper tumors or tumors of bone (e.g., Tru-cut for soft tissue, Jamshidi needle for bone). This type of tissue sampling usually can be performed with sedation and local anesthesia. Disadvantages of the incisional biopsy approach are that it often requires a second surgical procedure and in some cases creates a direct communication between the tumor tissue and a portion of the surrounding normal tissue, possibly increasing the chance of local recurrence. The approach for incisional biopsy must be planned so that the incision site and entire dissection tract can be excised easily during the definitive resection. For example, for a mandibular oral tumor the biopsy should be per­ formed through the overlying oral mucosa rather than through skin intended to be preserved. In contrast, excisional biopsy is the removal of the entire tumor (usually a small mass) with a surrounding barrier of normal tissue. The main advantage is that biopsy and gross tumor removal are performed in a single procedure. The main disadvantage is that if the tumor is highly invasive and the surgeon does not know the iden­ tity of the tumor, he or she may not plan a wide enough resection to remove the tumor completely. Cytology results and the anatomic location are important factors in deciding which approach to use. For example, cytology results may be diagnostic for an MCT, obviating the need for a tissue biopsy. Tumors in the flank region may allow an excisional biopsy to be performed with wide (i.e., 3-cm) margins, whereas the same approach on a distal extremity would result in a large open wound that may not allow primary closure. Other instances in which exci­ sional biopsy is performed almost exclusively include intrathoracic and intraabdominal masses because the invasiveness of the biopsy procedure may involve too much risk or equal the morbidity of the definitive resec­ tion if an open biopsy is performed. When performing an incisional or excisional biopsy on a tumor of unknown histotype, clinicians should fore­ warn the owner that the main purpose of the biopsy is to establish a diagnosis; additional diagnostic tests, addi­ tional surgery, or other forms of therapy may be necessary after receipt of the histopathology results.

Role of Regional Lymph Nodes Palpation (or ultrasonographic evaluation in deeper loca­ tions such as the sublumbar area) of regional LNs should become a reflex for clinicians evaluating tumors; and whenever needle aspirates can be performed safely, cytol­ ogy is recommended. Some controversy still surrounds the role of the LN in tumor biology. The older Halstedian theory suggested that tumor cells disseminate in an orderly anatomic manner of ever-larger circles (e.g., from the primary tumor to the closest draining LN and so on). An alternative theory is that cancer cells do not spread in an

WEB CHAPTER  32  Surgical Oncology Principles orderly manner and that regional LNs are largely ineffec­ tive barriers to cancer spread. Experimentally, tumor cells have been shown to pass through LNs and appear in the efferent lymph within hours. Regardless of the role of the LN, removal of LNs along with excision of the primary tumor is worthwhile. First, staging of the tumor can be performed if it were not possible via cytology before surgery. Other advantages to LN removal include cytore­ duction before adjunctive therapy and removal of enlarged nodes causing physical impairment (e.g., sublumbar nodes compressing the colon in dogs with anal sac adenocarci­ noma). If preoperative LN cytology shows the node to be negative for metastatic cells, it is still possible that tumor cells could be present (e.g., in an afferent lymphatic or in the subcapsular sinus). Thus the surgeon must consider the tumor type, its likelihood of nodal metastasis, and the impact of LN status on postoperative decision making.

Palliative Surgery Surgery performed to make a patient more comfortable or improve quality of life with the knowledge that the procedure will not cure the patient of the disease is con­ sidered palliative. A good example of palliative surgery is limb amputation for canine osteosarcoma. Although pul­ monary metastasis almost invariably has occurred by the time of diagnosis, surgery can alleviate the pain associ­ ated with the primary bone tumor and dramatically improve the quality of life that remains.

Curative-Intent Resection A thorough knowledge of anatomy is necessary when palpating the extent of a primary tumor and planning the resection. Aside from tumor size, factors that influ­ ence resectability include proximity to nonexpendable anatomic structures, degree of local tissue invasion, and tumor grade. Advanced imaging modalities such as com­ puted tomography and magnetic resonance imaging provide a great deal of preoperative information. However, in some instances it is not clear whether a given tumor is excisable until it is approached surgically. The final preoperative physical evaluation typically is performed just after induction of anesthesia. In planning the resec­ tion the surgeon must appreciate the limits of various resection procedures. Consideration must be given to sur­ rounding normal anatomic structures that can be sacri­ ficed to achieve a complete excision yet not cause unacceptable postoperative morbidity or complications. For most cutaneous malignancies, the general rule is to make a plan that allows the surgeon to excise all tissue necessary for complete removal and consider wound closure secondarily. If an aggressive, curative-intent resec­ tion is performed and the wound cannot be closed rou­ tinely, the defect may be closed with a reconstructive surgical technique such as a skin flap or graft. Alterna­ tively, the wound can be left to heal by second intention. Skin flaps should be used with some caution because they usually increase the size of the surgical field and thereby complicate postoperative RT planning. In some cases prudent care may involve planning a more conservative resection and accepting that the

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surgical plan may result in microscopic residual disease. For example, a low-grade subcutaneous STS of moderate size on the extremity of a 14-year-old dog could be removed via a marginal excision if the dog’s owner were opposed to performing postoperative wound manage­ ment. Although this approach alone likely would not result in a cure, the owner may prefer the possibility of local recurrence over a protracted course of wound man­ agement or limb amputation. However, this surgical approach should be questioned if the same patient is entirely asymptomatic and the tumor is slow growing. Several technical aspects should be considered when performing tumor resections, including but not limited to the following: 1. Perioperative antibiotics and strict aseptic technique may be necessary because some cancer patients may be immunosuppressed. 2. An open incisional biopsy creates a communication between the tumor tissue and the edges of the normal tissues in the dissection path. Thus excision of the biopsy tract is indicated to ensure removal of all tumor cells. Adequate excision of the biopsy tract is facilitated by well-planned biopsy approaches. Biopsy incisions should be oriented in a direction parallel to the tension lines (e.g., parallel to the long axis of a long bone) to facilitate closure of the surgical wound after definitive resection of the mass and associated biopsy tract. 3. In some procedures such as nephrectomy for a renal neoplasm or lung lobectomy, it has been advocated to ligate the venous side first to minimize embolization of tumor cells into the venous circulation that may occur as a result of tumor manipulation. 4. Manipulation and handling of the tumor should be minimized. In addition to possibly causing more cells to gain access to systemic circulation, rupture of the tumor capsule may occur and allow tumor cells to seed the surgical field. Moistened laparotomy sponges wrapped around large tumors (such as a splenic mass) can be used to minimize the possibility of tumor rupture and glove contamination during the procedure. Excessive manipulation of MCTs can cause degranulation of mast cells and profound hypotension. For this reason, patients with MCTs often are pretreated with diphenhydramine before surgery. 5. Once the tumor has been excised and removed from the surgical field, gloves and instruments should be changed, and a new pack of surgical towels should be placed over the original surgical drape to help prevent seeding of the wound. The wound also should be lavaged to wash away exfoliated tumor cells. Consideration should be given to the order of procedures if more than one mass resection or some other unrelated procedure (such as on ovariohysterectomy) is planned during the same anesthetic episode. For example, a subcutaneous lipoma should be removed before a cystotomy to excise a transitional cell carcinoma because of fear of seeding the incision with tumor cells.

Incomplete Resection and Local Recurrence Local recurrence often can be predicted with a good his­ tologic assessment of the surgical margins. When “dirty margins” are not treated, a mass may appear along or beneath the line of incision weeks to months after the initial surgery, depending on the tumor histotype. In this scenario location, tumor histotype and the results of restaging dictate the course of action. For example, a local recurrence of a synovial cell sarcoma of the tarsal joint previously excised in an aggressive manner may be treated best by limb amputation in the absence of evidence of LN or pulmonary metastasis. In other cases, additional surgery on the same operative site may be possible to remove the remaining neoplastic cells. In general, this approach is more likely to be effective soon after the initial surgery (i.e., when cells are still present at micro­ scopic levels). Failing to include a fascial plane in the resection is one of the most common reasons for incomplete excision of subcutaneous masses. Although

clinicians should advise the client against taking the “wait-and-see” approach when incomplete margins have been documented histologically, a small percentage of these cases may never develop local recurrence.

References and Suggested Reading Enneking WF: Surgical procedures. In Enneking EF, editor: Musculoskeletal tumor surgery, New York, 1983, Churchill Living­ stone, p 89. Gilson SD: Clinical management of the regional lymph node, Vet Clin North Am Small Anim Pract 25:149, 1995. Gilson SD, Stone EA: Principles of oncologic surgery, Comp Cont Educ Pract Vet 12:827, 1990. Levine SH: Surgical therapy. In Slatter D, editor: Textbook of small animal surgery, ed 2, Philadelphia, 2002, Saunders, p 2048. Simpson AM et al: Evaluation of surgical margins required for complete excision of cutaneous mast cell tumors, J Am Vet Med Assoc 224:236, 2004. Withrow SJ: Surgical oncology. In Withrow SJ, MacEwen EG, editors: Small animal clinical oncology, ed 3, Philadelphia, 2001, Saunders, p 70.

SECTION V Dermatologic and Otic Diseases Chapter Chapter Chapter Chapter Chapter Chapter Chapter

90: 91: 92: 93: 94: 95: 96:

Chapter 97: Chapter 98: Chapter 99: Chapter 100: Chapter 101: Chapter 102: Chapter 103: Chapter 104:

Chapter 105: Chapter 106: Chapter 107: Chapter Chapter Chapter Chapter Chapter Chapter Chapter Chapter Chapter Chapter Chapter Chapter

108: 109: 110: 111: 112: 113: 114: 115: 116: 117: 118: 119:

Diagnostic Criteria for Canine Atopic Dermatitis Treatment Guidelines for Canine Atopic Dermatitis Cyclosporine Use in Dermatology Allergen-Specific Immunotherapy Systemic Glucocorticoids in Dermatology Topical Therapy for Pruritus Elimination Diets for Cutaneous Adverse Food Reactions: Principles in Therapy Flea Control in Flea Allergy Dermatitis Treatment of Ectoparasitoses Canine Demodicosis Staphylococci Causing Pyoderma Treatment of Superficial Bacterial Folliculitis Topical Therapy for Infectious Diseases Methicillin-Resistant Staphylococcal Infections Nontuberculous Cutaneous Granulomas in Dogs and Cats (Canine Leproid Granuloma and Feline Leprosy Syndrome) Treatment of Dermatophytosis Dermatophytosis: Investigating an Outbreak in a Multicat Environment Disinfection of Environments Contaminated by Staphylococcal Pathogens Principles of Therapy for Otitis Topical and Systemic Glucocorticoids for Otitis Topical Antimicrobials for Otitis Systemic Antimicrobials for Otitis Ototoxicity Ear-Flushing Techniques Primary Cornification Disorders In Dogs Alopecia X Actinic Dermatoses and Sun Protection Drugs for Behavior-Related Dermatoses Superficial Necrolytic Dermatitis Cutaneous Adverse Drug Reactions

403 405 407 411 414 419 422 424 428 432 435 437 439 443

445 449 452 455 458 459 462 466 468 471 475 477 480 482 485 487

The following web chapters can be found on the companion website at www.currentveterinarytherapy.com Web Chapter 33: Web Chapter 34:

Acral Lick Dermatitis Avermectins in Dermatology 401

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Web Web Web Web Web Web Web Web Web Web Web

Chapter Chapter Chapter Chapter Chapter Chapter Chapter Chapter Chapter Chapter Chapter

35: 36: 37: 38: 39: 40: 41: 42: 43: 44: 45:

Canine Papillomaviruses Diseases of the Anal Sac Feline Demodicosis Feline Viral Skin Disease House Dust Mites and Their Control Interferons Pentoxifylline Pyotraumatic Dermatitis (“Hot Spots”) Therapy for Sebaceous Adenitis Malassezia Infections Topical Immunomodulators

CHAPTER 

90 

Diagnostic Criteria for Canine Atopic Dermatitis CLAUDE FAVROT, Zurich, Switzerland

C

anine atopic dermatitis (AD) is an inflammatory and pruritic disease driven most commonly by immunoglobulin E (IgE) antibody reactions to environmental, food, and microbial allergens. Numerous flare factors, such as microbial infections, psychologic factors, and climate, may contribute to the clinical signs. Furthermore, breed-associated phenotypes of canine AD have been described. Thus it is not surprising that the disease may present with highly variable clinical signs, none of which is pathognomonic. The diagnosis of AD requires a meticulous workup and evaluation of historical and clinical information, and includes two different and complementary steps: the exclusion of similar diseases and confirmation of the suspected AD.

Differential Diagnosis: Exclusion of Similar Diseases Exclusion of similar diseases is a mandatory first step, because many are readily manageable and straightforward to rule out. Practitioners should first exclude ectoparasitic infections, especially sarcoptic mange, flea infestation, and possibly cheyletiellosis and chigger bites. Because the regional localization (face, ears, elbows, hocks) of pruritus and lesions in sarcoptic mange resembles those in canine AD, this disease is an important rule out. Numerous superficial skin scrapings should be examined. However, the sensitivity of skin scraping analysis is low, and “diagnostic treatment” (see Chapter 98) or IgG serologic testing (where available) should be performed if the clinical presentation is compatible with scabies and the superficial skin scrapings are negative for the mites. Fleabite hypersensitivity usually affects the caudal dorsum and tail base initially; these are atypical sites for AD. However, many dogs also have lesions and pruritus of the abdomen, groin, medial thigh, and perineum, which can mimic AD. Thus fleabite hypersensitivity also should be ruled out in all dogs during the AD workup using trials of parasiticidal agents (see Chapter 97). Bacterial and Malassezia (yeast) infections often develop secondary to canine AD, and it is critical that these disorders be identified and treated (see Chapters 100 to 102 and Web Chapter 44). Additionally, microbial hypersensitivity may play a role in some dogs with AD, in which significant clinical improvement may be anticipated with treatment of the infection.

Currently food allergy is considered a triggering factor for canine AD. Thus, in dogs with the typical clinical presentation of AD triggered by food allergens, the food allergy is regarded as a causal agent of AD, not as a separate entity. The role of diet should always be assessed in dogs with suspected AD that have a nonseasonal history of clinical signs (see Chapter 96). However, cutaneous adverse food reactions can be immune mediated or non– immune mediated and associated with a wide range of clinical signs (e.g., vomiting, diarrhea, urticaria)—signs that are dissimilar from those of typical AD. In rare cases diseases such as epitheliotropic lymphoma or sebaceous adenitis demonstrate clinical signs with pruritus mimicking that of AD. If these diseases are suspected, skin biopsy for histopathologic analysis (a procedure rarely helpful in the diagnosis of AD) is indicated.

Clinical Signs of Canine Atopic Dermatitis In a recent study of over 800 dogs, the frequency of each clinical sign of AD was studied. Data were collected from dogs with chronic or recurrent pruritus examined by veterinary dermatologists on four continents. Typical characteristics of AD in these dogs were identified as follows: • Most dogs (68%) show the first clinical signs before 3 years of age. • Fifty percent of dogs had chronic otitis; otitis was the first sign of disease in 43% of this group. • Owners observed pruritus before lesions in 61% of cases. • Pruritus was responsive to glucocorticoids in 78% of cases. • Breed predispositions were identified but varied by geographical area. • AD was seasonal in 24% of dogs, causing recurrent disease. • The distributional pattern of lesions can be strongly suggestive of AD, with the following areas most frequently affected: front feet (79%), hind feet (75%), abdomen (66%), axillae (62%), ear pinnae (58%), genitalia (43%), lips (42%), eyelids (32%), and chest (32%). • Secondary bacterial infection (66%) or yeast infection often develops, with some breed predispositions (German shepherd and West Highland white terrier) observed for yeast infections. 403

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BOX 90-1  Sets of Criteria for the Diagnosis of Canine Atopic Dermatitis Set 1 1.  Age at onset 2%) these acids are more useful in cases of less inflamed acute and chronic otitis. PCMX is a phenolic antiseptic found in several veterinary ear cleansers. In vitro, PCMX-containing ear preparations are effective against Escherichia coli, Staphylococcus species, and P. aeruginosa (Swinney et al, 2008). In one in vivo study, approximately 70% of infected ears were cleared of their infection within 2 weeks when an ear preparation containing PCMX, lactic acid, and salicylic acid was used (Cole et al, 2003). Both S. pseudintermedius and P. aeruginosa infections were cleared along with M. pachydermatis infections, although the antiyeast activity may be due more to the lactic and salicylic acids than the PCMX. PCMX does not appear to be irritating, so it may be useful in inflamed ears. Another antiseptic commonly added to veterinary ear cleansers is Tris-EDTA. Tris-EDTA is best known for its ability to increase the permeability of the outer membranes of gram-negative bacteria such as Pseudomonas, which allows increased penetration by antibiotics. Studies report varying degrees of antimicrobial activity of TrisEDTA by itself. One in vitro study showed no effect of one Tris-EDTA preparation against S. pseudintermedius, P. aeruginosa, or M. pachydermatis, whereas another study showed that a different Tris-EDTA preparation alone significantly decreased the number of Pseudomonas organisms but not Streptococcus, Staphylococcus, or Proteus (Cole et al, 2006; Swinney et al, 2008). In another in vitro study, a different ear preparation containing Tris-EDTA and 0.15% chlorhexidine was tested. The combination was very effective against both methicillin-resistant and methicillin-sensitive S. aureus and S. pseudintermedius, E. coli, P. aeruginosa, and M. pachydermatis. P. mirabilis was the organism most resistant to the combination (Guardabassi et al, 2010; Swinney et al, 2008). Chlorhexidine is no longer commonly incorporated into cleansers specifically labeled for use in the ear because of the potential for ototoxicity, although at the low concentrations used (0.15%) biguanide compounds like chlorhexidine have not demonstrated ototoxic effects in dogs (Mills

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et al, 2005). Tris-EDTA is usually nonirritating, so it can be used in very inflamed ears with little problem; however, the author has seen a small number of dogs develop a significant contact reaction characterized by a very watery brown discharge and moderate erythema. Tris-EDTA is not good at removing debris, so it should be used in combination with another agent if the ears are very waxy or contain thick, purulent debris.

Unique Ingredients Several veterinary ear cleansers are available that contain ingredients with unique properties, but unfortunately there are few in vivo studies confirming their efficacy. The first of these ingredients is phytosphingosine. Phytosphingosine is one of the most widely distributed natural sphingoid bases found in plants, fungi, and animals. In vitro it has good antiinflammatory and antimicrobial activity against Staphylococcus and Pseudomonas as well as mild activity against M. pachydermatis. No in vivo otic studies have been done with phytosphingosine-containing products. Phytosphingosines are also the base for ceramides, one of the components of the stratum corneum lipid barrier. Besides helping to maintain normal barrier function, ceramides are important in normal cell turnover since they can arrest epidermal proliferation. Stabilized hypochlorous acid is another ingredient that has been introduced into a veterinary otic cleanser for its antimicrobial activity. Hypochlorous acid is a weak acid formed by acidification of hypochlorite or by electrolysis of a salt solution. In vitro studies have shown excellent antibacterial, antiviral, and antifungal activity, but these types of studies have not been published for veterinary pathogens. The only in vivo studies published are human case reports. No reports of randomized placebo-controlled human or veterinary studies have been published at this time using stabilized hypochlorous acid. Bioactive enzymes (lactoperoxidase, lactoferrin, and lysozyme) have been added to a veterinary ear cleanser for their antimicrobial activity. In a single in vitro study the product containing all three of these enzymes demonstrated antimicrobial activity against several laboratory strains of bacteria and yeast (Atwal, 2003). At this time no in vivo veterinary studies have been performed using these enzymes topically in the ear. Monosaccharide and polysaccharide sugars have been added to a veterinary otic cleanser to decrease microbial adherence to the epidermis and reduce the release of proinflammatory cytokines. In vitro studies have demonstrated a decrease in the adherence of both P. aeruginosa and S. pseudintermedius to cultured canine corneocytes (McEwan et al, 2006, 2008). An in vivo study found that the sugar-containing ear cleanser was effective in controlling the clinical signs of otitis externa and dramatically reducing the number of bacteria and yeast in dogs with otitis externa (Reme et al, 2006).

Ototoxicity Many ingredients found in veterinary ear cleaners are considered ototoxic to the middle and inner ear (see Chapter 112), although most of these ingredients have not been examined in clinical settings and there are very few studies reported in the veterinary literature evaluating the ototoxicity of topical otic products. However, products containing squalene (Mansfield et al, 1997) or Tris-EDTA and polyhexamethylene biguanide (Mills et al, 2005) were found to be nonototoxic in the dog. The integrity of the tympanic membrane should be ascertained if possible before any ear cleanser is used. If the status of the tympanic membrane cannot be determined or if the tympanic membrane is found to be ruptured after cleaning, the canal should be flushed with saline to remove any residue of the cleanser. If it is necessary to use a cleanser in an ear with a known ruptured tympanic membrane, a product without known ototoxic ingredients should be used if possible and the owners should be warned of the chance of ototoxicity.

References and Suggested Reading Atwal R: In vitro antimicrobial activity assessment of Zymox otic solution against a broad range of microbial organisms, Int J Appl Res Vet Med 1:240, 2003. Cole LK et al: Evaluation of an ear cleanser for the treatment of infectious otitis externa in dogs, Vet Ther 4:12, 2003. Cole LK et al: In vitro activity of an ear rinse containing tromethamine, EDTA and benzyl alcohol on bacterial pathogens for dogs with otitis, Am J Vet Res 67:1040, 2006. Guardabassi L, Ghibaudo G, Damborg P: In vitro antimicrobial activity of a commercial ear antiseptic containing chlorhexidine and Tris-EDTA, Vet Dermatol 21:282, 2010. Mansfield PD et al: The effects of four, commercial ceruminolytic agents on the middle ear, J Am Anim Hosp Assoc 33:479, 1997. McEwan NA et al: Monosaccharide inhibition of adherence by Pseudomonas aeruginosa to canine corneocytes, Vet Dermatol 19:221, 2008. McEwan NA, Mellor D, Kalna G: Sugar inhibition of adherence by Staphylococcus intermedius to canine corneocytes, Vet Dermatol 17:151, 2006. Mendelsohn CL et al: Efficacy of boric-complexed zinc and acetic-complexed zinc otic preparations for canine yeast otitis externa, J Am Anim Hosp Assoc 41:12, 2005. Mills PC, Ahlstrom L, Wilson WJ: Ototoxicity and tolerance assessment of a TrisEDTA and polyhexamethylene biguanide ear flush formulation in dogs, J Vet Pharmacol Ther 28:391, 2005. Reme CA et al: The efficacy of an antiseptic and microbial antiadhesive ear cleanser in dogs with otitis externa, Vet Ther 7:15, 2006. Sanchez-Leal J et al: In vitro investigation of cerumenolytics activity of various otic cleansers for veterinary use, Vet Dermatol 17:121, 2006. Swinney A et al: Comparative in vitro antimicrobial efficacy of commercial ear cleaners, Vet Dermatol 19:373, 2008.

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Primary Cornification Disorders in Dogs ELIZABETH A. MAULDIN, Philadelphia, Pennsylvania

T

he term cornification (keratinization) refers to the process by which epidermal cells undergo terminal differentiation from basal keratinocytes to the highly specialized corneocytes. Traditionally, disorders of cornification have been divided into those with primary and those with secondary causes. In primary cornification disorders, the excessive scale is due to a direct defect in one or more steps involved in the formation of the stratum corneum. Some authors include abnormalities of sebaceous gland function (e.g., sebaceous adenitis, sebaceous gland dysplasia) as primary cornification disorders as well. Secondary disorders are those in which excessive scaling develops as a result of another condition such as fleabite hypersensitivity, sarcoptic mange, hypothyroidism, or epitheliotropic lymphoma. More than 80% of scaling disorders arise from secondary causes. Primary disorders of cornification are generally diagnosed by ruling out secondary causes. The signalment, age of onset, and presence or absence of pruritus aid in the formation of differential diagnoses and determination of the diagnostic approach. In a standard veterinary practice, a minimal dermatologic data set (e.g., skin scrapings, acetate tape preparations, impression smears, trichograms, dermatophyte culture) along with routine blood work can effectively rule out secondary disorders. Skin biopsies are often needed to establish a definitive diagnosis. Primary cornification disorders are generally nonpruritic and arise in young animals. These disorders have strong breed predilections; however, it should be kept in mind that spontaneous mutations can arise in any breed or mixed-breed animal.

Ichthyosis In veterinary medicine, the term ichthyosis has been limited to rare congenital or hereditary disorders believed to be due to primary defects in the formation of the stratum corneum. A skin biopsy is invaluable in establishing a definitive diagnosis. For breeding dogs, molecular testing may be needed to further characterize the defect and identify carrier dogs.

Epidermolytic Ichthyosis Epidermolytic ichthyosis (epidermolytic hyperkeratosis) can be diagnosed on light microscopic examination by an experienced dermatopathologist. The main histopathologic features (suprabasal keratinocyte vacuolation and

lysis, hypergranulosis, and hyperkeratosis) are uniquely correlated with mutations in epidermal keratins. This disorder has been identified in a few dog breeds (Rhodesian ridgeback, Labrador cross), but has been well characterized only in Norfolk terriers. The affected dogs have regions of mild pigmented scale with alopecia and roughening of the skin.

Nonepidermolytic Ichthyosis Nonepidermolytic ichthyosis in golden retrievers appears to be common, relatively mild, and unique in its variable presentation and onset. An autosomal-recessive mode of inheritance has been shown. Affected dogs develop large, soft, white to gray adherent scale that is prominent on the trunk and may be associated with ventral hyperpigmentation. A definitive diagnosis can be achieved by skin biopsy. Histologically, affected dogs have diffuse lamellar orthokeratotic hyperkeratosis in the absence of epidermal hyperplasia and dermal inflammation. Dogs are typically diagnosed at younger than 1 year of age; however, adultonset cases are not uncommon. Some dogs develop secondary bacterial folliculitis, which may lead to pruritus. The disease may wax and wane with periodic bouts of exacerbation and remission. Nonepidermolytic ichthyosis has been characterized in American bulldogs at the author’s institution. Unlike golden retrievers, bulldogs consistently develop clinical signs before weaning. Extensive pedigree analysis suggests an autosomal mode of inheritance. Young puppies have a disheveled hair coat compared with normal littermates. In puppies as young as 1 to 2 weeks of age, the glabrous skin becomes erythematous with tightly adherent brown scale, which gives the abdominal skin a “wrinkled” appearance. The remainder of the pelage has widely distributed large white scale. Malassezia overgrowth may be severe. In the absence of yeast infection, the histologic features are similar to those seen in the golden retriever. The development of otitis externa, intertrigo, and pododermatitis corresponds with the yeast proliferation and the onset of pruritus. In adult dogs, this clinical presentation can be easily confused with atopic skin disease. Occasionally adult dogs may have footpad hyperkeratosis. Unlike in golden retrievers, the skin lesions in bulldogs do not wax or wane and are generally more severe. Nonepidermolytic ichthyosis in Jack Russell terriers appears to be less common and has a more severe phenotype than that in golden retrievers and American  475

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bulldogs. Affected dogs have large, thick, adherent  parchment paper–like scales that have the histologic appearance of marked, tightly laminated, orthokeratotic hyperkeratosis. The dogs develop severe Malassezia infections. A congenital and autosomal-recessive form of keratoconjunctivitis sicca with scaling has been documented in cavalier King Charles spaniel dogs. The dogs have a syndrome that includes the following features: keratoconjunctivitis from the time the eyelids open, roughened curly pelage, scaling with abdominal hyperpigmentation, footpad hyperkeratosis, nail dystrophy, and periodic nail sloughing.

Treatment In both human and veterinary medicine, the therapy for ichthyosiform disorders has not kept pace with the research into the pathogenesis and molecular characterization. Topical therapy remains the treatment of choice for all forms of ichthyosis. The importance of ruling out secondary forms of scaling cannot be overemphasized. One should keep in mind that the skin barrier is abnormal. Dogs with primary cornification defects have excessive water loss through the skin and are susceptive to skin infections (bacterial and yeast), and are theoretically prone to allergen penetration and sensitization (i.e., atopic dermatitis and cutaneous adverse food reaction). The goal of therapy should be to restore the skin barrier, remove excessive scale, and keep the skin subtle and pliable. Initially, baths may be required every other day to twice weekly. Shampoos containing 2% sulfur and salicylic acid help soften the scale and break apart the keratin squames. The shampooing should always be followed by application of a good moisturizer. Products containing humectants such as propylene glycol (e.g., Humilac) may be helpful between baths. One should avoid the use of harsh topical products that may further harm the skin barrier (e.g., tar-based shampoos) and ensure that the product does not cause erythema or pruritus. Topical lipid-based spot-ons such as Duoxo Seborrhea Spot-on or micro-emulsion spray, which contains 1% phytosphingosine (a major component of ceramides), and Allerderm spot-on, which contains a combination of ceramides and fatty acids, are helpful products that can be administered between baths and may prolong the required bathing intervals. Severe cases may require a treatment regimen similar to that for sebaceous adenitis: pretreatment with bath oil soaks to remove excessive thick scale, followed by a keratolytic shampoo and generous application of a moisturizer. Oral omega-3 and omega-6 fatty acids may also be beneficial, but the true efficacy is difficult to quantify. The topical regimen is tailored to the degree of scale and then tapered based on the clinical response. Periodic rechecks (e.g., impression smears, acetate tape preparations) are warranted to assess scale production and secondary infection. American bulldogs and Jack Russell terriers are more likely to need oral antifungal therapy (e.g., ketoconazole 5 to 8 mg/kg/day for 21 days) for secondary yeast infections. In refractory cases, retinoids can

be considered; however, the use of retinoids by veterinarians has become problematic, because some pharmacies will dispense only with permission from an authorized physician and a patient consent form. The retinoid currently on the market is acitretin (dosed at 0.5 to 1 mg/kg q24h); however, it may not be as effective as etretinate, which is currently off the market. If retinoids are used, the dog should be monitored for keratoconjunctivitis sicca and liver toxicity, and the drugs should not be used in intact females due to the threat of teratogenicity. Oral vitamin A is unlikely to be beneficial. Immunomodulatory-lacrimostimulant therapy may decrease progression of keratitis in cavalier King  Charles spaniels; however, the therapy does not result  in a clinical cure.

Vitamin A–Responsive Dermatosis Vitamin A–responsive dermatosis is most commonly seen in adult cocker spaniels although it reportedly occurs in Labrador retrievers, miniature schnauzers, and Gordon setters as well. Clinical lesions consist of hyperkeratotic plaques with follicular plugging and follicular casts on the ventral and lateral chest and abdomen. The dogs may have greasy hair coat with ceruminous otitis. The diagnosis is achieved by skin biopsy findings and observation of a response to vitamin A supplementation. The major histologic feature is marked follicular orthokeratotic hyperkeratosis, which is more severe than the epidermal surface hyperkeratosis. The standard vitamin A dosage for a cocker spaniel is 10,000 IU/day or 500 to 800 IU/kg/day. A clinical response is typically seen in 3 to 8 weeks, and dogs may require lifelong therapy.

Labrador Retriever Nasal Parakeratosis Nasal parakeratosis arises in Labrador retrievers at less than 1 year of age and is thought to have an autosomalrecessive pattern of inheritance. The dogs develop thick, slightly verrucous, brown scale on the nasal planum with variable depigmentation. The disorder has characteristic histologic features: marked parakeratotic hyperkeratosis with serum lake formation and a variable band of lymphocytes and plasma cells in the superficial dermis. Topical emollients are generally all that is needed for treatment. Daily applications of white petrolatum (petroleum jelly) or propylene glycol in water are effective; however, the hyperkeratosis will recur if the therapy is stopped.

Generalized Sebaceous Gland Hyperplasia of Terriers Idiopathic generalized sebaceous gland hyperplasia has been reported in both Border terriers and wirehaired terriers. This disorder is different from the nodules of sebaceous gland hyperplasia seen in aging dogs. The terriers have a greasy hair coat that is most severe on the dorsum. Some dogs, particularly wirehaired terriers, have been documented with Demodex injai infestation. These longbodied Demodex mites are often found in sebaceous gland ducts in addition to hair follicles. Skin biopsy specimens

CHAPTER  115  Alopecia X reveal diffuse sebaceous gland hyperplasia independent of the mite infestation. The true relationship of the sebaceous gland hyperplasia to the Demodex mites is unknown. Treatment of mite infestation improves the skin but does not reverse the sebaceous gland hyperplasia. It is plausible that the sebaceous gland hyperplasia is the primary lesion and predisposes the dogs to Demodex infestation.

References and Suggested Reading Credille KM: Primary cornification defects. In Guaguère E, Prélaud P, editors: A practical guide to canine dermatology, Paris, 2008, Kalianxis, pp 425-438. Credille KM et al: Mild recessive epidermolytic hyperkeratosis with a novel keratin 10 donor splice-site mutation in a family of Norfolk terrier dogs, Br J Dermatol 153(1):51, 2005. Credille KM et al: Transglutaminase 1-deficient recessive lamellar ichthyosis associated with a LINE-1 insertion in Jack Russell terrier dogs, Br J Dermatol 161:265, 2009.

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Dedola C et al: Idiopathic generalized sebaceous gland hyperplasia of the Border terrier: a morphometric study, Vet Dermatol 21:494, 2010. Hartley C et al: Congenital keratoconjunctivitis sicca and ichthyosiform dermatosis in 25 Cavalier King Charles spaniel dogs. Part I: clinical signs, histopathology, and inheritance, Vet Ophthalmol 15:315, 2012. Epub December 29, 2011. Marsella R, Olivry T, Carlotti DN; for the International Task Force on Canine Atopic Dermatitis: Current evidence of skin barrier dysfunction in human and canine atopic dermatitis, Vet Dermatol 22:239, 2011. Mauldin EA et al: The clinical and morphologic features of nonepidermolytic ichthyosis in the golden retriever, Vet Pathol 45:174, 2008. Ordeix L et al: Demodex injai infestation and dorsal greasy skin and hair in eight wirehaired fox terrier dogs, Vet Dermatol 20:267, 2009. Pagé N et al: Hereditary nasal parakeratosis in Labrador retrievers, Vet Dermatol 14:103, 2003.

115 

Alopecia X ROSARIO CERUNDOLO, Six Mile Bottom, Suffolk, United Kingdom

A

lopecia X is a form of canine adult-onset alopecia that was formerly known by various names (Box 115-1). However, this diversity in names is merely descriptive and is based on the differences in endocrine findings or clinical responses to various therapeutic modalities. Alopecia X mainly affects Nordic breeds (Samoyed, Siberian husky, spitz, and Alaskan malamute) but may also affect the chow-chow, Pomeranian, and miniature poodle. Alopecia X is probably a clinical spectrum of different conditions. It is not yet proven that Alopecia X in the aforementioned breeds actually is a single disease entity with similar causes and pathogenesis. Alopecia X usually starts in dogs between 1 and 3 years of age, although cases have been reported in 9-month-old puppies and 11-year-old dogs. Intact males seem to be predisposed.

Pathogenesis The pathogenesis of alopecia X remains poorly understood. A genetic predisposition to a hormone production defect or abnormal hormone action on the hair follicle is suspected. Arguments in favor of a defect in sex hormone production include hair regrowth in affected dogs following neutering or treatment with products that affect sex hormone production and elevated levels of certain sex

hormones, especially 17-hydroxyprogesterone (17-OHP), following adrenocorticotropic hormone (ACTH) stimulation in some affected dogs. It has been proposed that alopecia X in miniature poodles and Pomeranians may be a variant of pituitary-dependent hyperadrenocorticism (Cerundolo et al, 2007).

Clinical Signs Alopecia X is a disease that exclusively affects the hair coat and skin of dogs. Dogs are normally healthy. If there are signs of systemic disease, other endocrine diseases should be suspected. Initially there is sparse loss of guard hairs resulting in a dull, dry coat. Sometimes a more generalized loss of guard hairs gives the coat a “puppy” appearance. The hair coat may also appear lighter or a different color with the loss of guard hairs. Hair loss may be noted first in frictional areas such as around the neck, tail head region, and caudal thighs, and these areas become more severely involved with time. The progression from early changes in hair coat to complete hair loss may take several years in some dogs. The retained secondary hairs are also lost with time, which results in complete alopecia of the affected areas. The exposed skin may become hyperpigmented. It is likely that the increased pigmentation is the

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result of sun exposure and can be minimized with sun restriction or use of clothing. Owners may first become aware of the problem when the dog’s hair coat fails to regrow after clipping. This can also be seen in endocrine diseases or in Nordic or plush-coated breeds that were shaved during the normal telogen phase of the hair cycle. Hair regrowth is often seen in areas of trauma (e.g., skin scraping or biopsy sites). Secondary skin infections are rare in this condition.

and anagen effluvium, should be ruled out. Sometimes affected dogs have thyroid test results suggestive of hypothyroidism (low total thyroxine level), but other thyroid test results are normal. In those cases thyroid supplementation fails to cause hair regrowth. Skin biopsies are helpful to support the diagnosis of alopecia X and are useful to rule out inflammatory causes of the alopecia. Histologically, there is orthokeratotic hyperkeratosis, epidermal melanosis, follicular keratosis, and follicular dilatation. Hairs have excessive trichilemmal keratinization (flame follicles), a sign of late catagen suggesting catagen arrest. Hair regrowth may occur at the site of the biopsy. Evaluation of the steroids produced by the adrenal gland may be supportive in the diagnosis of alopecia X and can be assessed by performing an ACTH stimulation test, but the test results can be inconclusive. The classic ACTH stimulation test is performed; however, the prestimulation and poststimulation test samples must be sent to a laboratory that is capable of measuring concentrations of adrenal and sex hormones, including cortisol, 17-OHP, estrogen, progesterone, and testosterone. Results may demonstrate increased levels of progesterone or 17-OHP in both males and females, intact or neutered, which suggests abnormal steroid production or conversion, although this should not be considered pathognomonic of alopecia X. Additional diagnostic testing that may be useful in the workup of alopecia X includes the oral or intravenous low-dose dexamethasone suppression test (LDDST) and the urinary cortisol : creatinine ratio (UCCR). A normal oral or intravenous LDDST result can help rule out alopecia X because most dogs with alopecia X show abnormal suppression. This was demonstrated in Pomeranians with alopecia X, which showed lack of complete suppression when compared with healthy dogs of other breeds and with healthy Pomeranians (Cerundolo et al, 2007). The UCCR can be determined for urine samples collected on several days, and subsequently the average of the ratios can be calculated (Cerundolo et al, 2007). Dogs with alopecia X should have ratios higher than those commonly found in normal dogs, whose UCCRs range from 0.3 to 8.3 × 10−6 with a mean ± 1 standard deviation of 2.9 ± 1.4 × 10−6 (Van Vonderen et al, 1997). However, overlap of UCCRs may occur between dogs affected with alopecia X and normal dogs (Cerundolo et al, 2007), and dogs with other illnesses can have elevated UCCRs. It is reemphasized that this disease is one in which diagnosis can be difficult because none of the tests described earlier is pathognomonic for alopecia X. However, the aforementioned battery of tests should be useful in the workup and help to rule out other causes of the alopecia.

Diagnosis

Treatment

There is no test that can definitively diagnose alopecia X in a dog. The diagnosis is often made by exclusion (Box 115-2). Other endocrine diseases such as hyperadrenocorticism, hypothyroidism, and hyperestrogenism, as well as breed-specific hair cycle abnormalities, color dilution alopecia, black hair follicular dysplasia, telogen effluvium,

The pros and cons of each therapeutic option listed in the following sections must be explained to the owner because alopecia X is a cosmetic disorder. “Benign neglect” could be an option and may be the best treatment. The various medical and surgical treatments, sometimes contradictory, reflect the difficulty in treating this type of hair

BOX 115-1  Synonyms of Alopecia X 1. Pseudo–Cushing’s syndrome 2. Growth hormone deficiency of the adult dog 3. Hyposomatotropism of the adult dog 4. Growth hormone–responsive dermatosis 5. Castration-responsive dermatosis 6. Sex hormone dermatosis 7. Estrogen-responsive dermatosis 8. Testosterone-responsive dermatosis 9. Biopsy-responsive alopecia 10. Adrenal sex hormone disorder 11. Congenital adrenal hyperplasia 12. o,p′DDD-responsive dermatosis 13. Nordic breed follicular dysplasia 14. Follicular dysplasia of the Siberian husky and malamute 15. Malamute coat funk 16. Woolly syndrome 17. Black skin disease 18. Hair cycle arrest o,p′DDD, Mitotane.

BOX 115-2  Criteria Commonly Used by the Author to Confirm a Diagnosis of Alopecia X 1. Predisposed breed 2. Age of onset between 1 and 6 years 3. Clinical pattern of alopecia: truncal progressive hair loss and/or woolly coat quality, with or without cutaneous hyperpigmentation 4. Absence of systemic clinical signs 5. Normal hematologic and biochemical findings 6. Normal thyroid function 7. Increase in concentration of 17-hydroxyprogesterone before and/or after stimulation with adrenocorticotrophic hormone (often present) 8. Increase in cortisol : creatinine ratio in morning urine samples (often present) 9. Mild or moderate suppression of cortisol : creatinine ratio by intravenous or oral low-dose dexamethasone suppression test 10. Histologic findings of hair follicle cycle arrest

CHAPTER  115  Alopecia X loss. The following therapeutic options are currently recommended to the owners of affected dogs.

Neutering Castration may lead to hair regrowth in a few weeks (Rosser, 1990). Although response may be complete, the owner should be warned that some animals relapse and lose their hair again after a few years. Although less well documented, hair may also regrow in females following ovariohysterectomy.

Melatonin Melatonin treatment results in partial to complete hair regrowth in approximately 40% of cases. It is very safe, although it is contraindicated in dogs with diabetes mellitus because melatonin can cause insulin resistance at high doses. The mode of action is unknown, but melatonin may affect the metabolism of sex hormones (Ashley et al, 1999). The recommended dosage of melatonin is 3 mg q12h PO for small breeds and 6 to 12 mg q12h PO for large breeds. Many dogs subsequently lose hair even if current treatment is maintained; therefore it is recommended to stop treatment once hair regrowth is established and to restart treatment only if the hair loss recurs. There appear to be no adverse effects apart from mild sedation.

Mitotane and Trilostane Two drugs used to treat hyperadrenocorticism, mitotane and trilostane, have been used to manage dogs with alopecia X. The exact mechanisms by which mitotane or trilostane causes hair regrowth in dogs with alopecia X are unknown. These drugs may work through manipulation of the adrenal-gonadal steroids, since these hormones are known to have both stimulatory and inhibitory effects on the hair follicle cycle. Mitotane Mitotane (Lysodren) causes selective necrosis and atrophy of the zona fasciculata and zona reticularis of the adrenal cortex. It has been used to treat dogs with alopecia X at induction dosages of 15 to 25 mg/kg q24h PO followed by twice weekly dosing (Frank et al, 2004; Rosenkrantz and Griffin, 1992). Routine ACTH stimulation tests should be performed to monitor cortisol concentrations and prevent hypocortisolemia or iatrogenic Addison’s disease. Unfortunately, some dogs may subsequently lose hair again despite achievement of good hormonal control and continued therapy. Therefore it is best not to continue therapy once hair regrowth is achieved and to restart only if hair loss recurs. Mitotane should be used only after other treatments have failed and, in view of the potential adverse effects (e.g., vomiting and weakness due to hypoadrenocorticism), with consent of a fully informed owner. Trilostane Trilostane (Vetoryl), an inhibitor of 3β-hydroxysteroid dehydrogenase, has been used with success to treat Pomeranians, miniature poodles, and Alaskan malamutes

479

with alopecia X (Cerundolo et al, 2004; Leone et al, 2005). The dosages used by the authors include 3.0 to 3.6 mg/kg q12h PO in Alaskan malamutes and 2.5 to 5.0 mg/kg q24h PO in Pomeranians and miniature poodles. Complete hair regrowth within 4 months has been reported in Alaskan malamutes, miniature poodles, and Pomeranians. Once full hair regrowth has been achieved the trilostane can be given two or three times a week to maintain a good coat because withdrawing it completely results in hair loss after a few months. Adverse effects (e.g., vomiting, diarrhea) are rare, and dogs should be reexamined routinely and monitored for signs of hypoadrenocorticism. An ACTH stimulation test is normally performed 10 days after beginning the treatment, then after 4 weeks, 12 weeks, and 6 months, and finally twice yearly. Large-scale trials are still needed to further evaluate the exact dosage needed to treat affected dogs of various breeds.

Antiandrogens Recently antiandrogens have been used in an attempt to stimulate hair regrowth in dogs with alopecia X. These include the oral antiandrogen finasteride (Propecia), which has been anecdotally reported to result in partial to complete hair regrowth in alopecic Pomeranian dogs, and a deslorelin-based implant (Suprelorin) used to reversibly induce infertility in male dogs. To the author’s knowledge no studies have been conducted evaluating the efficacy or side effects of these treatments for  alopecia X.

References and Suggested Reading Ashley PF et al: Effect of oral melatonin administration on sex hormone, prolactin, and thyroid hormone concentrations in adult dogs, J Am Vet Med Assoc 215:1111, 1999. Cerundolo R et al: Treatment of canine Alopecia X with trilostane, Vet Dermatol 15:285, 2004. Cerundolo R et al: Alopecia in Pomeranians and miniature poodles in association with high urinary corticoid:creatinine ratios and resistance to glucocorticoid feedback, Vet Rec 160:393, 2007. Erratum in Vet Rec 160:547, 2007. Frank LA: Oestrogen receptor antagonist and hair regrowth in dogs with hair cycle arrest (Alopecia X), Vet Dermatol 18:63, 2007. Frank LA, Hnilica KA, Oliver JW: Adrenal steroid hormone concentrations in dogs with hair cycle arrest (Alopecia X) before and during treatment with melatonin and mitotane, Vet Dermatol 15:278, 2004. Leone F et al: The use of trilostane for the treatment of alopecia X in Alaskan malamutes, J Am Anim Hosp Assoc 41:336, 2005. Rosenkrantz WS, Griffin C: Lysodren therapy in suspect adrenal sex hormone dermatosis. In Proceedings of the 2nd World Congress of Veterinary Dermatology, 1992, p 121. Rosser EJ: Castration responsive dermatosis in the dog. In von Tscharner C, Halliwell REW, editors: Advances in veterinary dermatology, vol 1, Philadelphia, 1990, Baillière Tindall, p 34. Shibata K, Koie H, Nagata M: Clinicopathologic and morphologic analysis of the adrenal gland in Pomeranians with nonillness alopecia, Jpn J Vet Dermatol 11:115, 2005. Van Vonderen IK, Kooistra HS, Rijnberk A: Intra- and interindividual variation in urine osmolality and urine specific gravity in healthy pet dogs of various ages, J Vet Intern Med 11:30, 2007.

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Actinic Dermatoses and Sun Protection AMANDA K. BURROWS, Perth, Australia

S

olar-induced lesions in dogs and cats occur on skin with no or light pigmentation and sparsely haired regions that are exposed frequently to sun. Lesions are more common in dogs and cats that spend substantial time outdoors or sunbathe (lying in dorsal or lateral recumbency for extended periods), or are housed where there is reflective ground cover (including snow) and little sun protection. The most commonly affected dog breeds are white English bull terriers, dalmatians, beagles, fox terriers, whippets, white boxers, American Staffordshire bull terriers, basset hounds, and American bulldogs. White-haired areas of short-haired cats are most at risk. Blue-eyed white cats are most susceptible.

Clinical Features of Actinic Dermatoses in Dogs and Cats Canine Disease In dogs lesions range from patchy or confluent erythema and scaling affecting nonpigmented thickened skin to scaly erythematous papules or crusted indurated linear plaques and nodules with erosions and ulcers and hemorrhagic crusts. Actinic comedones may be present, filled with darkly colored keratinous or caseous debris in nonpigmented lightly haired skin and may be irregularly thickened and firm on palpation. Lesions may be discrete pigmented subepidermal foci or small nodules. Comedones may rupture, eliciting a foreign body response and furunculosis. Intact hemorrhagic bullae are a distinctive feature secondary to actinic comedone rupture with crusted erythematous nodules that may be intact or fistulated. A coexistent bacterial pyoderma may make the clinical diagnosis more difficult. Actinic keratoses are premalignant epithelial lesions that can transform into invasive squamous cell carcinoma. These lesions are either single or multiple and are erythematous, scaly red to reddish-brown, ill-defined macules that progress to indurated, crusted plaques and are rough on palpation. Induration, erosion, ulceration, or increasing diameter should raise the suspicion of evolution into squamous cell carcinoma. Lesions often are found abruptly adjacent to normal pigmented skin. In dogs that sunbathe lesions commonly are observed on the glabrous skin of the ventral and lateral abdomen, 480

flank folds, inner thighs, scrotum, and perineum. The hock and distal hind limb, bridge of the nose, pinnae, dorsal muzzle, periorbital regions, and tail tip also may be affected.

Feline Disease In cats early lesions appear on the margins of the sparsely haired pinnae and are characterized by mild erythema and fine scaling. These progress to erythematous plaques, crusting, erosions and superficial ulceration with pain, scratching, and twitching of the pinnae. The margins of the lower eyelids, lips, nasal planum, preauricular region of the face, and dorsal muzzle may be affected similarly.

Diagnosis of Actinic Dermatosis The diagnosis of actinic dermatitis is based on the correlation of breed, coat color, coat length, ultraviolet (UV) light exposure, and lesion localization to body sites  commonly affected by solar damage. Comedones in sunexposed skin, with or without evidence of other solarinduced lesions, should increase suspicion of actinic dermatosis. The lesions of actinic furunculosis need to be differentiated from deep bacterial folliculitis and furunculosis, demodicosis with deep pyoderma, systemic or opportunistic fungal infections, and neoplasia. Actinic dermatitis is diagnosed by histopathologic analysis. It is important to resolve any secondary infections before collection of biopsy samples. Biopsy specimens should be obtained from different types of lesions and different stages of the disease. A complete history should be provided with the biopsy submission, including signalment, degree of solar exposure, and distribution and clinical description of lesions, and the specimens should be examined by a veterinary dermatohistopathologist if possible. Characteristic microscopic lesions include vacuolated keratinocytes with pyknotic nuclei and eosinophilic cytoplasm (“sunburn cells”), epidermal hyperplasia, follicular keratosis, laminar alteration of collagen in the superficial dermis (dogs) with superficial laminar fibrosis, perivascular to lichenoid inflammation, solar elastosis, and actinic comedones with pyogranulomatous folliculitis and furunculosis as common sequelae to comedonal rupture.

CHAPTER  116  Actinic Dermatoses and Sun Protection

Sun Protection The best treatment for solar dermatitis is prevention, and owners should be educated to practice sun avoidance and protection for their pets at an early age. Once chronic actinic dermatitis is present, the disease is incurable.

Sun Avoidance Dogs and cats should be kept inside from 9 AM to 3 PM and should not be permitted to sunbathe near open doors and windows (normal window glass does not block UV radiation). For animals that cannot be kept inside, pro­ viding generous shade is highly recommended. White concrete floors should be avoided because they reflect sunlight.

Sun-Protective Clothing Cotton T-shirts may assist in decreasing sun exposure; however, they rarely cover all at-risk areas of the  skin. Body suits made from synthetic fabrics (Lycra, Dacron) with a high sun protection factor (SPF) (www.  designerdogwear.com) are recommended, or owners may be able to make sunsuits for their pets using sun-protective fabric. In the author’s experience, most dogs tolerate the flexible and comfortable protection suits.

Sunscreens Sunscreen should be applied 10 to 15 minutes before sun exposure and, if solar exposure is unpredictable, should be applied twice daily. Titanium or zinc oxide products should not be rubbed in because they work best when applied as a thin smear. A waterproof SPF  30 (or higher) sunscreen containing a broad-spectrum UV-absorbing chemical in combination with titanium or zinc oxide should be used for maximal efficacy. Ingestion of some ingredients may cause adverse gastrointestinal effects, and zinc toxicity may result from ingestion of zinc-based products; excessive ingestion should be prevented. Colorants absorb or reflect visible light but offer no protection against UV rays. Thus recommendations to apply black ink and tattoo skin surfaces should be disregarded.

Treatment of Actinic Dermatoses

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been used in dogs and cats with actinic dermatitis and  is effective and well tolerated. The adverse effects are limited to mild pruritus and irritation at the site of application. Imiquimod Five percent imiquimod (Aldara cream) has good efficacy with moderate morbidity in the treatment of human actinic keratosis. Recently pinnal lesions in a cat were treated with topical 5% imiquimod three times weekly for 12 weeks, which resulted in resolution of the lesions. Adverse effects were limited to erythema, crusting, alopecia, and mild discomfort at the sites of application during the first 3 weeks. These results suggest that topical imiquimod might be a therapeutic option for cats for which surgery and radiation therapy are not feasible. Retinoids Tretinoin is a topical retinoid considered to be of low efficacy for the treatment of actinic keratoses in humans, but there are anecdotal reports of its use to treat actinic dermatitis in dogs and cats.

Oral Treatments Synthetic Retinoids Partial to complete resolution of actinic keratoses in dogs was achieved with the administration of etretinate 1 mg/ kg q12h PO for 3 months. Etretinate is no longer available, but acitretin administered at 0.5 to 1 mg/kg q24h PO for 4 to 6 weeks, with the frequency then reduced to q48h for 4 to 6 weeks and finally to twice a week, is effective in dogs with actinic dermatitis in the author’s experience. Potential adverse effects include keratoconjunctivitis sicca, vomiting, diarrhea, elevation in triglyceride levels, and hepatotoxicity; regular monitoring for these adverse effects is critical. Retinoids are teratogenic and very expensive, which limits their use, particularly in largerbreed dogs. Vitamin A Oral vitamin A has been recommended for canine and feline actinic dermatitis, but controlled clinical trials are lacking. The recommended dosage is 800 to 1000 IU/kg q24h for 3 months, with frequency then tapered to three times a week.

Topical Treatments

Other Treatment Options

Topical therapy for actinic dermatoses can include glucocorticoids, diclofenac, imiquimod, and retinoids.

The principal surgical therapeutic options for actinic keratosis in dogs and cats are excisional surgery, cryosurgery, and carbon dioxide laser ablation of the affected epidermis. For optimal success with cryosurgery, temperature probes should be used to ensure adequate freezing time. Laser ablation with a carbon dioxide laser is an effective treatment modality in human actinic keratosis and is used by some veterinary dermatologists. Cutaneous dermabrasion and chemical peeling with 35% trichloroacetic acid, α-hydroxy acid, and liquid nitrogen spray also are treatment options for diffuse actinic keratoses in humans and their use has been advocated in dogs.

Glucocorticoids For acute solar dermatitis 1% to 5% hydrocortisone ointment or cream is applied q12-24h for 7 to 10 days. If systemic therapy is required to reduce erythema, oral prednisolone (1 mg/kg q24h for 7 to 10 days) is used. Diclofenac Topical 3% diclofenac in 2.5% hyaluronan gel (Solaraze Gel), developed for humans with actinic keratoses, has

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References and Suggested Reading Frank LA, Calderwood Mays MB: Solar dermatitis in dogs, Compend Contin Educ Pract Vet 16:465, 1994. Gross TL, Ihrke PJ, Walder EJ: Veterinary dermatopathology: a macroscopic and microscopic evaluation of canine and feline skin disease, St Louis, 2005, Mosby Year Book. Peters-Kennedy J, Scott DW, Miller WH Jr: Apparent clinical  resolution of pinnal actinic keratoses and squamous cell

CHAPTER 

carcinoma in a cat using topical imiquimod 5% cream, J Feline Med Surg 10(6):593, 2008. Power HT, Ihrke PI: The use of synthetic retinoids in veterinary medicine. In Bonagura JD, editor: Kirk’s current veterinary therapy XII: small animal practice, Philadelphia, 1995, Saunders, p 585. Rosenkrantz WS: Solar dermatitis. In Griffin CE, Kwochka KW, Macdonald JM, editors: Current veterinary dermatology: the science and art of therapy, St Louis, 1993, Mosby Year Book, p 309.

117 

Drugs for Behavior-Related Dermatoses MEGHAN E. HERRON, Columbus, Ohio

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ommon behavior problems that manifest with dermatologic disease include overgrooming (i.e., feline psychogenic alopecia), repetitive licking (i.e., lick granulomas), and self-mutilating behaviors. Differentiation between dermatologic and psychologic disease is a complex process. These behaviors can be a response to underlying pain or pruritus, or the symptoms of anxiety and compulsive disorders. Recent studies suggest that a behavioral cause for self-inflicted dermatologic disease may be overdiagnosed. Despite the repetitive and seemingly compulsive nature of self-injurious behavior disorders, often the initial trigger is pruritic disease, such as atopic dermatitis, cutaneous adverse food reactions, or flea allergy dermatitis. Many patients have comorbidities, and special care should be taken to address the underlying medical conditions before or simultaneously with the treatment of behavior disorders. A thorough medical and behavioral history should be obtained and a full dermatologic workup performed before diagnosing and treating a patient for a behavior disorder. Psychotropic medications often are indicated for patients with primary behavior disorders or for those with behavior that may be complicating or caused by an underlying dermatologic disease. These medications can mitigate the behavioral aspects of primary dermatologic disease as well as allow medical treatment to be more effective when both dermatologic and behavioral conditions are suspected. This chapter offers an overview and clinical insight into the use  of psychotropic medications to treat behavior-related dermatoses. Psychotropic medications are used for their ability to mitigate anxiety and the animal’s response to external

stressors. Several classes of drugs offer these benefits, some of which also have antipruritic properties, which makes them especially helpful when both dermatologic and behavioral problems are present. Before the patient begins treatment, baseline laboratory testing should be performed to ensure that it is safe to administer hepatically metabolized and renally excreted medications long term. Typically this includes a complete blood count, chemistry profile, total thyroxine level, and urinalysis. These tests should be performed every 6 to 12 months during treatment, depending on the age and health status of the pet. The initial goal should be to achieve therapeutic effects and to minimize adverse effects. This is best accomplished by starting the patient at the low end of the dosage range for the first 2 weeks of treatment, then titrating up to effect, while keeping in mind that therapeutic effects of some medications may take 4 to 6 weeks to appear. In mild to moderate cases, particularly those in which an instigating medical disease can be identified and treated, the patient can be weaned from medications by decreasing the dose by 25% every 2 weeks beginning 3 to 6 months after the cessation of clinical signs. In patients with severe compulsive disorders, however, treatment with psychotropic medications may be lifelong.

Classes of Psychotropic Medications Tricyclic Antidepressants The tricyclic antidepressants (TCAs) are named for their three-ringed molecular structure. Commonly used TCAs in veterinary medication include clomipramine (Clomicalm), doxepin, and amitriptyline (Elavil). Clomipramine,

CHAPTER  117  Drugs for Behavior-Related Dermatoses under the brand name Clomicalm, is approved by the U.S. Food and Drug Administration for use in dogs with separation anxiety and carries a veterinary label. The author recommends the use of the brand name drug Clomicalm, rather than the generic drug clomipramine, unless an allergy to the meat flavoring is suspected, because anecdotally many patients seem not to respond as well to the generic product. Each TCA has properties that block the reuptake pumps for the neurotransmitters serotonin, norepinephrine, and, to a lesser extent, dopamine. The blockade of neurotransmitter reuptake pumps results in greater neurotransmitter availability, which leads to receptor changes that allow for therapeutic anxiety relief within approximately 4 to 6 weeks. Specifically, activation of the serotonin 1A (5-HT1A) receptor because of the persisting increase in serotonin levels is responsible for the anxiety-relieving effects. Clomipramine has the greatest specificity for serotonin, which makes it more effective for anxiety relief. Amitriptyline tends to be heavily sedating and to have poorer anxietyrelieving effects and is therefore rarely used by the author. Furthermore, this class of drugs also exerts anticholinergic (muscarinic), antiadrenergic (α1), and antihistaminic (H1) properties and can block sodium channels in the brain and heart. These additional properties are responsible for adverse effects, such as sedation, dry mouth, constipation, urine retention, increased seizure potential, and arrhythmias. In cats the sedative effect can be profound and often leads to owner dissatisfaction and noncompliance. Preparing owners about the potential for these adverse effects may increase compliance and encourage communication about the pet’s response. In animals with a history of obstipation, seizures, or cardiovascular disease, this class of drugs should be avoided. When a concurrent pruritic disease is being treated, the antihistamine properties of TCAs offer an additional benefit. Doxepin has the most potent antihistamine properties of any of the TCAs and, in fact, has 600 to 800 times the antihistamine effects of diphenhydramine. Unfortunately, the serotonin-enhancing effects of doxepin are the lowest in its class, which makes it a poor choice when anxiety or compulsion is the primary cause for the dermatosis. Each clinician should weigh the effects of both anxiety/compulsion and pruritus when choosing a TCA that will affect skin and behavior. See Table 117-1 for dosing recommendations.

Selective Serotonin Reuptake Inhibitors The selective serotonin reuptake inhibitors (SSRIs) are a class of drugs that produce potent and selective blockade of the serotonin reuptake pump. This is a property shared with the TCAs, but this class is much more specific for serotonin and has little to no effect on reuptake of other neurotransmitters. The specificity of this class of drugs for the treatment of anxiety often makes them a better choice when treating a primary anxiety or compulsive disorder when little to no pruritus is present. As with the TCAs, therapeutic effects of SSRIs take 4 to 6 weeks to manifest and occur primarily through activation of the 5-HT1A receptors. Commonly used SSRIs in the treatment of compulsive, self-directed behaviors are fluoxetine (Reconcile,

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TABLE 117-1  Systemic Drugs and Suggested Dosages for   the Treatment of Behavioral Dermatoses Drug Name (Trade Name)

Dog

Cat

Tricyclic Antidepressants (TCAs) Allow 4-6 wk for therapeutic effects to manifest. This class of drugs has antihistamine properties and may be useful if allergic disease is also suspected. Clomipramine (Clomicalm)

1.0-3.0 mg/kg q12h PO

0.25-1.0 mg/kg q24h PO

Doxepin

3.0-5.0 mg/kg q12h PO

0.5-1.0 mg/kg q12-24h PO

Selective Serotonin Reuptake Inhibitors (SSRIs) Allow 4-6 wk for therapeutic effects to manifest. Fluoxetine (Reconcile)

0.5-2.0 mg/kg q24h PO

0.25-1.5 mg/kg q24h PO

Paroxetine

0.5-1.5 mg/kg q24h PO

0.25-1.0 mg/kg q24h PO

Sertraline

1.0-4.0 mg/kg q24h PO

0.25-0.5 mg/kg q24h PO

Serotonin Antagonist Reuptake Inhibitors (SARIs) May see some immediate effect with greater effect over 4-6 weeks. This class of drugs has antihistamine properties and may be useful if allergic disease is also suspected and can be used to augment the effects of TCAs or SSRIs. Trazodone

1.0-10.0 mg/kg q12h, not to exceed 600 mg per 24h

No published dose

Benzodiazepines Allow 30-60 min for onset of therapeutic effects. Alprazolam

0.05-0.25 mg/kg q4h PO

0.025-0.2 mg/kg q8h PO

Diazepam

0.5-2.2 mg/kg q4-6h PO

Avoid

Clorazepate

0.5-2.2 mg/kg q8-12h PO

Avoid

Clonazepam

0.1-0.5 mg/kg q12h PO

0.025-0.2 mg/kg q12h PO

Lorazepam*

0.1-0.5 mg/kg q12h PO

0.025-0.25 mg/kg q12h PO

Oxazepam*

0.2-1.0 mg/kg q121h PO

0.2-1.0 mg/kg q12h PO

*No active hepatic metabolites—may be safer in geriatric and feline patients. PO, Orally.

Prozac), paroxetine (Paxil), and sertraline (Zoloft). Unlike the TCAs, SSRIs have minimal anticholinergic, antiadrenergic, and antihistaminic effects, which gives them a lower side effect profile. This also means that there are little to no antipruritic benefits to this class of drugs. Fluoxetine is the most frequently used SSRI in behavioral medicine, has been the subject of the most published

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SECTION  V  Dermatologic and Otic Diseases

Serotonin antagonist reuptake inhibitors (SARIs) are relatively new to veterinary medicine. Their primary mode of action is potent blocking of the 2A serotonin receptor (5-HT2A). Active 5-HT2A receptors have inhibitory effects on 5-HT1A receptors. Since 5-HT1A receptor activation caused by increased serotonin is what is responsible for the anxiety-relieving effects of SSRIs and TCAs, active 5-HT2A receptors can prevent other serotonin-enhancing drugs from working to their full capacity. Therefore the use of a SARI to block 5-HT2A receptors in combination with an SSRI or TCA should lead to synergistic effects. Trazodone (Desyrel) is the only SARI with reported use in dogs, and there are no published reports of its use in cats. This drug can be added to the treatment plan of canine patients whose compulsive or anxious behaviors have been minimally responsive to SSRI or TCA monotherapy. Some immediate improvement may occur, and more can be expected over 4 to 6 weeks of therapy. Trazodone and other SARIs also have mild serotonin reuptake inhibition properties, which makes them a reasonable choice for monotherapy if needed. Unique to trazodone within this class are its antihistamine properties. The use of this medication alone or in combination with other medications may therefore provide additional relief of pruritus when underlying dermatologic disease is also suspected. For dogs with marked anxiety-related and pruritic disease, perhaps the combination of an SSRI and trazodone may provide the greatest relief. Adverse effects are uncommon but may include sedation, gastrointestinal upset, and agitation. See Table 117-1 for dosing recommendations.

binding to a site on the γ-aminobutyric acid A (GABA-A) receptor complex. This then potentiates the effects of GABA when binding to this complex, causing an immediate and potent reduction in firing of the corresponding neuron. This is the only class of drugs discussed in this chapter with the ability to quickly halt the cascade of anxiety and panic in animals. These drugs have no effect on the reuptake of serotonin or other neurotransmitters and have no antihistaminic properties; therefore they are best used in patients with primary anxiety or compulsive behaviors as opposed to those resulting from underlying dermatologic disease. This class of drugs is most often reserved for patients whose self-directed behaviors occur at predictable times or in predictable contexts. For example, this medication can be administered as needed when the behavior is predicted to occur in response to experiencing a thunderstorm or loud noise, being home alone, traveling by car, or boarding. The onset of action is approximately 30 to 60 minutes and effects persist as long as the active drug remains in the system. In some cases in which marked generalized anxiety or compulsive behaviors are constant, daily use in combination with serotonin-enhancing drugs (SSRIs, TCAs) may be helpful. Behavioral clinicians frequently augment treatment of anxiety-based overgrooming or self-directed behaviors with 24-hour dosing of a benzodiazepine when SSRIs or TCAs alone have provided only marginal relief. Although around-the-clock use of a benzodiazepine provides substantial relief in many cases, as-needed dosing is often preferred because both drug dependence and tolerance develop with prolonged daily use. There is also a significant potential for drug diversion and human drug abuse. Accordingly, caution must be exercised when prescribing benzodiazepines to animal patients. Commonly used benzodiazepines are alprazolam (Xanax), diazepam (Valium), clorazepate (Tranxene), clonazepam (Klonopin), lorazepam (Ativan), and oxazepam (Serax). The choice among various benzodiazepines is based on the required duration of action and the health status of the patient. For patients taking constant daily doses of benzodiazepines, drugs such as lorazepam, clonazepam, and oxazepam may be better options because they provide 12 hours of relief. In contrast, alprazolam would need to be dosed six times daily to provide 24-hour relief. Caution should be used when administering benzodiazepines to feline patients because acute hepatic necrosis has been reported after oral administration of diazepam. The author has observed this toxicosis with the use of clorazepate in cats as well. If benzodiazepine use is indicated in a cat, lorazepam and oxazepam may be safer options because they lack active hepatic metabolites. These two drugs also may be more appropriate for geriatric dogs or those with known hepatic disease. Table 117-1 summarizes dosing recommendations.

Benzodiazepines

Other Considerations

Benzodiazepines are part of a group of drugs known as anxiolytic sedatives-hypnotics. Their primary effects on behavior include an almost immediate relief of anxiety, but they also produce appetite stimulation, sedation, and muscle relaxation. The effects are a result of the drug’s

When treating behavioral dermatoses, the clinician should keep in mind that many of these compulsive or anxiety-driven behaviors are a result of underlying stressors in the animal’s environment. The clinician should talk to owners about identifying triggers for the behavior.

reports of SSRI use in companion animals, and carries a veterinary label for treatment of separation anxiety (Reconcile). The most common adverse effects of fluoxetine are decreased appetite and mild lethargy, both of which resolve over the course of a few weeks. For animals with finicky appetites, especially cats, this medication may be problematic. Owners seem to have little tolerance for inappetence in their pets, and an SSRI such as paroxetine or sertraline may be a better option, despite the lower availability of published information on their use in animals. Of the SSRIs, paroxetine has the highest potential for anticholinergic effects, although still lower than that of the TCAs. Although typically the use of paroxetine allows the avoidance of anorexigenic effects, the potential for constipation, urine retention, and dry mouth persists. Sertraline is the newest of the SSRIs to come off patent and tends to have the fewest adverse effects. Another potential benefit of sertraline is that its excretion is primarily fecal, and therefore it may be safer in patients with renal compromise. See Table 117-1 for dosing recommendations.

Serotonin Antagonist Reuptake Inhibitors

CHAPTER  118  Superficial Necrolytic Dermatitis Owners should be assisted in finding ways to remove the pet from such situations or to provide the pet with other coping mechanisms. Emphasis should be placed on managing the home environment and training new behaviors that are incompatible with self-injury. For example, dogs can be taught to engage with food enrichment toys to redirect their behavior and to prevent them from licking and traumatizing their skin. Food enrichment, in the form of puzzle toys that have been stuffed with canned food and frozen or rolling toys that dispense dry kibble or treats, can be especially helpful in directing pets to other oral behaviors. Time spent interacting with puzzle toys means less time spent on self-directed behaviors that can perpetuate dermatologic disease. However, if the underlying dermatologic disease is due to cutaneous adverse food reactions, care must be taken to select a food that is compatible with the restricted diet. Pheromone enrichment in the form of feline facial pheromones (Feliway) and canine appeasing pheromones

CHAPTER 

485

(DAP, Adaptil, Comfort Zone) can also help to create a sense of safety and comfort in the pet’s home environment. Close follow-up with owners and frequent monitoring of both medical and behavioral progress is essential in any successful treatment plan.

References and Suggested Reading Crowell-Davis SL, Murray T: Veterinary psychopharmacology, ed 1, Ames, IA, 2006, Blackwell. Landsberg G, Hunthausen W, Ackerman A: Handbook of behavior problems of the dog and cat, ed 2, New York, 2003, Saunders. Stahl SM: Essential psychopharmacology: neuroscientific basis and practical applications, ed 2, Cambridge, UK, 2000, Cambridge University Press. Virga V: Behavioral dermatology, Vet Clin North Am Small Anim Pract 33:231, 2003. Waisglass SE et al: Underlying medical conditions in cats with presumptive psychogenic alopecia, J Am Vet Med Assoc 228:1705, 2006.

118 

Superficial Necrolytic Dermatitis KEVIN BYRNE, Bensalem, Pennsylvania

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uperficial necrolytic dermatitis (SND) was initially reported in dogs as “diabetic dermatopathy” because of the association of the disorder with diabetes mellitus (Walton et al, 1986). There is a similar skin disorder in humans: necrolytic migratory erythema. Necrolytic migratory erythema is usually associated with a malignant neuroendocrine tumor called a glucagonoma. Most cases of SND in dogs are associated with liver disease, are termed the hepatocutaneous syndrome (HS) form of SND, and are not associated with a glucagonoma. However, there have been a few reported cases of the glucagonoma syndrome (GS) form of SND in dogs. A small number of cases of SND have been associated with medications (phenobarbital, primidone) and mycotoxin ingestion. The number of reported cases of SND in cats is relatively low.

Clinical Findings in Dogs The disease is more common in middle-aged or older dogs. Primary complaints of SND in dogs include soreness of the dog’s paws and lethargy or anorexia. The most useful clinical findings in dogs are abnormalities of the

paws, including crusts, erythema, and oozing. Usually all paw pads exhibit varying degrees of hyperkeratosis with subsequent crusting and fissuring of the pads. Lesions including erythema, erosions or ulcerations, serous to purulent discharge, crusts, and hyperkeratotic plaques may occur in other sites such as perioral, perianal, peri­ vulvar, preputial, and scrotal skin. Differential diagnoses of the lesions of SND include zinc-responsive dermatosis, pemphigus foliaceus, erythema multiforme, epidermolysis bullosa acquisita, and bullous pemphigoid. Impression cytologic analysis of SND lesions is usually helpful in revealing the presence of secondary infections, which are commonly associated with this disease. Complete blood count (CBC) may reveal mild nonregenerative anemia and leukocytosis. Dogs with SND (HS) have elevated levels of liver enzymes (serum alkaline phosphatase, alanine transaminase) and increased bile acids; some have hyperglycemia with or without other features of diabetes mellitus. Abdominal ultrasonography is useful to check for the presence of the hyperechoic and hypoechoic pattern within the liver often seen in dogs with SND (HS). This

486

SECTION  V  Dermatologic and Otic Diseases

pattern is sometimes described as having a “Swiss cheese” or “honeycomb” appearance. The absence of abnormal results on the serum chemistry panel makes it more likely that the dog may have the GS form of SND. Thus, in cases of SND without evidence of liver disease, thought needs to be given to the possibility of SND (GS). Abdominal ultrasonography may not be able to detect small pancreatic tumors. Magnetic resonance imaging might be able to distinguish small tumors, although contrast enhancement may be necessary. It is recommended that the owners of dogs suspected of having SND (GS) submit a sample of the dog’s plasma for glucagon measurement and that the results be compared with published information on canine plasma  glucagon. High levels of plasma glucagon support the possibility that a glucagon-secreting tumor is present. Unfortunately, assays for canine plasma glucagon usually are not available, and the sample must be submitted to a human endocrinology laboratory that measures human plasma glucagon level. It may be beneficial to consult a specialist in internal medicine or endocrinology.

Clinical Findings in Cats Cats are likely to manifest lethargy, anorexia, or weight loss. Clinical findings of SND (HS) in cats include ulceration and crusting of oral mucocutaneous junctions, and ulceration of the pinnae, periocular areas, interdigital areas, ventral abdomen, and inguinal areas with or without crust formation. Lesions may not appear on the footpads, unlike in SND in dogs. Secondary bacterial infection may be present. The CBC may reveal neutropenia, and results of a serum biochemistry profile may show elevations in alanine transaminase, aspartate transaminase, or bilirubin. Abdominal ultrasonography may reveal a diffusely coarse echotexture with reticular pattern of the liver and may or may not reveal discrete nodules.

Dermatohistopathologic Analysis Once any secondary pyoderma has been treated, skin punch biopsy with dermatohistopathologic analysis is usually adequate to diagnose the condition. Collection of three or four biopsy specimens is more likely to produce at least one specimen with the findings required for diagnosis. Specimens must contain epidermis and so should be from areas where there is no ulceration. A good practice is to collect at least one specimen from a paw pad in each patient suspected of having SND. Biopsy specimens from perioral or perianal areas seem to carry a higher risk of secondary bacterial pyoderma even with appropriate antibiotic therapy, so these sites are used only if there are no better choices. In dogs, classic lesions of SND reveal epidermal hyperplasia, parakeratosis, and variable pallor of the upper epidermal keratinocytes. Pallor may not be present at all sites biopsied, which may lead to difficulty in distinguishing the condition from zinc-responsive dermatosis. In cats, lesions of SND show epidermal hyperplasia with focal compact hyperkeratosis or parakeratosis, acanthosis, and spongiosis, and may also reveal basal  cell hyperplasia. Once dermatohistopathologic diagnosis of SND is made, diagnostic tests can be ordered to

differentiate the HS form from the GS form in individual patients.

Treatment The prognosis for SND is poor, and therapy is palliative. Debilitation caused by painful crusting lesions, especially lesions of the paws, must be addressed. Bacterial pyoderma should be treated with antibiotics that are expected to be effective against Staphylococcus and are not contraindicated in dogs with compromised liver function. Topical therapy with shampoos that contain chlorhexidine may help reduce the numbers of bacterial and yeast organisms. Since patients with SND usually have low levels of plasma amino acids, nutritional therapy centers on giving foods that provide high-quality protein. However, partial to complete anorexia is common in pets with SND, and coaxing the pet to eat may be difficult. Any prescription food designed for critical-care patients can be used as a base diet. To this are added hard-boiled egg yolks, three to six per day, and a protein powder supplement. There are many over-the-counter protein powder supplements, but all are flavored for people. The use of chocolate flavors should be avoided. Optimum Nutrition 100% casein protein powder provides 24 g of protein per scoop. The recommended dosage is 1 4 scoop per 10 lb body weight per day, mixed with food. Palatability is a problem with protein powders, and some dogs eventually lose interest in eggs. If the pet refuses prescription critical-care diets, feeding any food that is high in protein, especially meat proteins, may be an option. The prognosis worsens when it becomes difficult to coax the pet to eat. It is also recommended that pets with SND be given an essential fatty acid supplement such as Allerderm Efa-Caps and a zinc supplement such as NutriVed Zinpro chewable tablets. Although intravenous amino acid therapy using a product such as Aminosyn has been reported to be helpful in some cases of canine SND, the author has treated numerous animals that did not respond to this therapy. Administration via a catheter inserted into a larger vein, such as the jugular vein, reduces the likelihood of phlebitis. For Aminosyn 10% solution a suggested dosage is 25 ml/kg of body weight administered over 6 to 8 hours. For Aminosyn 8.5% solution the dosage is 30 ml/kg of body weight administered over 6 to 8 hours. Two to three administrations should be given at weekly intervals before a decision is made as to whether continuation of the treatment is worthwhile. For many dogs with SND (HS), the condition progresses and the pet’s condition deteriorates. At this point many pet owners understandably elect euthanasia for their pets.

Treatment of Superficial Necrolytic Dermatitis with Glucagonoma Ideally, excision of a glucagon-secreting pancreatic tumor should result in resolution of lesions of SND as is the case in many humans with necrolytic migratory erythema. Unfortunately, the mortality rate for pancreatic tumor excision in dogs is high. Also, glucagonomas are quick to metastasize, and smaller tumors may be difficult to find.

CHAPTER  119  Cutaneous Adverse Drug Reactions For patients with GS in which excision of the glucagonoma is not feasible, temporary improvement of clinical signs may be possible with the use of octreotide.

Use of Octreotide Octreotide is a somatostatin-like drug that inhibits multiple hormones, including glucagon. It has been reported to result in improvement of skin lesions in a dog with SND (GS) (Oberkirchner et al, 2010). The author treated a 10-year-old male beagle dog with SND (GS) using generic octreotide at a dosage of 2 to 3 µg/kg q12h by SC injection. Two weeks after octreotide treatment began, significant improvement was observed in the skin and paw pads and the dog was feeling much better. Six weeks after the initiation of octreotide therapy there were no ulcerated areas of the skin and paw pads and only a small number of crusts. There might be some benefit to using octreotide in patients with SND (HS). However, adverse effects of octreotide in humans include hepatic/biliary problems. Adverse effects of octreotide injection therapy in dogs include decreased appetite. Given the debilitation that SND causes in the patient and the lack of consistently beneficial therapies, octreotide might be considered in

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SND (HS) patients whose owners are willing to try this therapy with the understanding that it is not an approved treatment in dogs and also that there is the potential for adverse effects, including the theoretical possibility that it could make liver disease worse.

References and Suggested Reading Byrne KP: Metabolic epidermal necrosis—hepatocutaneous syndrome, Vet Clin North Am Small Anim Pract 29:1337, 1999. Kimmel SE, Christiansen W, Byrne KP: Clinicopathologic, ultrasonographic, and histopathological findings of superficial necrolytic dermatitis with hepatopathy in a cat, J Am Anim Hosp Assoc 39:23, 2003. Oberkirchner U et al: Successful treatment of canine necrolytic migratory erythema (superficial necrolytic dermatitis) due to metastatic glucagonoma with octreotide, Vet Dermatol 21:510, 2010. Outerbridge CA, Marks SL, Rogers QR: Plasma amino acid concentrations in 36 dogs with histologically confirmed superficial necrolytic dermatitis, Vet Dermatol 13:177, 2002. Torres S et al: Superficial necrolytic dermatitis and a pancreatic endocrine tumour in a dog, J Small Anim Pract 38:246, 1997. Walton DK et al: Ulcerative dermatosis associated with diabetes mellitus in the dog: a report of four cases, J Am Anim Hosp Assoc 22:79, 1986.

119 

Cutaneous Adverse Drug Reactions IAN BRETT SPIEGEL, Levittown, Pennsylvania

A

dverse drug reactions are due to interactions between a pharmacologic agent, such as an antimicrobial, and the immune system. Common cutaneous clinical signs associated with cutaneous adverse drug reactions (CADRs) are listed in Table 119-1 along with the associated pharmacologic agents. These cutaneous signs may develop coincident with other clinical signs involving the gastrointestinal, respiratory, or cardiovascular systems. Signs can vary from lethargy and depression to fever, anemia, systemic hypotension, and shock. Reactions can develop within hours to months of exposure, but CADRs usually occur within 1 to 3 weeks. Many of the cutaneous clinical signs can persist for up to a month, even with medical intervention, and as well as

removal and avoidance of a known or suspected offending agent. Diagnosis of CADR is often supported by the results from a skin biopsy. Principles of management include (1) avoidance or discontinuation of the suspected causative agent(s),  (2) supportive symptomatic care as necessary, and  (3) client education regarding prevention of future  similar reactions. There are several specific drug eruption syndromes that warrant a more detailed discussion. These were selected for discussion in this chapter. These are erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis, itraconazole-associated reactions, methimazole reactions, injection site reactions (vasculitis/

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TABLE 119-1  Clinical Presentations of Cutaneous Adverse Drug Eruptions and Associated Pharmacologic Agents Clinical Presentation

Selected Pharmacologic Agents

Erythema/erythroderma/ violaceous lesions

Sulfonamides, cephalosporins, penicillins, macrolides, fluoroquinolones, tetracyclines, levothyroxine, acepromazine, levamisole, ivermectin, hydroxyzine, chlorpheniramine, shampoo (e.g., D-limonene), itraconazole, neomycin, propylene glycol

Wheals/hives (urticaria) and angioedema

Sulfonamides, cephalosporins, penicillins, tetracycline, allergen-specific immunotherapy, barbiturates, insecticides (e.g., avermectins and amitraz), transfusions

Scaling/exfoliative dermatitis

Sulfonamides, cephalosporins, penicillins, macrolides, acepromazine, levamisole, hydroxyzine, chlorpheniramine, shampoo (e.g., tar)

Erosion/ulceration

Sulfonamides, cephalosporins, penicillins, retinoids, moxidectin, spironolactone (cats)

Pruritus

Sulfonamides, cephalosporins, penicillins, methimazole, propylthiouracil, gentamicin, chloramphenicol, acepromazine, griseofulvin, niacinamide, tetracyclines, doxorubicin, clopidogrel, propranolol, cyclosporine

Vesicles and bullae (blisters), pemphigus-like lesions

Sulfonamides, cephalosporins, penicillins, amitraz, diethylcarbamazine, thiabendazole, phenytoin, triamcinolone, neomycin

Papules and macules (maculopapular lesions)

Sulfonamides, cephalosporins, penicillins, 5-fluorocytosine, diethylcarbamazine, shampoo, cimetidine, hydroxyzine, procainamide

Petechiae/ecchymosis (purpura)

Sulfonamides, cephalosporins, penicillins

Alopecia

Sulfonamides (follicular necrosis/atrophy), cephalosporins, penicillins, chemotherapy, corticosteroids, levamisole (follicular necrosis/atrophy)

Otitis (contact dermatitis)

Sulfonamides, cephalosporins, penicillins, neomycin, propylene glycol, thiabendazole

ischemic dermatopathy caused by rabies vaccine), reactions associated with flea and tick products, nonsteroidal antiinflammatory subcorneal to follicular neutrophilic dermatitis, cyclosporine-induced psoriasiform-lichenoid dermatosis, and corticosteroid-induced calcinosis cutis.

Erythema Multiforme and Stevens-Johnson Syndrome Erythema Multiforme Erythema multiforme (EM) is an uncommon skin disease that is often sudden in onset and can affect skin, mucous membranes, and the mucocutaneous junctions. The condition can wax and wane, and can be self-limiting or require diagnostic workup and therapeutic intervention. It is currently believed that with EM a cell-mediated hypersensitivity reaction is directed against infectious organisms (viral and bacterial), medications (griseofulvin, aurothioglucose, cephalosporins, penicillins, macrolides, gentamicin, tetracyclines, sulfonamides, polythiouracil), foods, antiparasitic agents (ivermectin, levamisole), levothyroxine, or various nutraceutical products (e.g., GlycoFlex). This disorder also may be associated with neoplasia (paraneoplastic syndrome) or connective tissue disorders. Usually the underlying cause is unknown and the disorder is categorized as idiopathic. The classic finding is a target lesion that is raised  on the borders with erythema centrally. Other lesions include hyperpigmented macules, raised erythematous papules, plaques, scaling, crusting, and oozing. Areas of the skin most affected include the ventral abdomen,

inguinal, and axillary regions; oral cavity; pinnae; and footpads. Almost 50% of cases have a mucocutaneous involvement. Management includes stopping current medications (oral, injectable, and topical) and supplements. The diet may need to be changed as well. More severe cases require corticosteroids and other medications. Treatments have included cyclosporine (5 to 10 mg/kg daily PO), tacrolimus (topical), leflunomide (3 to 4 mg/kg daily PO), pentoxifylline (25 mg/kg twice daily PO), retinoids (e.g., isotretinoin 2 to 3 mg/kg daily PO), chemotherapy medications (azathioprine 2 mg/kg daily PO initially, chlorambucil 0.2 mg/kg daily PO initially), vitamin E (400 to 800 IU daily PO), and the combination of vitamin B (niacinamide 500 mg two or three times daily for ≥15 kg body weight and 250 mg two or three times daily for 6 years), which is beyond the age of onset for the atopic dog unless a geographic or major habitat change has occurred.

WEB BOX 33-2  Primary Causes and Perpetuating Factors of Acral Lick Dermatitis (ALD)* Primary Causes Allergic dermatitis Arthropathies Foreign bodies Neuropathies Trauma Neoplasia Mycotic infection Parasitoses (e.g., scabies) Psychogenic factors

Perpetuating Factors Bacterial infection Osteomyelitis Keratin foreign bodies Periostitis Secondary arthritis Learned behavior Fibrosis

*Factors relating to the development of acral lick dermatitis involve both primary causes that initiate the compulsive licking and perpetuating factors, which are complications of the condition that tend to keep the problem ongoing. Perpetuating factors by themselves do not initiate the disease but influence the protraction of the lesion, even when the primary cause has been resolved. Identification of all factors is essential for adequate treatment.

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Perpetuating Factors Perpetuating factors may be as important as the primary cause and, if left untreated, ultimately result in failure to control the problem (see Web Box 33-2). One of the most important perpetuating factors involved in ALD is infection. The infectious agent most commonly isolated from lesions of ALD is Staphylococcus pseudintermedius, which usually starts as an area of folliculitis and progresses to furunculosis, with advancement to pyogranulomatous dermatitis. Deep tissue cultures of ALD lesions nearly always demonstrate infected tissue. It is not surprising to find methicillin-resistant staphylococcal infections as well. Treatment of bacterial infections should routinely be part of the treatment regimen, with antimicrobial selection based on culture and susceptibility from macerated biopsied tissue from the lesion(s) obtained under sterile conditions. Although lesions are not exudative, cultures of aseptically acquired tissue almost always reveal a staphylococcal organism and in chronic cases may include a gram-negative organism (Pseudomonas, Proteus, Escherichia coli spp.). Licking or scratching perpetuates the infection in the absence of sufficient antibiotic therapy. Furthermore, chronic licking may cause endorphin release, which could lead to a chemical imbalance that ultimately produces a pleasure sensation and hence repetition of the licking. Regardless of the mechanisms involved, chronic licking, a learned behavior, may be a perpetuating factor that impedes resolution. Most ALD cases have both primary factors and consequential perpetuating factors that must be identified and receive individual treatment. If the problem were as simple as a psychogenic or obsessivecompulsive behavior disorder, treatment with a variety of chemicals would demonstrate greater response.

Diagnostic Approach One of the most important elements in the treatment of ALD is performing the dermatologic diagnosis, starting with a complete history and clinical examination. A systematic approach to obtaining diagnostic criteria is paramount to successful treatment and management. Initial appraisal of focal or multifocal lesions should include documentation of location and size. Acetate film or plastic kitchen wrap and an indelible felt-tip pen provide a convenient method for tracing the lesion to validate size on successive evaluations. Recognition of the primary cause or causes is necessary for proper treatment.

Diagnostic Testing Routine blood work (complete blood count [CBC] and biochemical profile), urinalysis, and a minimal database of skin scrapings and dermatophyte test medium culture should be performed. The ruling out of neoplastic disease and fungal granulomas requires biopsy acquisition for dermatohistopathologic examination and microbiologic cultures and susceptibility. Preliminary evaluation with microscopic examination of a fine-needle aspirate helps to distinguish between neoplasm and inflammation.

Suspicion of possible underlying disease should influence the direction of diagnostics for that individual animal. Although some cases of ALD may represent a purely psychogenic phenomenon, the diagnostic plan must include tests to rule out other underlying causes of chronic licking and self-mutilation and complicating problems. History of allergic episodes should direct the specialist or practitioner toward pursuing allergic disease.

Radiography Depending on the chronicity and progression of the lesions, radiography may or may not be included in the initial diagnostic approach of these lesions. This is certainly indicated with chronic and larger lesions or if there is a concern for an underlying arthropathy. Foreign bodies are not easily recognized and may be difficult to rule out as an inciting cause. Radiography is most helpful when formulating the prognosis. Those dogs with more extensive radiographic evidence of bony lesions are least likely to be resolved satisfactorily.

Fine-Needle Aspirate and Cytology Fine-needle aspirates should be included in the initial phase of diagnostic workup. Early recognition of cutaneous neoplasia may be found, although lack of evidence does not rule it out. Cytologic examination of fluid or tissue acquired from typical lesions demonstrate very little cellularity aside from representative inflammatory cells and fibrocytes. Impression smears of the surface exudate contain different bacteria and white blood cells, findings characteristic of opportunistic colonization of an ulcerative lesion.

Lesion Biopsies Biopsies of the nodule should be considered a part of the routine diagnostics. This provides a relatively expedient differentiation between neoplastic diseases and inflammatory or fibrotic causes of the lesion. Mast cell tumors, histiocytomas, and squamous cell carcinoma are neoplastic problems that may be associated with compulsive licking. If the fine-needle aspirate is not consistent with neoplasia and is demonstrating inflammation, specimens should be submitted in tissue transport media for culture of aerobic bacteria, fungi, Nocardia, Actinomyces, or other suspected organisms. Impression smears made from biopsy specimens should be performed routinely with the hope of further distinguishing neoplasia or other infective diseases. Typical histopathologic features of ALD lesions include compact hyperkeratosis with intermittent parakeratotic hyperkeratosis. Profound irregular epidermal hyperplasia is observed with superficial dermal fibrosis, resulting in characteristic vertical streaking between intact hair follicles with demonstrable hyperplasia of the follicular epithelium. Prominent apocrine glands are observed. Bacteria are rarely observed in either hematoxylin-eosin (H&E)–stained sections or in tissue samples treated with special stains for the identification of bacteria. Nevertheless, bacteria are often isolated from macerated tissue cultures.

WEB CHAPTER  33  Acral Lick Dermatitis

Bacterial Culture and Susceptibility Testing Bacterial cultures are often included in the diagnostic workup but must be obtained aseptically through sterile surgical technique using a 6- or 8-mm biopsy punch for accurate specimen acquisitions. Biopsies are placed in transport tubes (Port-A-Cul) for submission to a microbiology laboratory for maceration and inoculation on culture medium to identify microorganisms. Transport media must be used if specimens cannot be taken to the laboratory promptly. Culturing the surface of the lesion provides little diagnostic help in antibiotic selection or understanding the perpetuating factors. Culturing the defect produced from the punch biopsy with a culturette is not considered relevant and may lead to disappointing results.

Electrodiagnostic Testing Electrodiagnostic testing including needle electromyography and motor/sensory nerve conduction velocities typically demonstrates an absence of nerve conduction across the lesion, but this finding is likely a consequence as opposed to the cause of the lesion. Studies may be performed away from the lesion to evaluate the presence of an underlying neuropathy or nerve root lesion. These evaluations do not typically provide useful information about the genesis of the disease. Electrodiagnostic studies are mostly helpful in situations in which automobile accidents or other types of trauma have caused peripheral neuropathy through entrapment of the peripheral nerve or by direct damage to the afferent sensory pathway.

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mechanical barriers should be considered in the initial phase of all therapy. Bandaging may have limited value due to rapid removal by the pet, but it may be helpful in certain cases. Wire muzzles in combination with bandaging have proven to be a good combination for deterring continued licking. Elizabethan collars, although not generally accepted by most pet owners (or pets), can be effective. An option to the Elizabethan collar is a plastic bucket with a hole cut in the bottom that can be slipped over the head and secured to a collar. Some innovative pet owners and veterinarians have used modified PVC piping to cover lesions and provide sufficient airflow through perforations so as not to cause a moist dermatitis. Intermittent examinations are critical to determine response to therapy. Serial “tracings” of the lesion provide a measurable means to record changes in the size of focal lesions to follow the progression.

Antibiotics Antibiotics are one of the most important treatments of ALD. Therapy should be used systemically and may require a protracted period of time (4 to 6 months). Selection of antibiotics should be based on culture and susceptibility testing when available. Cephalosporins have been used commonly with limited success in chronic cases owing to evolving methicillin-resistant bacteria. Cephalexin should be administered at 22 to 30 mg/kg BID (Web Table 33-1). Other cephalosporin choices

WEB TABLE 33-1 

Allergy Testing Allergy testing should be considered in cases of canine atopy but not for diagnostic purposes. Intradermal allergy testing (IDT) or serum allergy testing are desirable for identification of allergens with the anticipation of implementing antigen therapy. Although this will not provide an immediate benefit for the active granuloma lesion, it may be helpful for prevention of further lesion development. IDT may need to be deferred if repeated intralesional injections of glucocorticoids have been given. Treating the primary problem may not have a measurable benefit if the perpetuating factors represent a large component. Food trials should be considered routinely in cases with suspicion of CAFR, particularly for the golden retriever, Labrador retriever, Chinese shar pei, dalmatian, and German shepherd. Cyclosporin A (Atopica) may be considered for the treatment of the atopic dog once the infectious component has been sufficiently controlled (see Chapters 91 and 92).

Treatment Successful treatment of ALD is contingent on recognizing the predisposing, primary, and perpetuating factors contributing to the disease. Treating the primary cause and, equally important, the perpetuating factors is critical. Chronic unresponsive lesions have an extremely poor prognosis for resolution. Prevention of licking by

Common Antibiotics Used for ALD Antibiotic

Dosage

Amoxicillin trihydrate with clavulanate potassium

22 mg/kg BID

Lincomycin

22 mg/kg BID

Clindamycin

5.5-11 mg/kg BID (11 mg/kg QD)

Ormetoprimsulfadimethoxine

55 mg/kg day 1 loading dose; followed by 27 mg/kg QD

Trimethoprim-sulfadiazine or trimethoprim   Sulfamethoxazole (side 20-30 mg/kg QD-BID effects) Cephalosporins   Cephalexin   Cefpodoxime   Cefadroxil   Cefovecin

22 to 30 mg/kg BID 5-10 mg/kg QD 22 mg/kg BID 8 mg/kg SC repeated in 2 weeks

Chloramphenicol

30-50 mg/kg TID

Enrofloxacin

5-20 mg/kg QD

Marbofloxacin

2.75-5.5 mg/kg QD

Orbifloxacin

2.5-7.5 mg/kg QD

Difloxacin

5-10 mg/kg QD

Azithromycin

10 mg/kg QD

Clarithromycin

5-10 mg/kg BID

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include cefpodoxime 10 mg/kg once daily or cefovecin 8 mg/kg every 14 days × 3 treatments. Ormetoprimsulfadimethoxine (Primor) 27 mg/kg once daily is the preferred sulfa drug. Fluoroquinolone drugs (e.g., enrofloxacin, marbofloxacin) should be used only based on culture results and reserved for cases with methicillinresistant staphylococcus infection or when a gramnegative organism demonstrates in vitro susceptibility. Treatment of the dog for 3 to 4 weeks beyond regression of the lesion is ideal, although it is often difficult to determine the end point of the resolution of infection without repeat bacterial cultures and susceptibility testing. Maintenance antibiotic therapy may be required in the event of incomplete resolution of the lesion or when the problem recurs after the termination of the antibiotic administration. Pulse therapy has been successfully used in some cases wherein the antibiotic is administered and then alternated with periods in which no antibiotics are administered (e.g., weekend therapy—the antibiotic is administered at appropriate dose and frequency on the weekends only). Another alternative approach is suboptimal dosing therapy in which antibiotics are continued on a daily basis but at a lower-than-recommended dosage and decreased frequency. The development of resistance may be encouraged with pulse or suboptimal dosing therapy.

This may be an alternative when palatability or gastrointestinal (GI) intolerance is noted. A dietary challenge should always be considered for validation of an adverse food reaction.

Laser therapy has demonstrated some success, particularly in small and early lesions. Carbon dioxide laser emitting infrared light at 10,600 nm vaporizes intracellular water and ablates the treated cells without damaging adjacent tissue. Precise débridement of lesions can be successfully obtained and often desensitizes the tissue.

Treatment of Allergic Diseases

Radiation Therapy

Allergen-specific immunotherapy should always be considered as an alternative when canine atopy has been determined as one of the primary factors. The decreased use of systemic glucocorticoids is an objective of treatment of chronic infected lesions, and the use of antigen therapy may help to accomplish this goal. While allergen avoidance is important with any allergic condition, practically this approach is limited to CAFR or FAD. Acral pruritic dermatitis predominantly affecting the rear legs, with coexisting lesions over the pelvic area, should be pursued for documentation of FAD and treated with parasiticidal therapy regardless of gross observation of fleas. The products most helpful for this trial would include the on-the-animal adulticides, although insect growth regulators or insect development inhibitors are also integral to therapy. Topical spot-on parasiticidal or systemic adulticidal flea treatment should be employed. Dietary trials and challenges should be used to identify the optimal food for routine feeding of the food-allergic/ intolerant case. Owners should be cautioned about deviating from the restricted food. A food trial is typically administered for 8 to 10 weeks, although as many as 70% of food-allergic dogs may respond within the first 4 weeks; the remaining 30% may require longer. The concurrence of atopy with food-induced allergic disease is as much as 80%. This becomes problematic when dietary trials are conducted during times of the year when a greater representation of atopic dermatitis is present. Hydrolysate diets and the wide assortment of limitedingredient diets facilitate dietary treatment. Homeprepared diets may be considered as an alternative in the event of minimal response of the commercial diet when high suspicion of food-associated disease is suspected.

Radiation therapy has also shown success in small lesions, but there is a need for repetitive treatments. Varying degrees of success have been observed; lesions that are early and with minimal fibrosis and inflammation demonstrate the best response, whereas larger, chronic lesions with underlying bony involvement are less responsive. A radiation oncologist should be consulted when planning such therapy. Cost and limited availability make this option impractical in the vast majority of cases but this modality may be best when the underlying lesion is a radiosensitive neoplasia with minimal surgical options.

Surgery or Cryotherapy Surgical intervention is often met with postoperative complications and incomplete resolution of the problem. This is a salvage procedure and indicated only if underlying arthropathy is identified in a location where arthrodesis can achieve joint stability and pain reduction. Removal of any identified foreign bodies is another indication for surgery. Importantly, surgical excision of the lesion does not prevent recurrence. The primary disease must be treated and is often overlooked, with specific treatment focused on the lesion itself.

Laser Therapy

Topical Antipruritic/ Antiinflammatory Treatment The exclusive use of topical antiinflammatory drugs has limited effect in the majority of cases in the authors’ experience. These may be applied after initial resolution has been observed with antibiotic therapy. A variety of choices are available, including Tresaderm, Otomax, or a Synotic-Banamine combination. The latter is preferred, and the preparation is made by placing 3 ml of Banamine (flunixin meglumine) in a vial of Synotic (fluocinolone acetonide and dimethyl sulfoxide [DMSO] 60%) with application made twice daily for 30 days. The owners should be advised to wear gloves when applying the product. The substance P inhibitor capsaicin has been helpful in some cases and is available as an antiarthralgic/ antimyalgic compound preparation in ointment form for human application. The topical application on and around lesions may help decrease reinforcing sensation but must be used consistently at a rate of 3 to 4 times per day for the initial trial of 21 to 30 days. It is formulated

WEB CHAPTER  33  Acral Lick Dermatitis as a 0.025% and 0.075% ointment, with a more concentrated formulation (Dolorac) containing 0.25%. A combination of 2.0% mupirocin ointment in a 1 : 1 mixture with capsaicin has been helpful in acute lesions applied three times daily. Topical mupirocin sulfate ointment alone is a good adjunct to systemic antibiotics. The use of bitter apple and Heet Liniment in a ratio of two parts bitter apple to one part Heet has also been popular as a topical antipruritic therapy. Heet contains capsaicin (0.025%), methylsalicylate (15%), and camphor (3.6%). A substantial trial period is necessary (4 to 6 weeks) to evaluate these topical products. It must be stressed that this type of treatment by itself has little impact on chronic lesions. Specific treatment of the primary and perpetuating factors is critical for any hope of resolving the lesions.

Intralesional Injection Intralesional injections of glucocorticoids are not recommended, particularly in the early stage of disease management, since nearly all the lesions are infected with S. pseudintermedius and possibly gram-negative microorganisms. Many acute lesions become chronic in nature with progression of the infection. Acute lesions should be placed under a regimen of antibiotic therapy before consideration of intralesional steroid therapy. Topical antiinflammatory drugs are far more conservative and would be better employed in lieu of intralesional steroid therapy. Cases have been observed requiring protracted treatment with antibiotics (months) when the lesion had been treated with intralesional glucocorticoid therapy. Thus such therapy should be withheld until a complete appraisal of the case has been acquired and a course of antibiotic therapy evaluated.

Canine ALD and ObsessiveCompulsive Disorder There may be a correlation between the uncontrollable licking experienced by a group of dogs with ALD and the uncontrollable actions of those humans suffering from obsessive-compulsive disorder (OCD). This condition is characterized by recurrent, persistent thoughts or impulses (obsessions) or repetitive, unnecessary behavior (compulsions). OCD, expressed by such acts as chronic hair pulling (trichotillomania), hand washing, or nail biting, has been considered an exaggeration of normal grooming habits. Some believe that ALD is a manifestation of exaggerated grooming habits in animals. Investigations into the cause of OCD indicate that these patients have an abnormality in the pathway that links the frontal lobes of the cerebral cortex with the basal ganglia. The frontal lobes promote deliberation and judgment, with the basal ganglia serving as a relay station for planning and execution of movements. It is suspected that the caudate nucleus, a portion of the basal ganglia, is deficient in filtering messages from the frontal lobes to the rest of the brain. Biochemically, it appears that serotonin is directly linked to the presence of OCD. Serotonin-releasing fibers are distributed throughout the central nervous system (CNS), influencing the sleep cycle, sex drive, body

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temperature, appetite, respiration, cardiovascular activity, mood, and aggression. Following a meal, serotonin is converted from the amino acid L-tryptophan after reaching serotonin-releasing neurons in the brain. Once synthesized, serotonin is enclosed within vesicles at the presynaptic terminal; the action potential at the presynaptic terminal releases the serotonin into the synaptic gap, which allows it to bind to specialized receptors on the postsynaptic neuron, causing an alteration of the electrical and chemical activity. Serotonin is ultimately removed from its binding site and transported back to the presynaptic terminal, where it is reused or degraded to its primary metabolite, 5-hydroxyindoleacetic acid (5-HIAA). It has been shown experimentally that the primary function of the brain serotonin system is to facilitate tonic motor actions and inhibit sensory-information processing. Serotonin neuronal activity is low in patients with OCD, resulting in impairment of these functions. It is thought that the repetitive motor activities of an OCD patient increase serotonin neuronal activity, providing a means of self-medication. As the pattern of exaggerated grooming behavior applies to dogs, it would appear that the chronic licking of ALD may serve to increase serotonin neuronal activity as well.

Therapy Using Drugs That Modify Neurologic Activity Recent clinical investigations indicate that certain medications effective in the treatment of OCD in humans have a similarly positive effect on dogs with ALD. Drugs showing the most promise are tricyclic antidepressants (TCAs) and selective serotonin reuptake inhibitors (SSRIs), which affect central serotonin neurotransmission. The specific mechanism of action is based on the prevention of removal of serotonin from the synaptic cleft, increasing the functional activity of the serotonin. TCAs block the reuptake of both norepinephrine (NE) and serotonin by their presynaptic terminals. Adverse reactions in humans include cardiotoxicity resulting in arrhythmias or heart block or central nervous system toxicity. The mode of SSRIs is more specific, acting to block reuptake of serotonin by presynaptic terminals. This eliminates many of the adverse effects noted with the use of TCAs. These drugs are discussed in Chapter 117.

Key Points in Managing ALD Although behavioral and neurologic disorders are recognized in the pathophysiologic relationship to ALD, far more cases result from pruritic dermatopathies complicated by perpetuating factors. The following treatment objectives should be considered: 1. Avoid empirical glucocorticoid intralesional injections 2. Early, acute lesions may not require biopsy acquisition but initial workup should include fine-needle aspiration to evaluate the lesion for neoplasia. 3. Lesions should be considered infected and systemic antibiotic therapy instituted.

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4. Topical mupirocin sulfate ointment is a good adjunct to systemic antibiotics (also see Chapter 102). 5. Primary diseases should be considered in view of history and breed association. In many cases it is one of the allergic dermatoses. 6. Systemic behavior-modifying drugs or antihistamine therapy may be helpful. 7. There is no simple, magic solution to the problem.

References and Suggested Reading Feusner J, Hembacher E, Phillips KA: The mouse who couldn’t stop washing: pathologic grooming in animals and humans, CNS Spectr 14(9):503, 2009. Goldberger E, Rapoport JL: Canine acral lick dermatitis: response to the anti-obsessional drug clomipramine, J Am Anim Hosp Assoc 27:179, 1991. Jacobs BL: Serotonin, motor activity and depression-related disorders, Am Scientist 82:456, 1994. Luescher UA, McKeown DB, Halip J: Stereotypic or obsessivecompulsive disorders in dogs and cats, Vet Clin North Am 21:401, 1991. Marder AR: Psychotropic drugs and behavioral therapy, Vet Clin North Am 21:329, 1991.

WEB CHAPTER 

Noxon JO: Management of acral lick dermatitis, Proceedings of the North America Veterinary Conference, pp. 360-363, 2009. Patterson S, Midgley D, Barclay I: Canine acral lick dermatitis, In Practice 29:328, 2007. Rapoport JL, Rylord DH, Kriete M: Drug treatment of canine acral lick dermatitis: an animal model of obsessive compulsive disorder, Arch Gen Psychiatry 49:517, 1992. Rivers B, Walter PA, McKeever PJ: Treatment of canine acral lick dermatitis with radiation therapy: 17 cases (1979-1991), J Am Anim Hosp Assoc 29:542, 1993. Scott DW, Walton DK: Clinical evaluation of a topical treatment for canine acral lick dermatitis, J Am Anim Hosp Assoc 20:565, 1984. Shanley K, Overall K: Psychogenic dermatoses. In Kirk RW, Bonagura JD, editors: Current veterinary therapy XI, Philadelphia, 1992, WB Saunders, pp 552-558. Shoulberg N: The efficacy of fluoxetine (Prozac) in the treatment of acral lick and allergic inhalant dermatitis in canines, Proc Ann Memb Mtg, Am Acad Vet Derm Am Coll Vet Derm 6:31, 1991. Shumaker AK et al: Microbiological and histopathological features of canine acral lick dermatitis, Vet Derm 19:288-298, 2008. Virga V: Behavioral dermatology, Vet Clin Small Anim 33:231, 2003.

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Avermectins in Dermatology AMANDA K. BURROWS, Perth, Australia

T

he avermectin class of antiparasitic agents includes two distinct chemical families: avermectins (ivermectin, abamectin, doramectin, eprinomectin, and selamectin) and milbemycins (moxidectin and milbemycin oxime). These are important antiparasitic agents because of their wide spectrum of activity, high potency, safety margins, and unique mechanism of action. Each member exerts a similar mode of antiparasitic action, but there is variation in efficacy, which is presumed to relate to differences in the chemical structure. Avermectins and milbemycins are closely related macrocyclic lactones produced naturally as fermentation by-products of actinomycetes from the genus Streptomyces. In veterinary dermatology the avermectins and milbemycins of importance are ivermectin, selamectin, and doramectin and milbemycin oxime and moxidectin, respectively, and there is wide use of these compounds for management of parasitic diseases. Despite the clinical evidence for therapeutic efficacy and safety, many of the clinical indications and dosage regimens recommended for avermectins in dogs and cats are extralabel or unapproved. Accordingly, it is

recommended that the veterinarian secure written owner informed consent before embarking on an extralabel course of therapy, comply with any local legislation relating to extralabel drug use in animals, and appreciate the clinical signs and management of avermectin toxicosis (see Chapter 34).

Mechanism of Action Avermectins and milbemycins have two modes of action. The primary mode of action is selective high-affinity binding to specific glutamate-gated chloride channels in synapses between inhibitory interneurons and excitatory motor neurons in nematodes and in myoneural junctions in arthropods. These compounds also enhance the release of γ-aminobutyric acid (GABA) in presynaptic neurons, which in turn opens postsynaptic GABA-gated chloride channels. In either case the influx of chloride ions reduces cell membrane resistance, which prevents the potential hyperpolarization of neural stimuli to muscles and results in flaccid paralysis and death.

WEB CHAPTER  34  Avermectins in Dermatology Mammals, unlike nematodes and arthropods, have GABAmediated interneuronal inhibitors only in the central nervous system. It is believed that the mammalian bloodbrain barrier is impermeable to the avermectin class drug; thus toxicity in mammals occurs at a much higher concentration than in nematodes and arthropods.

Avermectins Ivermectin Ivermectin is a derivative of avermectin B1, and its use is licensed in dogs for the prevention of dirofilariasis at a dosage of 6 to 12 µg/kg once a month PO. Ivermectin in cats is labeled for prevention of heartworm infection and hookworms when dosed at 24 µg/kg to approximately 70 µg/kg once a month PO. The ivermectin formulation most commonly used in dogs and cats for the extralabel treatment of ectoparasites in veterinary dermatology is available commercially as a 1% nonaqueous injectable solution formulated in 60% propylene glycol and 40% glycerol (Ivomec). This can be diluted with sterile propylene glycol for accurate dosing in kittens and small dogs; however, propylene glycol can be irritating when administered subcutaneously and can cause bradycardia and respiratory and central nervous system depression. For this reason some veterinary dermatologists prefer to use the aqueous 0.8% oral drench approved for use in sheep and goats (Ivomec Liquid), which can be administered undiluted or diluted with sterile water. The oral solution of ivermectin must be given by mouth, whereas the injectable propylene glycol–based formulation can be administered subcutaneously or orally. A 0.5% alcoholbased pour-on ivermectin formulation (Ivomec Pour-On) approved for use in cattle has been used in dogs and cats. Ivermectin is sensitive to ultraviolet light and should be stored in the dark or dispensed in an opaque bag to prolong its shelf life. Ivermectin has a wide margin of safety in dogs and cats; however, an increased susceptibility to acute toxicity is evident in a subpopulation of collie and collie-type dogs. The oral dose of ivermectin shown to cause adverse effects in noncollie dog breeds is in the range of 2500 to 10,000 µg/kg. In contrast, clinical signs of toxicity develop after the administration of only 100 µg/kg in a subpopulation of susceptible breeds. Clinical signs include mydriasis, depression, ataxia, hypersalivation, bradycardia, hyperthermia, apparent blindness, decreased menace response, muscle tremors, and disorientation, which may progress to weakness, recumbency, unresponsiveness, stupor, and coma. Acute ivermectin toxicity has been reported in other breeds, including Australian shepherds, Shetland sheepdogs, Old English sheepdogs, Doberman pinschers, and their crossbreeds. Ivermectin sensitivity in collies has been traced to a mutation of the multidrug resistance (MDR1) or ABCB1-1 (the ABCB1-1 Delta genotype). The MDR1 gene encodes a large transmembrane protein forming an integral part of the blood-brain barrier, P-glycoprotein, which plays an important role in the integrity of the blood-brain barrier by limiting drug uptake into the brain. Altered expression

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or function of P-glycoprotein may allow elevated brain concentrations of ivermectin and thereby potentiate neurotoxicity. Because no functional P-glycoprotein is produced in the homozygous mutated genotype, there is an increased susceptibility to neurotoxicosis from several drugs, including macrocyclic lactones, due to their accumulation in the central nervous system. Dogs that are homozygous for the mutation show the ivermectinsensitive clinical phenotype. Approximately 35% of collies are homozygous for the ABCB1-1 Delta mutation, with a rate that varies from 24% to 73% based on data from global studies; only 10% to 26% of collies are homozygous for the normal (wild-type) gene. Dogs with heterozygous mutated as well as normal homozygous genotypes normally do not display the severe neurotoxicoses seen in dogs with the homozygous mutated genotype. The same mutation now has been identified with a lower frequency in 10 other dog breeds: Australian shepherd, Shetland sheepdog, longhaired whippet, Old English sheepdog, silken windhound, McNab, English shepherd, Border collie, and white Swiss shepherd as well as two mixed-breed dogs. Subchronic neurotoxicity occurs in noncollie breeds receiving ivermectin for generalized demodicosis, and in over one third of cases, drug interactions are responsible for these adverse neurologic signs. A number of drugs, including cyclosporin, fluoxetine, ketoconazole, itraconazole, calcium channel antagonists, and other macrocyclic lactones such as selamectin, are capable of P-glycoprotein inhibition and thus can precipitate neurotoxicity in patients receiving ivermectin. Furthermore, spinosad (Comfortis) may potentiate ivermectin toxicity (mydriasis, hypersalivation, lethargy, ataxia, trembling) when ivermectin is being administered at extralabel dosages. Clinical signs typically occur within 4 to 6 hours of administration of spinosad in conjunction with high-dosage ivermectin. These problems were not noted with concurrent use of spinosad and milbemycin in ivermectin-sensitive collies. The manufacturer has advised that veterinarians delay the administration of spinosad for at least 15 to 30 days after the completion of extralabel dosages of avermectin or milbemycin. Safety in administering oral ivermectin may be improved but not ensured by beginning with a low test dose and increasing the amount administered over several days until the desired dose is reached. In our dermatology clinic we initially administer 100 µg/kg PO and then increase the dose by 100 µg/kg every 48 hours to 200 µg/kg, 300 µg/kg, and so on, in an effort to identify ivermectin-sensitive dogs. Owners are instructed to observe their pets closely during this period and to cease administration if symptoms of lethargy, incoordination, or mydriasis develop. Because of the relatively long halflife of ivermectin, serum concentrations of ivermectin administered daily continue to increase before reaching equilibrium at much higher levels than with weekly therapy. Thus chronic toxicity caused by cumulative therapy may develop with prolonged daily ivermectin treatment. Because of this it is recommended that dogs receiving ivermectin be checked regularly for evidence of clinical signs suggestive of chronic toxicity; in our dermatology clinic we reevaluate dogs every 4 weeks for the

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first 3 months of treatment and then every 3 months thereafter. A commercial polymerase chain reaction (PCR)–based method for MDR1 genotyping using canine DNA from mouth cells is available for detecting the mutation in dogs and should be considered if ivermectin must be used in potentially susceptible breeds. Information is available at the Washington State University Veterinary Clinical Pharmacology Laboratory website (www.vetmed.wsu.edu/ depts-VCPL/test.aspx). A rapid PCR- based method that can discriminate between homozygous and heterozygous alleles using a small amount of genomic DNA from a blood sample also is available commercially (Geyer et al, 2005). Acute ivermectin toxicity is rare in adult cats, but kittens are susceptible to the toxic effects of ivermectin, and lethargy, ataxia, coma, and death have been reported after administration of a single 300 µg/kg subcutaneous injection. Adverse reactions to ivermectin have been encountered with the rapid destruction of the microfilariae of Dirofilaria immitis in dogs. Most reactions are mild, occur within 1 to 4 hours of administration, and manifest as ataxia, vomiting, and dyspnea. However, anaphylactic shock has been observed and is more likely to occur when the microfilaria counts are high. Dogs should be screened for heartworm infection before ivermectin administration, particularly in regions where the disease is endemic.

Selamectin Selamectin is a derivative of the avermectin endectocide doramectin. It is available as a solution (6% or 12%) in an isopropyl alcohol and dipropylene glycol methyl-ether vehicle (Revolution). It is licensed for topical application at a dose of 6 mg/kg for dogs and cats not younger than 6 weeks of age for the treatment and prevention of infestation or infection with fleas (Ctenocephalides spp.), sarcoptic (Sarcoptes scabiei) and otodectic (Otodectes cynotis) mites, ascarids (Toxocara spp.), and hookworms (Ancylostoma tubaeforme) and for the prevention of heartworm disease (D. immitis). A single dorsal application on the skin at the base of the neck in front of the scapulae is recommended. If the volume of the total dose exceeds 3 ml, the manufacturer recommends that the dose be divided among multiple areas in the dorsal neck region. Extensive safety studies have shown that selamectin has a wide margin of safety when administered to dogs and cats, including puppies and breeding animals. The drug is safe for topical administration in ivermectinsensitive breeds and in dogs and cats with dirofilariasis. The likelihood of accidental oral ingestion is reduced by dorsal application at the base of the neck, but inadvertent oral consumption of selamectin causes only mild salivation and intermittent vomiting in cats and no reaction in dogs.

Doramectin Doramectin (Dectomax) is a relatively new semisynthetic avermectin licensed as an endectocide for subcutaneous

administration in cattle, sheep, and swine. It is not licensed for use in dogs and cats, but its extralabel use as an endectocide in these species has been widely reported. It is available commercially as a 1% solution formulated in a 90 : 10 volume : volume sesame oil and ethyl oleate vehicle for subcutaneous injection in the lateral midline of the back as a single dose. It is well tolerated without pain or inflammatory reaction at the injection site. In ruminants and in equine species doramectin shows higher bioavailability and persistent efficacy compared with ivermectin; however, recent studies indicate that this is not the case in the dog. Doramectin reached a significantly lower plasma concentration than ivermectin following oral administration in the dog, whereas no significant differences were observed following subcutaneous administration (Gokbulut et al, 2006). This suggests that different formulations of doramectin for oral and subcutaneous administration may need to be developed for the dog. There is little reported information on the safety of doramectin in dogs and cats. Some avermectin-sensitive breeds in our dermatology referral practice have demonstrated clinical signs of salivation, mydriasis, vomiting, tremors, ataxia, and depression when doramectin was administered at dosages between 200 and 400 µg/kg by single subcutaneous injection. Similar toxicity was reported in a collie dog following the single subcutaneous administration of 200 µg/kg (Yas-Natan et al, 2003). Caution should be exercised in administering doramectin to potentially avermectin-sensitive breeds. It is recommended that clinicians take precautions similar to those for ivermectin administration (i.e., the dose of doramectin should be increased with each weekly injection, beginning at a test dose of 50 to 100 µg/kg). No toxic reactions have been recorded in cats.

Milbemycins Milbemycin Oxime Milbemycin oxime is a semisynthetic derivative of milbemycin A3/A4 and is licensed for use in dogs as a prophylactic against D. immitis and for control of gastrointestinal parasites at a dosage of 500 µg/kg q30d PO administered from 4 weeks of age. It is available in some countries as a tablet containing milbemycin oxime 23 mg in combination with praziquantel 228 mg (Interceptor Spectrum). Milbemycin oxime used to be available as a singleingredient preparation (Interceptor), but unfortunately this product has been discontinued. Milbemycin oxime has a wide margin of safety in dogs. Mild signs of lethargy have been reported when the drug is administered at the extralabel dosage of 2 mg/kg q24h PO, with transient, reversible signs of toxicity (stupor, trembling, and ataxia) observed at higher dosages of 3.8 mg/kg q24h PO. Results of a recent study suggest that dogs with the ABCB1-1 Delta mutation can experience adverse neurologic effects at these dosages (Barbet et al, 2009). Milbemycin oxime administered at 0.5 to 1 mg/kg daily is the treatment of choice for collies and dogs with the homozygous ABCB1-1 Delta mutation.

WEB CHAPTER  34  Avermectins in Dermatology These findings support the generally wide safety margin of milbemycin oxime. However, because occasional patients still develop neurologic adverse effects, particularly at higher dosages, thorough client education and appropriate monitoring are indicated, especially in breeds at risk. Treatment of heartworm-infected dogs with milbemycin oxime is not recommended because of the development of mild transient hypersensitivity reactions. There are no reports of adverse effects of milbemycin oxime use in cats. The major disadvantage of milbemycin is its cost, which precludes its use in larger-breed dogs. In the United States, milbemycin is available as a monthly heartworm preventive (Interceptor). Unfortunately, the drug currently is available in Australia and New Zealand only as an oral heartworm preventive combined with praziquantel (Interceptor Spectrum), which precludes its daily use for any extended period.

Moxidectin Moxidectin is a semisynthetic milbemycin derivative of nemadectin. It is available as an oral tablet licensed for the prevention of canine heartworm at a dosage of 3 µg/ kg once a month and as a 1% or 2.5% topical spot-on formulation combined with 1% or 10% imidacloprid (Advocate or Advantage Multi). The latter is licensed for application at a dosage of 0.1 ml/kg q30d for the treatment and prevention of infection with gastrointestinal parasites and the prevention of heartworm (D. immitis) infection in dogs and cats; infestation with sarcoptic (S. scabiei) mites and biting and sucking lice (Trichodectes canis Linognathus setosus) in dogs and otodectic (O. cynotis) mites in cats; and generalized infestation with demodectic (Demodex canis) mites in dogs (Europe and Australia). A single dorsal application on the skin at the base of the neck in front of the scapulae is recommended. If the volume of the total dose exceeds 4 ml, then the manufacturer recommends that the dose be divided among multiple areas in the dorsal neck region. The formulation employed most commonly in veterinary dermatology for extralabel use in dogs and cats is a 1% injectable solution (Cydectin) licensed for treatment of cattle. Evaluation of moxidectin has shown the drug to have a wide margin of safety in dogs. The oral dose of moxidectin shown to cause adverse effects in noncollie dog breeds is in the range of 2000 to 4000 µg/kg. There was no evidence of toxicity when ivermectin-sensitive collies were administered oral moxidectin doses up to 5 and 30 times the recommended dose of 3 µg/kg for heartworm prevention (Paul et al, 2000); however, the safety of higher moxidectin dosages in ivermectin-sensitive collies has not been evaluated. Transient ataxia, lethargy, inappetence, and vomiting have been reported in noncollie breeds administered 200 to 400 µg/kg q24h PO for the treatment of generalized demodicosis. Severe neurotoxicity, including ataxia, crawling, and acoustic and tactile hyperexcitability, was reported in an Australian shepherd with a homozygous MDR1 mutation after the administration of a single dose of moxidectin 400 µg/kg PO (Geyer et al, 2005). There are no reports of adverse effects or moxidectin toxicity in the cat.

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Common Uses of Avermectins in Veterinary Dermatology Sarcoptic Mange Sarcoptic mange is a highly contagious, nonseasonal, pruritic skin condition caused by infestation with the burrowing mite Sarcoptes scabiei. Several macrocyclic lactones (e.g., ivermectin, milbemycin oxime, oral and topical moxidectin, and selamectin) have been used successfully for the control of canine sarcoptic mange. With the exception of selamectin and topical moxidectin, these drugs are not licensed for this purpose, and the clinician should obtain informed consent from the client before beginning treatment. Ivermectin can be administered by subcutaneous injection, orally, or topically. Although experimental reports indicate that a single dose of 200 µg/kg SC is effective, 200 to 400 µg/kg q7d (PO) to q14d (SC) for 4 to 6 weeks achieves more reliable results. Because the mite can be highly contagious, all dogs and cats in contact with known affected animals also should be treated. The 0.5% pour-on formulation at a dosage of 500 µg/kg administered twice at 14-day intervals may be a convenient and economical alternative when large numbers of animals are involved. Precautions should be taken with the use of the topical formulation in ivermectin-sensitive collies and collie-like breeds. Selamectin is licensed as a topical spot-on formulation for application at a dosage of 6 to 12 mg/kg q30d for the treatment and control of canine scabies. Field studies conducted by the manufacturer reported efficacy rates comparable to those of a reference positive-control product when the drug was applied at 6 to 12 mg/kg on two occasions 30 days apart. However, veterinary dermatologists have observed a small number of treatment failures when using the drug according to the manufacturer’s recommendations, and there is concern about the potential misinterpretation of a negative response to a therapeutic trial. Consequently many dermatologists recommend using the extralabel protocol of 6 to 12 mg/kg q14d for three applications. This regimen also is effective against feline S. scabiei infestation, although the drug is not registered for this purpose in the cat. Milbemycin oxime at a dosage of 2 mg/kg q7d PO for 3 weeks or 5 weeks was effective in 71% and 100% of treated cases, respectively, in canine scabies. Although more expensive than ivermectin, milbemycin at these dosages is well tolerated in collies and related breeds and therefore is a safe alternative therapy in high-risk breeds. Topical 2.5% moxidectin spot-on formulation is licensed for the treatment and control of canine sarcoptic mange. More recently the efficacy of a combination of imidacloprid (10% weight per volume) and moxidectin (2.5% weight per volume) (Advocate) was compared with that of selamectin for the treatment of S. scabiei infestation in dogs. The dogs in each group were treated twice, 4 weeks apart, with either the combination product (0.1  ml/kg body weight) or with selamectin (0.05  ml/kg body weight) administered topically. Both medications were highly effective against S. scabiei and resulted in an almost complete resolution of clinical signs within

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50 to 64 days after the initial treatment (Fourie et  al, 2006). When the 1% injectable moxidectin formulation was used, 90% of dogs given 200 to 250 µg/kg q7d for 3 to 6 weeks either PO or SC were cured, but adverse effects such as urticaria, angioedema, and ataxia were observed in seven dogs. Adverse effects appeared to occur more frequently with subcutaneous administration, and this route of administration probably should be avoided. The 1% injectable doramectin preparation has been shown to be effective in the treatment of sarcoptic mange in cattle, sheep, pigs, and Angora rabbits, but published information on its efficacy in the treatment of canine sarcoptic mange is sparse. A single subcutaneous dose of 200 µg/kg has been used without adverse effect to treat notoedric mange successfully in cats.

Otodectic Mange Otoacariasis is caused by Otodectes cynotis, an obligate parasite that inhabits the ear canals of dogs and cats. O. cynotis infestation is common in kittens housed in crowded environments like animal shelters. Ivermectin is effective at a dosage of 200 to 400 µg/kg q7d PO. The same dosage can be administered every 14 days by the subcutaneous route. At least 3 to 4 weeks of therapy is needed. All dogs and cats in contact with the affected animal also should be treated. A 1% ivermectin solution diluted 1 : 9 with propylene glycol administered every 24 hours via the otic route for 3 weeks cured all cats in one study, although some authors suggest that topical otic application is less effective than the subcutaneous route. In a recent study, kittens 4 weeks of age or older with live O. cynotis in both ears were administered one 0.5 ml-dose of 0.01% ivermectin otic suspension (Acarexx) or one dose of selamectin on the skin following the manufacturer’s instructions. Repeat microscopic examination was performed on individual ears during the 72 hours after treatment based on a randomization schedule. There was no evidence of toxicity with either drug. The time to live mite–free status was significantly lower with administration of 0.01% ivermectin than with administration of selamectin. Both drugs have an effect against O. cynotis as early as 10 to 12 hours after administration, with an increasing effect over time (Nunn-Brooks et al, 2011). A topical 0.5% ivermectin pour-on formulation at a dosage of 500 µg/kg (0.1 ml/kg) administered twice at 14-day intervals also is effective. Selamectin is licensed at the registered dosage for the treatment and control of O. cynotis infestation in cats based on the results of controlled field trials conducted by the manufacturer. An independent uncontrolled trial using selamectin to treat naturally acquired feline otoacariasis failed to detect any mites within 17 days of treatment, although some cats had residual erythema or pruritus after testing negative for mites. Most dermatologists recommend the use of selamectin at 6 mg/kg at 14-day intervals for three applications for the treatment of otoacariasis, although the drug is not registered at this dosage. Topical 1% moxidectin is licensed for the treatment and control of otoacariasis in cats and kittens, and field

studies conducted by the manufacturers reported 100% efficacy when the drug was applied at 100 µg/kg on two occasions 4 weeks apart. Currently there are no independent studies available to verify these data. Oral or subcutaneous moxidectin at 200 µg/kg has been shown to be effective in dogs when given twice at 10-day intervals, but reinfestation occurred in cats when a single subcutaneous injection was administered.

Cheyletiellosis Cheyletiellosis is caused by the surface-dwelling parasites Cheyletiella blakei, Cheyletiella parasitovorax, and Cheyletiella yasguri in dogs and cats. Currently there are no veterinary products licensed for treatment of cheyletiellosis. Affected animals can be treated with oral or injectable ivermectin at 200 to 300 µg/kg q7d (PO) or q14d (SC) for 6 to 8 weeks, provided the owner gives informed consent. Topical pour-on 0.5% ivermectin resolved infestation when applied to cats at 14-day intervals for four treatments. Ivermectin applied by this route generally was well tolerated, but a few cats developed a transient alopecic patch and mild scaling at the site of application. Selamectin may provide a safer alternative for the treatment of canine and feline cheyletiellosis, although the drug is not licensed for this purpose. In one study selamectin was effective in resolving infestation in cats when applied topically at a dosage of 6 mg/kg once a month for three applications, whereas 6 to 12 mg/kg applied topically at 14-day intervals for four applications achieved a successful outcome in dogs (Mueller, 2002). In dogs milbemycin oxime has been shown to be effective in the control of cheyletiellosis when given at a dosage of 2 mg/kg q7d PO for 3 weeks. However, a relapse in several dogs necessitated repeating the course of treatment.

Demodicosis Canine demodicosis is a skin disease commonly encountered in veterinary practice. An evidence-based review concluded that oral ivermectin at a dosage of 300 to 600 µg/kg q24h is effective for the treatment of canine generalized demodicosis, but the dose needs to be increased gradually and dogs monitored for adverse effects. If such adverse effects occur, ivermectin administration should be discontinued. In some cases, an attempt to administer a lower dose of ivermectin may be indicated; if this is successful and clinical signs of toxicity resolve, therapy may be continued at the lower dose. This approach is not recommended in dogs that experience acute toxicity within days of beginning treatment but often is effective in dogs developing adverse effects after some weeks of therapy. Dogs of breeds known to be at risk should be tested for the ABCB1-1Δ (MDR1) mutation or should receive alternative treatments (Mueller et al, 2012). Ivermectin administered by subcutaneous injection at a dosage of 0.4 mg/kg once a week has variable and inconsistent results, and this protocol is not recommended. Topical 0.5% pour-on ivermectin solution is ineffective. Ivermectin is not licensed at any dosage for the treatment of canine demodicosis.

WEB CHAPTER  34  Avermectins in Dermatology Milbemycin oxime is licensed for the treatment of canine demodicosis in some countries at a dosage of 0.5 to 2 mg/kg q24h PO. In studies in the United States and Australia, a clearly higher success rate was seen with a higher dosage of 1 to 2 mg/kg q24h PO compared with 0.5 to 1 mg/kg. The success rate of milbemycin oxime therapy was shown to be much lower in dogs with adultonset demodicosis. Milbemycin oxime has been administered to collie dogs at a dose of 2.5 mg/kg q24h for 10 days without adverse effects, and there seems to be a high safety margin with this drug. However, dogs homozygous for the ABCB1-1 Delta mutation developed ataxia with milbemycin oxime at a dosage of approximately 1.5 mg/ kg q24h, although they tolerated the drug at 0.6 mg/kg q24h (Mueller et al, 2012). Moxidectin has been used in a number of studies at dosages of 200 to 500 µg/kg q24h PO with success comparable to that of ivermectin. Adverse effects are similar to those of ivermectin, and a gradual dose increase similar to that described for ivermectin was used in two of the studies. However, adverse effects including vomiting and inappetence were more common. Moxidectin also has become available as a 2.5% spot-on formulation (in combination with 10% imidacloprid). Initial studies evaluating the spot-on as monthly treatment for generalized demodicosis were encouraging. However, clinical use did not corroborate their findings, and subsequent studies revealed that the spot-on preparation was more effective in juvenile dogs with milder forms of the disease and that weekly therapy showed better results than twice-monthly or monthly administration. Based on these results, the label of this product was changed to recommend weekly administration in many countries where it has been approved for the treatment of canine demodicosis. Currently the spot-on product containing 2.5% moxidectin and 10% imidacloprid can be recommended as weekly treatment for dogs with juvenile-onset and mild forms of the disease. If significant improvement is not seen within the first few weeks, other therapy may be indicated. Doramectin has been reported to be a successful treatment for canine demodicosis. In one study, it was administered at 600 µg/kg once a week SC; in the second study, it was administered at the same dose once a week PO. In the latter study, two dogs that did not show clinical improvement responded to 600 µg/kg twice a week PO, but one of them, a golden retriever, developed ataxia and subsequently was treated twice weekly with 300 µg/kg doramectin. The recurrence rate was higher in dogs with adult-onset disease. Based on these two studies, there is evidence that doramectin at a dosage of 600 µg/kg q7d PO or SC may be used for the treatment of demodicosis. Caution should be exercised with the use of doramectin in ivermectin-sensitive breeds, and it is recommended that the doramectin dose be increased gradually to identify drug-sensitive dogs in a similar manner to that described for ivermectin and moxidectin.

Flea Infestation Selamectin has adulticidal, larvicidal, and ovicidal effects against Ctenocephalides felis and is the only avermectin or

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milbemycin with any activity against flea infestation. Selamectin administered at the registered dosage eliminates fleas between 12 and 24 hours after application in cats and between 24 and 36 hours after application in dogs. In multicenter field trials conducted by the manufacturer, selamectin applied at the registered dosage for 3 months reduced flea counts on day 30, 60, and 90 by 92.1%, 99%, and 99.8%, respectively, in dogs and by 92.5%, 98.3%, and 99.3%, respectively, in cats.

Tick Infestation Ivermectin reportedly has been used to treat tick infestation with Ixodes ricinus in cats, but our experience is that ivermectin is not overly useful for tick control in dogs. Selamectin is registered for the control of Rhipicephalus sanguineus and Dermacentor variabilis in dogs at 6 to 12 mg/kg q30d, but most dermatologists apply selamectin at 14-day intervals for three applications and then once a month for tick control, despite the fact that the drug is not registered at this dosage.

Lice Infestation A single injection of ivermectin at a dose of 200 µg/kg SC or a single application of topical selamectin at 6 mg/kg is effective in eliminating the biting louse Trichodectes canis in dogs and Felicola subrostratus in cats. Neither drug is registered for this purpose.

Fur Mite Infestation A single injection of ivermectin at a dose of 300 µg/kg SC is effective in eliminating Lynxacarus radovskyi infestation in cats.

References and Suggested Reading Barbet JL et al: ABCB1-1Δ (mdr1-1Δ) genotype is associated with adverse reactions in dogs treated with milbemycin oxime for generalized demodicosis, Vet Dermatol 20(2):111, 2009. Bissonnette S et al: The ABCB1-1Δ mutation is not responsible for subchronic neurotoxicity seen in dogs of non-collie breeds following macrocyclic lactone treatment for generalized demodicosis, Vet Dermatol 20(4):60, 2009. Curtis CF: Current trends in the treatment of Sarcoptes, Cheyletiella and Otodectes mite infestations in dogs and cats, Vet Dermatol 15:109, 2004. Fourie LJ, Heine J, Horak IG: The efficacy of an imidacloprid/ moxidectin combination against naturally acquired Sarcoptes scabiei infestations on dogs, Aust Vet J 84(1-2):17, 2006. Geyer J et al: Development of a PCR-based diagnostic test detecting a nt230(del4) MDR1 mutation in dogs: verification in a moxidectin-sensitive Australian shepherd, J Vet Pharmacol Ther 28:95, 2005. Gokbulut C et al: Comparative plasma disposition of ivermectin and doramectin following subcutaneous and oral administration in dogs, Vet Parasitol 135:347, 2006. Mueller RS: Efficacy of selamectin in the treatment of canine cheyletiellosis, Vet Rec 151:773, 2002. Mueller RS et al: Treatment of demodicosis in dogs: 2011 clinical practice guidelines, Vet Dermatol 23:86, 2012.

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Murayama N, Shibata K, Nagata M: Efficacy of weekly oral doramectin treatment in canine demodicosis, Vet Rec 167(2):63, 2010. Nunn-Brooks L et al: Efficacy of a single dose of an otic ivermectin preparation or selamectin for the treatment of Otodectes cynotis infestation in naturally infected cats, J Feline Med Surg 13(8):622, 2011. Paul AJ, Tranquilli WJ, Hutchens DE: Safety of moxidectin in avermectin-sensitive collies, Am J Vet Res 61:482, 2000.

WEB CHAPTER 

Shoop WL, Mrozik H, Fisher MH: Structure and activity of avermectins and milbemycins in animal health, Vet Parasitol 59:139, 1995. Tranquilli WJ, Paul AJ, Todd KS: Assessment of toxicosis induced by high-dose administration of milbemycin oxime in collies, Am J Vet Res 52:1170, 1991. Yas-Natan E et al: Doramectin toxicity in a collie, Vet Rec 153:718, 2003.

35 

Canine Papillomaviruses MASAHIKO NAGATA, Tokyo, Japan

T

he papillomavirus (PV) was first described in 1933, when Shope recognized the causative agent responsible for cutaneous papilloma in the cottontail rabbit. Watrach first recognized the structural characterization of the canine PV (CPV) in 1969. Yet this group of viruses has been refractory to standard virologic study because all efforts to date that have been aimed at tissue culture propagation of any PV have been unsuccessful. Since the mid-1980s there has been a virtual explosion in research and interest in the PVs because differentiation of PV by cleavage patterns produced by treating viral DNA has emphasized the heterogeneity of the PVs.

Viral Properties The PVs are grouped together with the polyomaviruses to form the papovaviruses. The PV is a small, naked virus with double-stranded, circular DNA. The size of the CPV has been estimated at 33 to 49 nm; the particles form closely packed crystalline structures within the nuclei. The lack of a lipid envelope may account for the relative resistance of the virus to physical or chemical destruction. PV infections appear to be limited to the epidermis and epithelium. Epidermal DNA is present in the basal layer of the epidermis, and viral replication depends on epidermal cellular differentiation. The site of viral latency is in the basal layers, although complete viral particles are found at the granular level. The viral genome is divisible into several major early (E) and late (L) open reading frames. The early viral proteins E1 and E2 play a role in replication of the viral genome, while E5, E6, and E7 control cell growth and cell cycle to maximize viral DNA replication. The function of E3 and E4 is not well known, and E3 is expressed in only bovine PV type 1 (BPV1),

whereas the late protein L1 and L2 genes encode for viral capsid proteins. More than 100 different strains of PVs have been identified in humans, and at least seven genetically distinct PV types have been sequenced thus far in dogs.

Clinical Features The clinical manifestation of PV depends on the host, the PV type, and the anatomic site infected, even though the most common outcome of PV infection may be asymptomatic infection. Clinical and histopathologic features, as well as the viral strains identified by transmission studies, immunohistochemistry, in situ hybridization methods, and polymerase chain reaction, have suggested that there are at least five or more distinct PV-associated skin disorders in dogs.

Canine Oral Papilloma Canine oral papilloma (COP) is a self-limited infectious disease that is normally confined to mucosal tissue of the oral cavity or lips in young dogs, but it also can produce papillomas on the conjunctiva and external nares. The lesions begin as white, flat, smooth, shiny papules and plaques and progress to whitish-gray, pedunculated or cauliflower-like hyperkeratotic masses. Light microscopy reveals papillomatous proliferations of thick squamous epithelium in which some cells are swollen with vesicular cytoplasm. Canine oral PV (COPV)–induced generalized papillomas occasionally may be the presenting sign in immunocompromised and cyclosporine-administered dogs (Favrot et al, 2005). The lesions regress spontaneously in most cases, although malignant transformation into carcinomas has been reported.

WEB CHAPTER  35  Canine Papillomaviruses

Cutaneous Exophytic Papilloma Cutaneous exophytic papilloma (CEP) occurs at any age but is most often seen in dogs less than 2 years of age. CEP lesions may be single or multiple and occur mainly on the head, eyelids, and feet. The lesions present as white, pink, or pigmented papillated masses that may be sessile or pedunculated. Lesions are typically less than 1 cm and have a fimbriated surface. Microscopically CEP consists of marked epithelial proliferations on numerous thin fibrovascular stalks. Many but not all CEPs spontaneously regress over a period of weeks to months.

Cutaneous Inverted Papilloma Cutaneous inverted papilloma (CIP) was described as single or several nonpigmented, raised, firm masses covered by skin with a central pore opening to the surface (Stokking et al, 2004). It is usually seen in dogs less than 3 years of age and occurs commonly on the ventral abdomen including the inguinal region. Lesions are less than 2 cm. Light microscopy shows an inverted flasklike structure with marked papillary projections from the wall into a keratin core. A possible subtype of CIP may exist, reported in middle-aged dogs as multiple whitish papules up to 4 mm at the neck and thorax that spontaneously regressed (Shimada et al, 1993; Lange et al, 2009). It also shows an inverted flasklike structure, but less papillary projections centripetally.

Canine Pigmented Plaques PV-associated canine pigmented plaques (CPPL) occur in some pugs and miniature schnauzers during young adulthood (Le Net et al, 1997). Boston terriers, French bulldogs, and shar-peis, as well as immunocompromised individuals, are also suspected of having an increased incidence of this wart (Stokking et al, 2004). Lesions are multiple, scaly, deeply pigmented macules, plaques, and sometime papules commonly seen on the ventral neck, ventral trunk, and extremities. Histopathologically, it is characterized as demarcated, irregularly digitated acanthosis with marked hyperkeratosis and hyperpigmentation. In general, CPPL develop progressively over time and do not regress. The potential for transformation to squamous cell carcinoma (SCC) has also been reported. The presumed familial nature of CPPL suggests that it might be equivalent to epidermodysplasia verruciformis (EV) in humans. EV is considered genetically determined and is caused by unusual susceptibility to EV-specific human PV infection.

Canine Pigmented Papules PV-associated canine pigmented papules (CPPA) have been reported to occur in a boxer under long-term corticosteroid therapy (Le Net et al, 1997). Multiple black, rounded papules up to 2 mm were recognized on the ventral skin. A single lesion was also reported at the concaved aspect of pinna of a Rhodesian ridgeback (Lange et al, 2009). Light microscopy showed well-demarcated foci of epidermal endophytic hyperplasia and a markedly thickened, abnormally cornified layer. Viral cytopathic

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effect was characterized by enlarged cells in the epidermis. Spontaneous regression occurred within 3 weeks after cessation of corticosteroids.

Miscellaneous Forms Suggesting Different CPV Infections The following forms of CPV infection are less frequently reported and have yet to be given a properly detailed description. Canine Digital Papillomatosis Multiple papillomas, strictly limited to the junction of the footpad and adjacent skin on multiple digits on all four feet, were reported to occur in a 9-month-old intact male beagle (Debey et al, 2001). Histopathologic findings were similar to those of CPPA, and immunohistochemical and electron microscopic study confirmed the presence of CPV particles. All the papillomas had been completely resolved within 2 months after diagnosis. Nail Bed Epithelial Inclusion Cyst Nail bed epithelial inclusion cyst has been described as analogous to follicular cysts of infundibular origin in the subungual regions. It likely results from trauma, but recently PV-induced subungual cyst formation with cytopathic findings has been reported (Plattner and Hostetter, 2009). Nail Bed Inverted Squamous Papillomas Nail bed inverted squamous papilloma has been described as a single swollen digit, usually with a thickened, abnormally soft nail, which may be broken or absent. Histopathologic features show a well-circumscribed, cup-shaped, thick layer of squamous epithelial cells that form papillary projections extending into the keratin core. Pad Inverted Papilloma Pad inverted papilloma was reported as an 8-mm-diameter grayish nodule (Lange et al, 2009). Microscopically, it is characterized by a cup-shaped appearance of the papillary projections of the squamous epithelium. Canine Genital Papillomatosis Canine genital papillomatosis is probably caused by a different CPV, since neither the oral nor the cutaneous CPV induces tumors of the lower genital tract (Debey et al, 2001). Squamous Cell Carcinoma PVs appear to be involved in the cause of certain forms of SCC in dogs. Sundberg and O’Banion reported that some dogs treated with a live virus vaccine made from PV isolated from naturally occurring COP experienced SCCs at their vaccine inoculation sites. In naturally occurring SCC, COPV DNA was demonstrated in nests of the epithelial tumor cells surrounding horn pearls or disseminated in the carcinoma tissue. In addition, PV-associated SCC in situ following chronic administration of cyclosporine and prednisone and invasive SCC related to bone marrow–transplanted canine X-linked severe combined immunodeficiency have also been reported in dogs. It was suggested that a progression of viral papillomas into carcinomas in dogs may occur and that a genetic variety of CPV exists.

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Treatments The search for an effective treatment against PV-associated skin diseases has been frustrated by the nature of CPV immunity, which remains inadequately understood. In addition, PVs are very resistant within the environment and are difficult to eliminate with disinfectants. Fortunately routine treatment of these lesions is not crucial. The majority of PV infections regress spontaneously after the development of a cell-mediated immune response and disappearance of inciting cause, and older animals have developed solid immunity as a result of previous exposure to the virus. However, lack of regression of the papillomas, interference with function, cosmetic embarrassment, or risk of malignancy may indicate vigorous therapy. In humans no treatment has had a very high success rate (average 60% to 70% clearance in 3 months), and the highest clearance rates for various treatments are usually found in younger individuals who have a short duration of infection. Surgery and destructive therapies such as cryotherapy and laser therapy have been discussed in the previous edition of the text (Bonagura, 2000); antiviral treatments are the focus of this revised chapter and represent the most current therapies for PV-associated skin diseases.

Immunotherapy Imiquimod (Aldara), an imidazoquinoline amine, is an immune response modifier (see Web Chapter 45). Imiquimod differs in that it does not have direct antiviral properties but rather it induces a significant production of cytokines, including interferon (IFN)-α, IFN-γ, interleukin (IL)-6, IL-12, and tumor necrosis factor-α. These cytokines stimulate the helper T cell (Th) Th1 pathway and inhibit the Th2 pathway via stimulation of monocytes and dendritic cells. In addition, imiquimod activates immune cells via binding to cell surface receptors such as the toll-like receptors that play an important role in host defense by regulating both innate and adaptive immune responses. Moreover, imiquimod was found to be effective in human cutaneous premalignancies and malignancies. Since tumor development depends on blood vessel supply, the inhibition of angiogenesis could be responsible for the antitumor activity. In humans imiquimod is applied before bedtime and after washing areas to be treated once a day for 3 days a week. It is well tolerated; however, occasional side effects include erosion, excoriation, flaking, edema, and erythema. No controlled studies have been reported in dogs, and the cost is fairly high. Autogenous vaccines have been used especially for treatment of mucous membrane warts in humans and dogs. It has been demonstrated by Bell and associates (1994) that systemic administration of a formalininactivated COP vaccine can protect against mucosal infection with COPV. In this study 26 dogs received two doses of phosphate-buffered saline intradermally, and 99 dogs received two doses of the inactivated vaccine. One month after the second dose, all dogs were challenged with infectious COPV by scarification of the oral mucosa. All control dogs acquired papillomas 6 to 8 weeks after

infection, whereas none of the vaccinated dogs did. Sundberg and associates (1994) reported that the vaccine might be protective against COPV epidermal infections that develop as a consequence of the spread of oral lesions to the skin in immunocompromised dogs. In addition, the vaccination might play a role in protecting against the development of SCC in dogs infected with COPV. Sensitization to dinitrochlorobenzene followed by an application of dinitrochlorobenzene to lesions and contact sensitization with diphenylcyclopropenone has proven to be a useful treatment of cutaneous malignancies and refractory warts in humans. However, such treatment has been tried in only a limited number of human studies, and no canine studies have been conducted. Antiviral Therapy IFN is produced in the body and exerts the biologic action to protect cells from any kind of virus infection. There are three main classes of human IFNs (i.e., IFN-α, IFN-β, and IFN-γ, as well as a minor class called IFN-ω). IFN-α elicits broad activities inhibitory to virus replication (see Web Chapter 40). An intracellular mechanism, by which IFN-α2a inhibits human papillomavirus (HPV)–transformed cell proliferation and presumably HPV-induced papillomas, operates through the suppression of viral oncoprotein expression and the cytostatic arrest of cycling at G1. In dogs it was reported that 1.5 to 2 million units/ m2 of IFN-α2a (Roferon-A) given subcutaneously three times a week is effective for the treatment of severe cases of oral or cutaneous viral papillomatosis or both. In addition, IFN-α2a therapy, 1000 units given orally on a 21-day on, 7-day off schedule was reported as an adjunctive therapy for CPPL (Stokking et al, 2004; Bonagura, 2009). The effectiveness of IFN-α2b (Intron A), 30 units/kg given orally, has been reported anecdotally, but the recommended dose and frequency varied widely. In some instances combining IFN-α with other treatments could increase the likelihood of effective treatment. Besides IFN-α the efficacy of IFN-γ therapy has been evaluated in several studies in humans, but it remains controversial. There are no reports on use of IFN-γ in dogs, but one report (Andre, 2004) indicated that IFN-ω could be useful as an alternative with the aim of reducing the size of papillomas. A 4 1 2 -month-old dog with papillomatosis on the mucocutaneous junctions was treated with 2 million units (MU) of intralesional IFN-ω (Virbagen Omega; Intercat) (Andre, 2004). The lesions regressed in both size and number without side effects and were removed surgically. Furthermore, my experience has suggested that IFN-ω, 1 MU/kg given subcutaneously three times a week for a month, could be helpful in the treatment of CPPL. In humans the common side effects of IFN treatment are the influenza-like symptoms such as fever, chills, nausea, fatigue, myalgia, and loss of appetite. Such side effects usually show a tendency to be less severe with time and are usually tolerable. It should be emphasized that no properly controlled studies or safety studies on IFN therapy against canine papillomatosis have been conducted so far; thus IFN is best considered as a treatment of last resort because of its high cost and inconsistent effects.

WEB CHAPTER  36  Diseases of the Anal Sac

References and Suggested Reading Andre F: Juvenile papillomatosis in a female dog, L’Action Veterinaire 1668:11, 2004. Bell JA et al: A formalin-inactivated vaccine protects against mucosal papillomavirus infection: a canine model, Pathobiology 62:194, 1994. Bonagura JD, editor: Kirk’s current veterinary therapy XIII (small animal practice), Philadelphia, 2000, Saunders, p 569. Bonagura JD, editor: Kirk’s current veterinary therapy XIV (small animal practice), Philadelphia, 2009, Saunders, p 446. Campbell KL et al: Cutaneous inverted papillomas in dogs, Vet Pathol 25(1):67, 1988. Debey BM et al: Digital papillomatosis in a confined beagle, J Vet Diagn Invest 13:346, 2001. Favrot C et al: Evaluation of papillomaviruses associated with cyclosporine-induced hyperplastic verrucous lesions in dogs, Am J Vet Res 66(10):1764, 2005.

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Lange CE et al: Canine inverted papillomas associated with DNA of four different papillomaviruses, Vet Dermatol 21:287, 2009. Le Net JL et al: Multiple pigmented cutaneous papules associated with a novel canine papillomavirus in an immunosuppressed dog, Vet Pathol 34:8, 1997. Nagata M et al: Pigmented plaques associated with papillomavirus infection in dogs: is this epidermodysplasia verruciformis? Vet Dermatol 6:179, 1995. Plattner BL, Hostetter JM: Cutaneous viral papilloma with local extension and subungual cyst formation in a dog, J Vet Diag Invest 21:551, 2009. Shimada A et al: Cutaneous papillomatosis associated with papillomavirus infection in a dog, J Comp Pathol 108(1):103, 1993. Stokking LB et al: Pigmented epidermal plaques in three dogs, J Am Anim Hosp Assoc 40:411, 2004. Sundberg JP et al: Involvement of canine oral papillomavirus in generalized oral and cutaneous verrucosis in a Chinese Shar Pei dog, Vet Patrol 31:183, 1994.

36 

Diseases of the Anal Sac RUSSELL MUSE, Tustin, California

D

iseases and abnormalities of the anal sac are common concerns faced by pet owners and the general practitioner. Unfortunately, the volume of research, literature, and information available about anal sac disease does not correspond to the frequency with which these problems occur. Fortunately, over the past few years, a number of papers have begun to establish normal and abnormal parameters associated with anal sac contents and disease. Knowledge of normal anal sac structure and function, and an appreciation of the various disorders that can involve these tissues, are critical to successful recognition and management of anal sac diseases. Anal sacs are paired invaginations of the skin located between the internal and external sphincters of the anus. Each sac is connected to the surface by a duct that opens at the mucocutaneous junction of the anus in the dog. The anal duct of cats opens onto a prominence just lateral to the anus. The anal sacs are lined with stratified squamous epithelial cells and contain large apocrine glands with smaller numbers of sebaceous glands. In addition, the walls of the anal sac are lined with elastic and smooth muscle fibers. The duct is lined with both apocrine glands and large sebaceous glands. The anal sacs provide a reservoir for the secretions of these glands admixed with desquamated epithelial cells. This forms the brown, oily to waxy secretion that normally is evacuated as a result of pressure from fecal excretions. However, change in character of the secretion or alteration in muscle tone or fecal form may cause

overfilling and plugging of the sacs and resultant fermentation, inflammation, and infection. Because of the thinness of the anal sac and the ease with which it is normally evacuated, it is not distended in normal dogs. However, if enlarged, it can be palpated easily at the 4 and 8 o’clock positions between the smooth muscle of the anal canal and the striated muscle of the external anal sphincter.

Physical Characteristics The normal characteristics of anal sac secretion and histologic evaluation long have been used to attempt to discern disease of the anal sac; however, these data also have been evaluated and reported only occasionally. Several studies have provided sources of information regarding the gross, cytologic, and bacteriologic characteristics of anal sac secretions in the normal dog (Lake et al, 2004; Robson et al, 2003) and in dogs with various dermatologic diseases (Pappalardo et al, 2002). Another recent study assessed the value of cytologic analysis in differentiating between normal dogs and dogs with anal sac disease and explored the relationship between cytologic findings and the frequency of behaviors associated with anal sac disease (James et al, 2010).

Gross Characteristics In the studies by Robson and colleagues (2003) and Lake and colleagues (2004), the anal sac secretions in normal dogs ranged from thin liquid or watery to thick liquid or

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pasty. Color of the discharge was quite variable and was noted to be light or dark brown, creamy whitish-yellow, grayish-tan, orange-yellow, or reddish-brown. Color and consistency were similar in the right and left anal sacs in most dogs in the study by Robson and associates, whereas Lake and associates reported similar consistency in fewer than half of the dogs they examined. In a study that compared anal sac secretions in normal dogs and in dogs with various dermatologic disorders (atopic dogs, dogs with pyoderma, and atopic dogs with Malassezia dermatitis) (Pappalardo et al, 2002), no significant differences were noted among the groups in anal sac size, color, or consistency, or in the presence of granules in the content. However, an unpleasant odor was found significantly more frequently in dogs with Malassezia infection and in those with atopy.

Cellular Characteristics Cellularity of anal sac secretions in normal dogs was found to be somewhat similar in two studies, which identified keratinocytes (Robson et al, 2003) and parabasal epithelial cells (Lake et al, 2004). Neutrophils were noted in both studies, although degenerate neutrophils were predominant in the Robson study and nondegenerate cells in the report by Lake and colleagues. In another study (Pappalardo et al, 2002) neutrophils were noted in anal sac secretions of 12.5% of normal dogs but 30% of dogs with Malassezia and atopic dermatitis, 70% of dogs with pyoderma, and 80% of dogs with uncomplicated atopic dermatitis. Erythrocytes and eosinophils were not noted with any regularity in any study. In an evaluation of cellularity of secretions in normal dogs versus dogs that exhibited behaviors typical of anal sac disease (scooting and anal pruritus), although a larger mean count of neutrophils was noted (25% of normal dogs versus 31% of dogs with behavior typical of anal sac disease), the difference was not statistically significant (James et al, 2010).

Bacterial Characteristics Bacterial counts also were detailed in these studies. One report (Robson et al, 2003) indicated that coccoid bacterial counts in anal sac secretions were low, with 77.9% of microscopic examination fields containing few coccoid organisms and only 2.4% demonstrating more than 319 organisms per oil immersion field. These findings are in contrast to a study by Lake and colleagues (2004), which reported that 86% of anal sac secretions contained mostly gram-positive cocci. Pappalardo and associates (2002) reported that anal sac secretions from 48.75% of normal dogs had “abundant” numbers of bacteria present. However, all dogs with skin diseases had higher bacterial counts, ranging from 60% in dogs with atopic dermatitis without complications to 90% in dogs with pyoderma. Finally, James and colleagues (2010) showed that although intracellular bacteria were present more frequently in secretions from normal dogs than in those from dogs with behaviors associated with anal sac disease (14% versus 4%, respectively) the difference was not statistically significant. Each of these studies did find that intracellular bacteria and large numbers of Malassezia

organisms are a relatively uncommon finding. Previous studies revealed various gram-positive coccoid and rodshaped bacteria to be a normal part of the flora of the anal sac; these include Streptococcus faecalis, Streptococcus faecium, Escherichia coli, Clostridium perfringens, Staphylo­ coccus intermedius, Proteus spp., and coagulase-negative staphylococci. The most recent study to evaluate cultures of anal sac secretions (Pappalardo et al, 2002) found that the most common organisms were Proteus mirabilis, E. coli, Staphylococcus intermedius, β-hemolytic Strepto­ coccus spp., S. faecalis, Bacillus spp., and Pseudomonas aeruginosa. Thus, although these recent studies seem to indicate variability in the physical characteristics of anal sac secretions, they do add new information to this field to help the clinician assess the presence or absence of disease of the anal sac. Despite these advances, evaluation and observation of clinical behavior still is the most important component in establishing the existence of an anal sac disorder.

Disorders of the Anal Sac Impaction Diseases of the anal sac vary from impactions to infections (sacculitis) with or without abscess to neoplasia. Anal sac impactions have been reported to occur in 2% to 12% of dogs (Scott et al, 2001). Clinically these usually result in pruritus or the classic scooting behavior that is noted by most owners. Although anal sac disease is a common cause of anal pruritus, the clinician should be alert to the fact that many other causes of pruritus of the anal or perianal area have been documented and include any number of dermatologic, psychologic, metabolic, nutritional, and gastrointestinal diseases. Skin diseases such as atopy, cutaneous adverse food reaction, insect hypersensitivity, Malassezia or bacterial dermatitis, parasitic skin disease, and keratinization defects all may result in persistent pruritus of the anal or perianal area. Diagnostic procedures such as cutaneous cytologic evaluations, examination of skin scrapings, culture for dermatophytes, food trials, and allergy testing may be necessary to uncover the causes of any residual pruritus. However, if the pruritus completely resolves after expression of the anal sac, a true anal sac disorder is likely. In addition, I strongly recommend that the routine expression of anal sacs in dogs during grooming, bathing, and boarding by veterinarians, technicians, groomers, and others be discouraged. Repeated manipulation and inadvertent trauma may predispose normal dogs to chronic recurrent anal sac disease. The incidence of impactions is increased in smaller breeds (50% reduction of pruritus), compared with only 20% in the control group given antihistamine spray (Iwasaki and Hasegawa, 2006). Based on this study the manufacturer recommended a dosage of rCaIFN-γ of 10,000 U/kg three times a week SC. The dosage of rCaIFN-γ required for the treatment of canine atopic dermatitis was investigated further in 2010. Yasukawa and colleagues evaluated the efficacy of lowdose rCaIFN-γ in an open-label randomized clinical trial that tested two doses, 2000 U/kg and 5000 U/kg. The efficacy of the 5000-U/kg dose was found to be comparable to that of the 10,000-U/kg dose, whereas the 2000-U/ kg dose was less effective than either of the larger doses (Yasukawa et al, 2010).

WEB CHAPTER  40  Interferons Although the mode of action of this drug has not yet been clarified, modification of the TH1 and TH2 cytokine profiles may play some role in the improvement of clinical signs in canine atopic dermatitis. Only a few adverse effects, including pain at the injection site, were noted. Hyperplastic dermatosis of the West Highland white terrier, known as epidermal hyperplasia or armadillo Westie syndrome, is a severe and chronic hyperplastic disease associated with Malassezia overgrowth. Although the prognosis for this disease usually is guarded even with successful control of Malassezia, one West Highland white terrier with the disease showed marked improvement of clinical signs (pruritus and erythema) when treated with rCaIFN-γ at a dosage of 10,000 U/kg SC, initially three times weekly for 2 weeks and then as a maintenance treatment every 7 to 14 days.

Interferon-ω The use of rFeIFN-ω produced by silkworms has been launched in Europe and Japan for the treatment of feline calicivirus and canine parvovirus infections. The efficacy of rFeIFN-ω for the treatment of canine atopic dermatitis has been reported in two studies. In the first study, rFeIFN-ω administered to 20 atopic dogs at a dosage of 1 million U/kg three times a week SC for 3 weeks resulted in a 60% decrease in clinical sign and symptom scores at day 42. In a second 6-month double-blind controlled study, there was no significant difference in the efficacy of rFeIFN-ω injected intermittently (1 to 4 million U per dog based on body weight) and oral cyclosporine administered daily (50 to 200 mg per dog based on body weight) for the treatment of canine atopic dermatitis. Further large-scale clinical studies are needed to demonstrate that intermittent injections of rFeIFN-ω are effectual and cost effective for the treatment of canine atopic dermatitis. Siebeck and colleagues (2006) examined the effects of both rFeIFN-ω and rHuIFNα on in vitro replication of feline herpesvirus 1. When used at higher concentrations, rFeIFN-ω showed stronger inhibition of viral replication than rHuIFNα, which indicates the efficacy of rFeIFN-ω against feline herpesvirus infection. Clinical efficacy of rFeIFN-ω in the treatment feline herpesvirus– induced facial dermatitis has been described in one cat (Gutzwiller et al, 2007). The rFeIFN-ω was administered

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by intralesional, intradermal, and subcutaneous injection, and improvement was apparent 2 days after the first injection of 1.5 million U. Lesions had resolved almost completely at 6 weeks after the initiation of treatment, which consisted of a total of six injections, three at a dose of 1.5 million U and three at a dose of 0.75 million U.

References and Suggested Reading Callan MB, Preziosi D, Mauldin E: Multiple papillomavirusassociated epidermal hamartomas and squamous cell carcinomas in situ in a dog following chronic treatment with prednisolone and cyclosporine, Vet Dermatol 16:338, 2005. Carlotti DN et al: Use of recombinant omega interferon therapy in canine atopic dermatitis: a pilot study, Vet Dermatol 15(Suppl 1):32, 2004. Carlotti DN et al: The use of recombinant omega interferon therapy in canine atopic dermatitis: a double-blind controlled study, Vet Dermatol 20:405, 2009. Gutzwiller MER et al: Feline herpes dermatitis treated with interferon omega, Vet Dermatol 18:50, 2007. Hasegawa A, Sakurai T, Iwasaki T: A placebo-controlled, doubleblinded study of recombinant IFN-γ in dogs with atopic dermatitis, Vet Dermatol 15(Suppl 1):55, 2004. Iwasaki T et al: Effect of treatment with recombinant canine IFN-γ on the clinical signs, histopathology and Th1/Th2 cytokine mRNA profiles in Shih Tzu and a basset hound with atopic dermatitis, Adv Vet Dermatol 5:82, 2005. Iwasaki T, Hasegawa A: A randomized comparative clinical trial of recombinant canine interferon-gamma (KT-100) in atopic dogs using antihistamines as control, Vet Dermatol 17:195, 2006. Nishifuji K et al: A case of hyperplastic dermatosis of the West Highland White Terrier controlled by recombinant canine interferon-γ therapy, J Vet Med Sci 69:445, 2007. Shibata S et al: Effect of recombinant canine interferon-γ on granulocyte-macrophage colony-stimulating factor, transforming growth factor-β and CC chemokine ligand 17 mRNA transcription in a canine keratinocyte cell line (CPEK), Vet Dermatol 22:24, 2010. Siebeck N et al: Effects of human recombinant alpha-2b interferon and feline recombinant omega interferon on in vitro replication of feline herpesvirus-1, Am J Vet Res 67:1406, 2006. Thompson LA et al: Human recombinant interferon alpha-2b for management of idiopathic recurrent superficial pyoderma in dogs: a pilot study, Vet Ther 5:75, 2004. Yasukawa K et al: Low-dose recombinant canine interferon-γ for treatment of canine atopic dermatitis: an open randomized comparative trial of two doses, Vet Dermatol 21:42, 2010.

WEB CHAPTER 

41 

Pentoxifylline ROSANNA MARSELLA, Gainesville, Florida

P

entoxifylline (PTX) is a methylxanthine derivative with multiple hemorheologic and immunomodulatory properties. PTX is available as a generic formulation or a brand name drug (Trental, 400-mg tablets). This drug has been used for almost 40 years in humans with intermittent claudication caused by peripheral and cerebrovascular atherosclerotic disease and for at least 10 years in veterinary medicine to treat a variety of conditions. The list of conditions for which PTX has been found to be potentially beneficial in dogs has grown rapidly (Marks et al, 2001). The drug is rarely used in feline dermatology (Nichols et al, 2001). This chapter reviews the use of PTX in small animal dermatology.

Properties of Pentoxifylline PTX is a nonspecific phosphodiesterase (PDE) inhibitor. Through its hemorheologic properties, PTX changes the conformation of red blood cells and improves microcirculatory blood flow and tissue oxygenation. Aged red blood cells have rigid membranes because of reduced adenosine triphosphate levels and increased calcium levels. By increasing levels of cyclic adenosine monophosphate (cAMP, the second messenger of the β-adrenergic system) and by modulating intracellular calcium levels, PTX increases red blood cell deformability. Besides affecting red blood cells, PTX also exerts beneficial effect on platelets by decreasing platelet aggregation and blood viscosity. Once again, this is caused by the inhibition of PDE and the decrease in cAMP degradation. It is interesting to note that PTX restores normal cAMP levels and has an effect on aggregation only in conditions in which the platelets are hyperaggregable and have altered levels of cAMP. PTX does not appear to affect normal platelets and therefore does not prolong bleeding. Therefore it is not necessary to discontinue PTX therapy before surgical procedures. PTX exerts multiple beneficial effects on the inflammatory cascade by increasing intracellular cAMP levels and decreasing synthesis of tumor necrosis factor-α (TNFα). Since TNF-α is a proinflammatory cytokine with a broad spectrum of actions, its decrease leads to multiple antiinflammatory effects. These include decreased release of other proinflammatory cytokines such as interleukin-1 (IL-1) and IL-6, decreased leukocyte adhesion and aggregation, decreased neutrophil degranulation and superoxide release, inhibition of B-cell activation (by suppression of IL-6 synthesis), and inhibition of T-cell activation (through the CD23 and CD26 pathway) (Bruynzeel et al, 1995). Based on in vitro studies, the decrease of cytokine expression is dose dependent. The beneficial effects of PTX have been shown in numerous animal studies using e202

models of ischemia-reperfusion and septic shock (Zhang et al, 1994). In these studies PTX significantly improved survival rates by both decreasing the inflammatory reaction and improving tissue oxygenation. Finally, PTX also improves wound healing by increasing fibroblast collagenases and decreasing collagen production, fibronectin, glycosaminoglycans, and fibroblast response to TNF-α.

Pharmacokinetics The pharmacokinetic and pharmacodynamic properties of PTX have been well characterized in human patients. PTX is absorbed rapidly and extensively after oral administration (Marsella et al, 2000). After absorption from the gastrointestinal tract, it binds to the red blood cells, where it is reduced immediately to metabolite 1 (M1). This transformation is reversible, and M1, which also binds to the erythrocyte membrane, serves as a reservoir for PTX. The other six metabolites are formed in the liver and appear in plasma soon after dosing. Extensive enterohepatic recycling occurs, and more than 90% of the absorbed drug is excreted in the urine in the form of metabolites. M1 and M5 are the major metabolites, and the plasma levels of these compounds are five and eight times greater, respectively, than that of the parental drug. Bioavailability in humans averages 20% to 30% and is affected by food. Excretion is almost completely urinary. M1 and M5 are present in the highest concentration in the urine, whereas no PTX is found in the urine. Only a few studies have been done in dogs to evaluate the disposition of PTX and its active metabolites. In one study (Marsella et al, 2000) PTX was found to be absorbed and eliminated rapidly after oral administration. Peak plasma concentration for PTX (15 mg/kg) was achieved 30 minutes after oral administration. Concentrations declined rapidly, and no drug was detected after 4 hours. After intravenous administration (15 mg/kg), elimination proceeded rapidly, and no drug was detectable after 3 hours. Peak plasma concentration of M1 and M5 after intravenous and oral administration was achieved after 20 minutes and 60 minutes, respectively. Mean bioavailability after oral administration ranged from 15% to 32% among treatment groups and was not affected by the presence of food. Higher plasma PTX concentrations and apparent bioavailability were observed after oral administration of the first dose than after the last dose during the 5-day treatment regimens. It was concluded that oral administration of PTX at 15 mg/kg resulted in plasma concentrations similar to those produced by therapeutic doses in humans and that a three-times-daily dosing regimen was the most appropriate. No adverse effects were observed.

WEB CHAPTER  41  Pentoxifylline In another study (Rees et al, 2003) PTX was readily metabolized and bioavailable (50% ± 26%). Both active metabolites (M1 and M5) were detectable, with M5 predominating. Human drug therapeutic concentrations (1000 ng/ml) were present for 170 ± 24 minutes following intravenous administration and 510 ± 85 minutes after oral dosing. This study emphasized the large variability in absorption and disposition of PTX in dogs. None of the dogs experienced any adverse effects after PTX administration. No hematologic effects were detected.

Adverse Effects In contrast to other methylxanthines, PTX has few cardiac effects. PTX can be a gastric irritant, and in humans the main adverse effect is gastrointestinal upset (e.g., vomiting and diarrhea). Other reported adverse effects in humans are angina/chest pain, agitation, dizziness, headache, and tremors. Adverse effects are dose related and can be decreased by lowering the dose. Dogs appear to tolerate oral PTX very well, even on an empty stomach. Gastrointestinal upset can be seen, although it is not common. No significant changes in chemistry values have been reported in dogs receiving PTX (Rees and Boothe, 2003). There are anecdotal reports of transient cutaneous flushing and erythematous macules in shortcoated dogs.

Indications for Use in Veterinary Dermatology PTX has been used to treat a variety of dermatologic conditions, with success dependent on dose. Since several of the conditions have a waxing and waning course and many of the studies done were open studies, a scientific evaluation of the efficacy of the drug was not always possible. Nevertheless, the list of dermatologic diseases for which PTX has been reported to be beneficial is quite extensive.

Dermatomyositis Canine familial dermatomyositis is an inflammatory disease in which microvascular vasculopathy is thought to play a role. Therefore dermatomyositis was one of the first dermatologic diseases in which PTX was tried and reported to have useful effects. In the management of dermatomyositis cases PTX usually is considered as a steroid-sparing agent and rarely as the only form of treatment (Rees et al, 2003). The advantage of using PTX is its better safety profile and lack of atrophogenic properties compared with glucocorticoids. The response to treatment is variable and typically slow (2 to 3 months). Historically a large range of dosages and treatment regimens have been suggested. Recommended dosage ranges from 10 to 20 mg/kg orally every 8 to 12 hours depending on the severity of the disease. Based on a study by Rees and Boothe (2003) it appears that a dosage of 25 mg/ kg twice daily resulted in positive clinical response (four complete and six partial responses in the 10 dogs treated). In that study the authors investigated whether a direct correlation could be established between concentrations

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of PTX and its metabolites and clinical response; they concluded that, because of the variability in disposition and metabolite formation among individual dogs, monitoring of PTX concentration did not offer a therapeutic advantage.

Contact Allergy PTX has also been used with success for the prevention of clinical signs caused by contact allergy. The rationale behind the use of PTX for contact allergy is its ability to decrease the production of TNF-α, an important inflammatory mediator in this condition; to down-regulate the expression of adhesion molecules on keratinocytes; and to suppress T-cell adherence to keratinocytes. PTX has been reported to suppress patch test reactions in human patients and, when taken 48 hours before exposure, either abolished or drastically decreased the development of clinical signs of contact allergy (Schwarz et al, 1993a, 1993b). Another study found similar results for dogs with contact allergy to plants of the Commelinenceae family. In this study PTX was able to prevent contact allergy in exposed dogs at a dosage of 10 mg/kg every 12 hours (Marsella et al, 1997). The protective effect of PTX in contact allergy appears to be dose related. Clinical benefit seems to be evident after 2 days of oral therapy (at 10 mg/kg every 12 hours) and does not last for a prolonged period of time after discontinuation of therapy (1 week) (Marsella et al, 1997). PTX is most effective when used before exposure, although it can help reduce the amount of glucocorticoids needed to control symptoms in cases in which exposure has already occurred. Based on information regarding the pharmacokinetic properties of this drug in dogs (Marsella et al, 2000), PTX is best used at 15 mg/kg every 8 to 12 hours to control more severe cases. PTX should be given with food to decrease gastric irritation. In some patients irritability and nervousness have been reported.

Canine Atopic Dermatitis The efficacy of PTX for treatment of canine atopic dermatitis (CAD) also is dose dependent. The rationale behind its use is that PTX is a PDE inhibitor and thereby stabilizes a variety of cells, including mast cells. The drug also can suppress the synthesis of proinflammatory cytokines that play a role in atopic dermatitis (e.g., TNF-α, IL-6), indirectly affecting the release of chemokines that would mediate the recruitment of leukocytes in the skin. Although we still lack a comprehensive understanding of the pathogenesis of this disease, all of the antiinflammatory properties of PTX have been proposed to be beneficial in patients suffering from atopic dermatitis. Although a pilot study using PTX at 10 mg/kg every 12 hours for 4 weeks showed only moderate benefit (Marsella and Nicklin, 2000), a more recent study using PTX at higher dosages (20 mg/kg every 8 hours) and for a longer time (60 days) showed a more significant improvement, particularly when PTX was combined with essential fatty acids (Singh et al, 2010). In this study, 30 atopic dogs were randomly allocated to three groups: two treatment groups (n = 12 per group) and one control group (n = 6).

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Group I was treated with PTX 20 mg/kg body weight three times daily; group II was treated with PTX 20 mg/ kg body weight three times daily plus polyunsaturated fatty acids (PUFAs). The PUFA therapy was administered twice daily PO and included linoleic acid, linolenic acid, and oleic acid at 50 mg/kg each; eicosapentaenoic acid at 2.5 mg/kg; docosahexaenoic acid at 1.5 mg/kg; and γ-linoleic acid at 0.5 mg/kg. The group treated with PTX plus PUFAs showed a 56.75% and 47.76% reduction in clinical scores and pruritus scores, respectively, on day 30, whereas the corresponding reductions on day 60 were 90.92% and 92.59%, respectively. The PTX-treated group had a 38.78% and 43.34% reduction in clinical scores and pruritus scores, respectively, on day 30, whereas on day 60, the corresponding reductions were 84.81% and 90.40%, respectively. The largest percentage reductions in clinical and pruritus scores from baseline on both day 60 and day 30 were seen in the group receiving the combination of PTX and PUFAs. On day 30 there was a 56.75% and 47.76% reduction in CADESI and VAS pruritus scores, respectively, while the corresponding reductions on day 60 were 90.92% and 92.59%, respectively. The reductions were particularly evident in 5 of the 12 animals. It therefore is reasonable to conclude that PTX is a beneficial adjunctive treatment (e.g., in combination with PUFAs) for CAD, especially to reduce the frequency of administration of glucocorticoids. PTX does not need to be discontinued before intradermal skin testing if only immediate reactions are scored. In one study, no suppression of immediate intradermal skin test reactivity was detected after treatment with PTX for 4 weeks. In contrast, delayed reactions were decreased (Marsella and Nicklin, 2000). PTX was reported to be a useful adjunctive therapeutic agent in an open study involving dogs with CAD that received allergen-specific immunotherapy (Scott and Miller, 2007). Anecdotally it appears that older dogs and dogs with reactions mostly to grasses have the best clinical response to PTX therapy. I tend to use this drug in geriatric dogs in which treatment with glucocorticoids or cyclosporine is contraindicated. This is based on the favorable safety and tolerability profile of PTX in dogs and the reported improvement in the overall cognitive function of these patients in conjunction with a beneficial effect on their skin condition. The better response in patients with mostly grass allergies is an interesting clinical observation in light of the recent observations on the importance of the epicutaneous route of allergen exposure in CAD and the speculation that some individuals may suffer from a combination of both contact allergy and atopic dermatitis.

Vasculitis PTX commonly is used as steroid-sparing agent for the treatment of vasculitis of various origins (Atzori et al, 1999; Milling and Falk, 1994; Morris, 2013). The most commonly used dosage is 10 to 15 mg/kg twice daily (Nichols et al, 2001). This is because of the combination of its potent hemorheologic properties (which increase erythrocyte deformability and thus allow the cells to pass through compromised blood vessels more readily) and its

antiinflammatory effects. Unfortunately, the onset of clinical benefit is slow, and several weeks to months may be required to observe clinical response. In human patients this time has been reported to range from 2 weeks to 14 months. Thus PTX rarely is used alone in the early phases of therapy; it usually is combined with glucocorticoids. This combination is hypothesized to have synergistic effects in decreasing inflammation, possibly through the common ability to decrease TNF-α synthesis. Because PTX commonly is used in combination with other treatments for vasculitis, it sometimes is difficult to assess the exact benefit of therapy in cases that show favorable response. Nevertheless, I have had several cases that were well controlled with just PTX therapy after glucocorticoids were discontinued and would relapse if PTX were discontinued. Similarly, I have seen cases that were well controlled with Trental but that showed relapse when a switch was made to generic PTX. This clinical observation has raised concerns about whether generic formulations can be considered equivalent to Trental. Unfortunately, no studies have been done to investigate this question; thus no definitive recommendation can be made at this time other than to consider switching to Trental when generic formulations of PTX do not show clinical benefit or initiating therapy with Trental and considering a switch to generic PTX if a clinical response is seen.

Symmetric Lupoid Onychodystrophy Symmetric lupoid onychodystrophy is a syndrome with multiple possible causes, including vasculitis and immune-mediated mechanisms. For this reason PTX has been used either as sole therapy or in conjunction with other immunomodulatory treatments. In one retrospective study (Mueller et al, 2003) PTX was administered to six dogs with lupoid onychodystrophy. Excellent response was observed in two dogs and a good response in two others. The remaining two patients showed no improvement. One of the dogs that showed an excellent response had not responded previously to 4 months of treatment with doxycycline, niacinamide, and fatty acids but then had undergone spontaneous remission for 6 months. When clinical signs recurred, this dog responded rapidly to PTX. As when PTX is used to treat other conditions, clinical benefit is slow; thus PTX must be tried for several months before improvement can be assessed fully.

Miscellaneous Conditions There are anecdotal reports of the use of PTX to treat other vasculopathies, including proliferative thrombovascular necrosis of the pinnae, ear pinna dermatosis, rabies vaccine–associated alopecia, vasculopathy of greyhounds, and metatarsal fistulation of the German shepherd dog. Similarly, PTX has been tried in condition in which necrosis is a concern, such as spider bites. Because of the role of TNF-α in erythema multiforme, PTX can be beneficial in cases in which an underlying cause of erythema multiforme cannot be identified, particularly in geriatric animals that have recurrent disease. Because of

WEB CHAPTER  41  Pentoxifylline its combined antiinflammatory properties and ability to decrease fibrosis, PTX also can be considered as adjunctive therapy for dogs with lick granulomas. Another potential use of PTX is as adjunctive therapy in canine patients diagnosed with cancer and undergoing chemotherapy to possibly counteract the negative consequence of excessive release of TNF-α. A recent case report described the beneficial effects of PTX in the treatment of bronchopneumonia and streptococcal toxic shock syndrome secondary to necrotizing fasciitis (Csiszer et  al, 2010). As for nondermatologic uses of PTX in dogs, it has been reported that high concentrations of PTX are able to induce capacitation and acrosome reaction and improve motility in canine ejaculated spermatozoa (Milani et al, 2010; Mirshokraei et al, 2011). PTX also has been demonstrated to decrease tissue damage after hemorrhagic shock (Coimbra et al, 2004) and to reduce postoperative cerebral damage in patients undergoing cardiac surgery with cardiopulmonary bypass (Durgut et al, 2004). However, clinical trials are needed before these applications can be recommended in clinical practice.

References and Suggested Reading Atzori L, Ferreli C, Biggio P: Less common treatment in cutaneous vasculitis, Clin Dermatol 17:641, 1999. Bruynzeel I, Liesbeth MH, Stoof TJ: Pentoxifylline inhibits T-cell adherence to keratinocytes, J Invest Dermatol 104:1004, 1995. Coimbra R et al: Intraarterial pulmonary pentoxifylline improves cardiac performance and oxygen utilization after hemorrhagic shock: a novel resuscitation strategy, Anesth Analg 98(5):1439, 2004. Csiszer AB, Towle HA, Daly CM: Successful treatment of necrotizing fasciitis in the hind limb of a Great Dane, J Am Anim Hosp Assoc 46(6):433, 2010. Durgut K et al: The cerebroprotective effects of pentoxifylline and aprotinin during cardiopulmonary bypass in dogs, Perfusion 19(2):101, 2004. Hargis AM, Mundell AC: Familial canine dermatomyositis, Compend Contin Educ 14:855, 1992.

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Marks SL, Merchant S, Foil C: Pentoxifylline: wonder drug? J Am Anim Hosp Assoc 37:218, 2001. Marsella R et al: Pharmacokinetics of pentoxifylline in dogs after oral and intravenous administration, Am J Vet Res 61:631, 2000. Marsella R, Kunkle GA, Lewis DT: Use of pentoxifylline in the treatment of allergic contact reactions to plants of the Commelinenceae family in dogs, Vet Dermatol 8:121, 1997. Marsella R, Nicklin CF: Double-blind placebo-controlled, crossover clinical trial on the efficacy of pentoxifylline in canine atopy, Vet Dermatol 11:255, 2000. Milani C et al: Effect of post-thaw dilution with caffeine, pentoxifylline, 2′-deoxyadenosine and prostatic fluid on motility of frozen-thawed dog semen, Theriogenology 74(1):153, 2010. Milling DM, Falk RJ: Vasculitis affecting the skin, Arch Dermatol 130:899, 1994. Mirshokraei P et al: Pentoxifylline induces capacitation and acrosome reaction and improves quality of motility in canine ejaculated spermatozoa, Res Vet Sci 91(2):281, 2011. Morris DO: Ischemic dermatopathies, Vet Clin North Am Small Anim Pract 43(1):99, 2013. Mueller RS, Rosychuk RA, Jonas LD: A retrospective study regarding the treatment of lupoid onychodystrophy in 30 dogs and literature review, J Am Anim Hosp Assoc 39:139, 2003. Nichols PR, Morris DO, Beale KM: A retrospective study of canine and feline cutaneous vasculitis, Vet Dermatol 12:255, 2001. Rees CA et al: Dosing regimen and hematologic effects of pentoxifylline and its active metabolites in normal dogs, Vet Ther 4:188, 2003. Rees CA, Boothe DM: Therapeutic response to pentoxifylline and its active metabolites in dogs with familial canine dermatomyositis, Vet Ther 4:234, 2003. Schwarz A et al: Pentoxifylline suppresses allergic patch test reactions in humans, Arch Dermatol 129:513, 1993a. Schwarz A et al: Pentoxifylline suppresses irritant and contact hypersensitivity reactions, J Invest Dermatol 101:549, 1993b. Scott DW, Miller WH Jr: Pentoxifylline for the management of pruritus in canine atopic dermatitis: an open clinical trial with 37 dogs, Jpn J Vet Dermatol 13:5, 2007. Singh SK et al: Therapeutic management of canine atopic dermatitis by combination of pentoxifylline and PUFAs, J Vet Pharmacol Ther 33(5):495, 2010. Zhang H et al: Pentoxifylline improves the tissue oxygen extraction capabilities during endotoxic shock, Shock 2(2):90, 1994.

WEB CHAPTER 

42 

Pyotraumatic Dermatitis (“Hot Spots”) WAYNE S. ROSENKRANTZ, Tustin, California

H

ot spots, more appropriately described as pyotraumatic dermatitis, are defined as a circumscribed, moist exudative dermatitis most commonly brought on by self-trauma. The self-trauma results from attempts to alleviate pain or pruritus associated with an underlying disease. Primary bacterial infections in theory could create localized moist exudative lesions with minimal self-trauma, but these are very rare. The most common causes of hot spots are allergic conditions such as flea allergy, atopic dermatitis, adverse food reaction, scabies, and anal gland problems (Web Box 42-1). Complications from clipping or grooming such as razor burn or trauma also can create localized inflammation that results in pruritus and hot spot formation. Occasionally other infectious conditions (infection with Staphylococcus spp. or Pseudomonas spp., demodicosis, or dermatophytosis) can cause localized multifocal areas of pain and pruritus leading to hot spot–like lesions. Other less common causes of hot spots are listed in Web Box 42-1. Although dogs of any breed can experience hot spots, certain breeds may be predisposed. These include the golden retriever, Labrador retriever, Saint Bernard, collie, and German shepherd. Importantly, many breeds at risk of hot spots also are predisposed to the common underlying causes of hot spots such as allergic dermatitis. Long hair coat length also has been thought to be associated with a predisposition to hot spots. However, in a report of 40 dogs with hot spots, 50% had short hair and 50% had long hair (Schroeder et al, 1996). The role of Staphylococcus in the development of hot spots remains controversial. Staphylococcus organisms can be isolated from the skin of healthy dogs. Higher numbers of these organisms are found in allergic dogs, even in those without active skin disease. Therefore allergies may contribute to hot spots not only by inducing pruritus but also by creating a favorable environment for larger numbers of staphylococci to inhabit the skin. One investigator proposes that hot spots are of two types based on histopathologic patterns (Reinke et al, 1987). One is a superficial lesion in which bacteria are considered surface colonizers. The other is a folliculitis that may be a deep lesion. Coagulase-positive Staphylococcus spp., particularly Staphylococcus pseudintermedius, are cultured most commonly from these lesions. This same study showed a strong tendency for young dogs, golden retrievers, and Saint Bernards to be predisposed to the deeper form e206

of hot spots. In another study, lesions in 44 privately owned dogs in a flea-scarce environment were separated histopathologically into four patterns based on the presence or absence of eosinophils or folliculitis (Holm et al, 2004). Eosinophils have not been recorded previously in pyotraumatic dermatitis but were seen in 29 cases. Acute folliculitis was seen in 20 cases. However, no correlation was found between histopathologic type and age, sex, breed, underlying cause, or site of lesion. Samples from 27 cases were cultured for bacteria, of which 25 grew S. pseudintermedius and 2 yielded negative results. In another study Staphylococcus was isolated from all lesions before topical treatment (Schroeder et al, 1996). In control groups treated with a placebo vehicle the condition cleared completely within 7 days without topical antimicrobial treatment. The role of Staphylococcus as a primary cause of hot spots certainly is unclear.

Clinical Features The historical hallmark of hot spots is intense pruritus, and hot spots represent one of the situations in which clients generally are correct when they report that the lesion “just happened.” The intense self-trauma can produce large lesions within minutes. Regardless of the cause, most hot spots have a similar clinical appearance. They generally are well circumscribed, moist, erosive or ulcerated, erythematous, and often painful lesions. The overlying hair is matted and coated with a serous or suppurative exudative discharge. Variable amounts of crusted debris may be present. It is not uncommon to see peripheral smaller lesions (satellite lesions that often are papular and crusted) adjacent to the primary site. Acute lesions tend to be edematous, whereas chronic lesions may be thickened with lichenified or scarred peripheral areas resembling acral lick dermatitis (lick granuloma–like). The most common body locations for pyotraumatic dermatitis are the rump, lateral upper thigh, perineal-rectal area, and lateral aspect of the face below the ear. The rump and lateral upper thigh are the most common locations of the lesions, which can be associated with flea allergy, adverse food reactions, or atopic dermatitis. Perineal-rectal area lesions generally are related to anal gland disease or adverse food reactions. Lateral cervical facial lesions can be associated with otitis, atopic dermatitis, or adverse food reactions.

WEB CHAPTER  42  Pyotraumatic Dermatitis (“Hot Spots”)

WEB BOX 42-1  Causes of Hot Spots Common Causes Allergies: flea allergy, atopic dermatitis, adverse food reaction Parasitosis: scabies, demodicosis Anal gland disease Clipping or grooming Deep pyoderma Uncommon Causes Dermatophytosis Injection site reactions Drug reactions Autoimmune disease Panniculitis Vasculitis

Diagnosis Diagnosis is generally made from the history and physical examination. The intensity of the pruritus, body location of the lesions, and physical appearance often are all that is necessary to make a diagnosis. Initially skin scrapings should be considered to rule out Demodex infestation and cytologic examination should be performed to detect the presence of bacterial overgrowth or pyoderma. In more chronic or relapsing conditions, fungal and bacterial cultures, biopsies for histopathologic analysis, and allergy workups (flea control, food elimination dietary trials, workup for atopic dermatitis) should be performed. If these tests do not lead to a diagnosis, laboratory testing for underlying immune-mediated or systemic problems may be considered.

Treatment Topical Therapy Regardless of the cause and independent of what is administered topically or systemically, shaving the hair and cleansing the hot spot is the most important initial form of therapy. To shave or clean the wound, topical sedation usually is necessary (or even general anesthesia in some cases) because of the pain and discomfort associated with the lesion. After the area is clipped, the full extent and nature of the lesion can be observed. An antimicrobial shampoo containing benzoyl peroxide or chlorhexidine (see Chapter 102) is one of the most commonly used cleansing agents. Over-the-counter antimicrobial shampoos such as those containing benzalkonium chloride also can be effective. After the site is clipped and washed appropriately, additional topical and, in some situations, systemic treatments are necessary. Occlusive vehicles (ointments and creams) should be avoided. Nonocclusive vehicles (sprays, rinses, gels, and lotions) are preferable to allow exudation to occur and prevent occlusion of follicles and progression into a deeper folliculitis.

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Many practitioners like to use an astringent on hot spots for the first 24 to 48 hours. Astringents precipitate proteins and usually do not penetrate deeply. These products do tend to dry out and decrease the exudation. An example of a currently used astringent is aluminum acetate solution (Burow’s solution, Domeboro) diluted 1 : 40 in cool water. Other less commonly used astringents are 5% tannic acid, 25% silver nitrate solution, and potassium permanganate in a 1 : 1000 to 1 : 30,000 solution. The author prefers Domeboro because it is tolerated best and does not stain as do the other astringents. The most common topical products used on hot spots are antipruritic sprays, gels, and lotions. Some of these products substitute another sensation for the pruritus, such as heat or cold. Examples are 0.12% to 1% menthol, 0.12% to 1% camphor, 0.5% to 1% thymol, and cold ice packs. Cooling tends to decrease pruritus. Other products use local anesthetic or desensitizing agents such as benzocaine, tetracaine, lidocaine, 1% pramoxine, benzoyl peroxide, and tars. These agents are short acting. Topical antihistamines are considered effective in humans but in the author’s experience have limited value in dogs. Anecdotal reports suggest that topical 2% diphenhydramine is effective in reducing pruritus in dogs with hot spots. Colloidal oatmeal rinses and shampoos also can give topical relief from pruritus (see Table 95-1). The topical products most effective in controlling the pruritus associated with hot spots are glucocorticoids. Hydrocortisone is the safest and has been reported effective anecdotally. A 1% hydrocortisone formulation is considered particularly safe and can be used long term with no adverse topical or systemic side effects. The author finds 1% hydrocortisone combined with a deterrent such as denatonium benzoate to be most effective (Pinnaclife). Another glucocorticoid, a low-dose 0.015% triamcinolone spray (Genesis) also has been evaluated and appears to be much more effective than the hydrocortisone-based products. In controlled studies it appeared to have no significant systemic absorption; however, when it is applied to the flanks and medial thighs, localized cutaneous atrophy reactions have been seen. The newest topical glucocorticoid released for use in dogs is hydrocortisone aceponate (HCA) (Cortavance). HCA belongs to the diester class of glucocorticoids. The diesters are lipophilic components ensuring an enhanced penetration into the skin but a low plasma bioavailability. HCA thus accumulates in the dog’s skin, which allows local efficacy at low dosage. Diesters applied topically have a high therapeutic index—high local activity with reduced systemic secondary effects—and theoretically would be an excellent product to control pruritus associated with pyotraumatic dermatitis (see Table 95-2). Topical antimicrobial agents can be used alone or in combination with other agents. Alcohol-based products can be bactericidal and astringent but also can be irritating to ulcerated surfaces. The most commonly used alcohol product is 2% benzyl alcohol. Some of the active agents mentioned in the shampoo section also are available in gel and solution forms and can be used on focal lesions. One of the oldest antimicrobials is iodine. The “tamed” iodines (povidone-iodine [Betadine] and polyhydroxydine [Xenodine]) are less irritating and less

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staining than their precursors but generally are not as effective as some of the other antimicrobials mentioned. Surface-acting agents such as the quaternary ammonium compounds (e.g., benzalkonium chloride) are effective broad-spectrum antibacterial agents. A new oxychlorine compound (Vetericyn) has board-spectrum antimicrobial properties and is available in spray and gel formulations. It can be used in some pyotraumatic dermatitis cases to control bacterial overgrowth and secondary infections, including those caused by some methicillin-resistant staphylococci. Many potent topical antibacterial agents are available. The author’s favorite veterinary topical antibiotic is mupirocin because of its high efficacy against coagulasepositive staphylococci (including methicillin-resistant strains) and its ability to penetrate deeper pyodermas. Other products that can be helpful are neomycin, gentamicin, bacitracin, and polymyxin B. Combination antibiotic and glucocorticoid products can produce the quickest healing as shown in one study (Schroeder et al, 1996) in which neomycin, prednisolone, and combination neomycin-prednisolone products were compared. The combination product produced the most rapid recovery. The author does not commonly use combination products that contain occlusive vehicles but occasionally will use spray- or lotion-based products such as thiabendazole/dexamethasone/neomycin sulfate (Tresaderm) and gentamicin sulfate/betamethasone valerate (Gentocin Topical Spray) for short-term treatment (2 or 3 days). These products contain potent glucocorticoids; thus they should be used for no longer than 7 days.

Systemic Therapy The need for systemic therapy for hot spots varies on a case-by-case basis. Most dogs benefit from a course of systemic antibiotics, particularly if the hot spot represents a deeper folliculitis. Antibiotic selection should be based on proven efficacy against S. pseudintermedius; treatment should be administered for a minimum of 14 days and generally should continue for 7 to 10 days beyond clinical

cure. The author’s personal favorites are cephalexin 20 to 30 mg/kg q12h PO, cefpodoxime proxetil (Simplicef) 10 mg/kg q24h PO, cefovecin (Convenia) 8 mg/kg q2wk SC, ormetoprim-sulfadimethoxine (Primor) 55 mg/kg PO for the first 24 hours and then 27.5 mg/kg q24h PO after that, amoxicillin/clavulanate (Clavamox) 15 to 20 mg/kg q12h PO, and enrofloxacin (Baytril) 5 mg/kg q24h PO or marbofloxacin (Zeniquin) 2.5 mg/kg q24h PO. The use of systemic glucocorticoid therapy is more controversial. Some dermatologists avoid glucocorticoids, especially for deeper pyotraumatic folliculitis, because of the concern for immunosuppression. If the practitioner elects to use glucocorticoids, injectable long-acting (repositol) steroids should be avoided, and only short courses of oral prednisone or prednisolone should be used to break the pruritic cycle. Suggested dosages are antiinflammatory dosages (1 mg/kg q24h for 3 to 5 days). The client should be warned about future lesions because this commonly is a recurring problem if the underlying disease is chronic. Therefore identifying, eliminating, or controlling the underlying disease (see section on diagnosis earlier) is the long-term goal for prevention of hot spots. The client should be educated about the various differential diagnoses, and diagnostic tests should be performed accordingly. Attention to increased episodes of pruritus after grooming and bathing should be stressed. Maintaining parasite control and routinely examining the ears and anal glands also are recommended.

References and Suggested Reading Holm BR, Rest JR, Seewald W: A prospective study of the clinical findings, treatment, and histopathology of 44 cases of pyotraumatic dermatitis, Vet Dermatol 6:369, 2004. Reinke SI et al: Histopathologic features of pyotraumatic dermatitis, J Am Anim Hosp Assoc 190:57, 1987. Schroeder H et al: Efficacy of a topical antimicrobial-antiinflammatory combination in the treatment of pyotraumatic dermatitis in dogs, Vet Dermatol 7:163, 1996. Scott DW, Miller WH, Griffin CE: Muller and Kirk’s small animal dermatology, ed 6, Philadelphia, 2001, Saunders, p 1104.

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43 

Therapy for Sebaceous Adenitis EDMUND J. ROSSER JR., East Lansing, Michigan

S

ebaceous adenitis is an inflammatory disease process directed against the sebaceous glands of the skin and has an unknown cause and pathogenesis (Rosser et al, 1987; Scott, 1986). In standard poodles, the results of pedigree analyses and prospective breeding studies of affected animals suggest that sebaceous adenitis is a heritable, autosomal-recessive skin disease of variable expression (Dunstan and Hargis, 1995), and a similar mode of inheritance has been proposed for Akitas with sebaceous adenitis (Reichler et al, 2001). However, thus far ongoing work by Boursnell and colleagues in the United Kingdom has not identified the genomic region involved in the inheritance of this disease in standard poodles. More recently, this project has been expanded, with collaboration from Dr. Niels Pedersen of the Veterinary Genetics Laboratory at the University of California–Davis; thirtyfive affected dogs from the United States and 23 affected dogs from the United Kingdom were examined, with encouraging results (Animal Health Trust website, research on Sebaceous Adenitis). The current theory regarding the alopecia observed in this disease is that the loss of sebaceous glands results in the loss of sebum at the level of the infundibulum. Sebum appears to be required for the subsequent dissolution of the outer root sheath of the growing hair (Gates and Karasek, 1965; Stenn et al, 1999), and this may not be occurring as is observed in mice with the hereditary absence of sebaceous glands. The resultant hair shaft has a less developed cuticle for strength and may simply fracture at the level of the follicular ostia as the hair shaft continues to push outward. This may explain why the various surface lipid therapy treatments are so successful in allowing for the normal regrowth of hair in these dogs, as the hair bulb regions are already predominantly in an anagen phase on histopathologic examination.

Clinical Features Sebaceous adenitis occurs primarily in young adult to middle-aged dogs, with no apparent sex predisposition. However, more recent reports have indicated the onset of this disease in older dogs, including those aged 7 to 11 years, and this has been the author’s experience as well more recently with this disease (Linek et al, 2005; Reichler et al, 2001). The disease can be divided into two major forms based on their differences in clinical presentation and histopathologic changes (Rosser, 1992). The first form occurs in long-coated breeds and has been recognized most frequently in the standard poodle, Akita, and Samoyed. Over the past decade the disease has been reported with an increasing frequency and has been

diagnosed in several other breeds of dogs including the golden retriever, English springer spaniel, Lhasa apso, Old English sheepdog, miniature poodle (Rosser, 2010); cairn terrier, English pointer, Labrador retriever (Spaterna et al, 2003), and Havanese (Frazer et al, 2010). Another recent study on the incidence of sebaceous adenitis in Swedish dogs included a total of 26 affected breeds (Tevell et al, 2008). This form of the disease is characterized by a dull, brittle haircoat, alopecia, moderate to severe scaling, and the formation of follicular casts. Pruritus and malodor are variable and tend to be mild or absent early in the course of the disease and may become moderate to severe in advanced cases or when a secondary bacterial folliculitis develops. In standard poodles, the lesions most commonly affect the dorsal regions of the body, including the dorsal planum of the nose, top of the head, pinnae, dorsal trunk, and tail. When the disease is progressive, the affected areas develop tightly adherent scales (varying from silver-white to brown, depending on haircoat color), with small tufts of hair matted within the scales. The disease in standard poodles may present in several clinical forms: (1) a subclinical form (detectable only on histopathologic examination of skin biopsy specimens of apparently normal skin); (2) a localized, mild, and selflimiting form; (3) a progressive moderate to severe form; and (4) a cyclic form with periods of spontaneous improvement or worsening independent of any treatment. In Samoyeds, the alopecia, scaling, and follicular casts most commonly affect the entire trunk and pinnae. The disease in the Akita may represent its own variant of sebaceous adenitis in long-coated breeds of dogs, as it differs by the additional presence of greasiness of the skin and haircoat and the frequent presence of papules and pustules. Akitas may also show signs of systemic illness, such as fever, malaise, and weight loss (Power and Ihrke, 1990). However, a more recent study of 23 Akitas reported a progression of the disease similar to that observed in standard poodles, both clinically and histologically, and an absence of any systemic signs (Reichler et al, 2001). Also, 16 of the 23 owners of the affected dogs in this study reported that an illness, glucocorticoid or progestagen treatment, general anesthesia, estrus, molting, neutering, or environmental change preceded the onset of the disease. The second form occurs in short-coated breeds of dogs and has been most frequently recognized in the vizsla. This form of the disease is characterized by “moth-eaten,” annular, or diffuse areas of alopecia and mild scaling, with occasional small firm nodules, affecting the trunk, head, and ears. Dogs usually do not have pruritus, and the development of secondary bacterial folliculitis is rare. e209

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Because this form of the disease is quite different from the disease in long-coated breeds of dogs, in both its clinical and its histopathologic features, it is believed that this disease may be more appropriately classified as a granulomatous to pyogranulomatous, nodular, periadnexal, dermal, and pannicular dermatitis than as a subgroup of sebaceous adenitis (Rosser, 2010).

Diagnosis The breed affected, historical development of the problem, and physical findings are what first lead the clinician to suspect sebaceous adenitis. The diagnosis is confirmed by the histopathologic examination of several skin biopsy specimens that are representative of the different degrees of lesion severity noted during the physical examination. Sites selected for biopsy should include any apparently normal skin, mildly affected areas, and severely affected areas. The most common histologic finding is a nodular granulomatous to pyogranulomatous inflammatory reaction at the level of the sebaceous glands (Rosser et al, 1987; Dunstan and Hargis, 1995; Gross et al, 2005). In the chronic stages of the disease in long-coated breeds of dogs, there is often a complete absence of sebaceous glands with little or no inflammation, perifollicular fibrosis, and marked follicular and surface hyperkeratosis. This may easily be misinterpreted as being consistent with an underlying endocrine skin disease. For this reason it is suggested that such biopsy samples be submitted to individuals specifically trained in veterinary dermatohistopathology. In contrast, in short-coated breeds of dogs, the periadnexal nodular granulomatous to pyogranulomatous inflammatory reaction is usually present throughout the disease process, extending to all adnexal structures (hair follicle wall and apocrine glands as well as the sebaceous glands), the reticular and deep dermis, and panniculus, with occasional complete obliteration and loss of all adnexal structures.

Treatment and Management Long-term management of sebaceous adenitis can be a frustrating experience for owners and veterinarians because the response to therapy varies, depending on the severity of the disease at the time of diagnosis; in addition there is a lack of a consistent response to any single treatment regimen. This problem has led to several treatment recommendations and much confusion about which treatments should be tried. For this reason, the author recommends a systematic approach to the treatment of sebaceous adenitis in dogs. The goal of therapy should be to remove the excess scales, improve the luster of the haircoat, and regrow hair whenever possible (in standard poodles, the hair regrowth may be straight rather than curled). When response to treatment is evident, some level of maintenance therapy is usually required to control the disease. In severe or chronic cases in which the sebaceous glands have been completely lost, the prognosis for accomplishing these goals is guarded. However, a successful response to treatment (White et al, 1995), as well as the reappearance of sebaceous glands (Dunstan, personal communication,

1997), can occur even when the initial histopathologic examination of skin biopsy specimens revealed follicular fibrosis and apparent loss of the sebaceous glands. Specifically, a significant regeneration of sebaceous glands was observed in dogs with sebaceous adenitis while being treated with cyclosporine for 12 months (Linek et al, 2005). In this study, follow-up biopsies taken every 4 months over a 12-month period indicated an increase from only 2% of hair follicles exhibiting sebaceous glands to 40%. However, the severity of the follicular keratosis did not change significantly. In mildly affected dogs, the regular use of antiseborrheic shampoos, conditioners, emollients, and essential fatty acid dietary supplements may be effective. If the response is inadequate, the author’s first recommendation is the consistent use of a combination of essential fatty acid dietary supplements (Free Form Snip Tips, DVM), one capsule PO every 12 hours, and evening primrose oil, 500 mg PO every 12 hours, per dog (Rosser, 1992). This treatment should be continued for 2 months before being considered ineffective. Occasionally observed side effects include vomiting, diarrhea, and flatulence. This treatment has been most effective in the standard poodle and Samoyed breeds and usually requires lifelong administration to control the disease. An alternative to this treatment is the use of vitamin A (esterified form) at an initial dosage of 8000 to 10,000 IU twice a day; if significant improvement is not observed within 3 months, the dosage may be increased to 20,000 to 30,000 IU twice a day (DeManuelle and Rothstein, 2002; Sousa, 2006). However, a recent study examining the potential benefits of adjunct vitamin A therapy failed to find any correlation between vitamin A supplementation and response to treatment (Lam et al, 2011). When this is ineffective, or in dogs with large areas of tightly adherent scales (as in standard poodles), a bath oil treatment can be recommended. This is carried out by mixing any light mineral oil–containing bath oil (e.g., Alpha Keri Bath Oil, generic bath oil) 50 : 50 with water and spraying over the entire coat (Blair, 1993). The bath oil is then rubbed well into the haircoat and allowed to soak into the coat for 1 hour. The dog should be put in a crate or kennel during the 1-hour soak. The bath oil is then removed by several bathings (usually three shampooings) using a liquid dishwashing detergent (e.g., Palmolive dish soap, Ivory dish soap) while scrubbing the haircoat with a soft hairbrush. A conditioner, humectant, or creme rinse (HyLyt, Humilac, Hydra-Pearls) should be applied after the final bath. This process results in the removal of a significant amount of the excess scaling and may control the scaling and allow regrowth of hair. The regimen is repeated every 7 days for the first month and then every 14 to 30 days as needed. This treatment, although relatively labor-intensive, is one of the most effective for the regrowth of normal hair. This response would support the theory of the importance of lipids at the level of the follicular ostia for dissolution of the external root sheath, allowing for a normalization of hair growth. An alternative to this form of treatment is the use of a 50 : 50 or 75 : 25 mixture of propylene glycol and water applied once daily as a spray to the affected areas (Griffin, 1988). Most recently, the author has had success by following

WEB CHAPTER  43  Therapy for Sebaceous Adenitis up the first month’s bath oil treatment with Dermoscent Essential 6 applied as a spot-on once weekly on a maintenance basis. When these treatments have been ineffective, the use of a synthetic retinoid may be considered (see Chapter 116). In the management of sebaceous adenitis in vizslas, isotretinoin (Accutane) has proven to be a most effective retinoid (Stewart et al, 1991; White et al, 1995). The recommended dosage of isotretinoin is 1 mg/kg PO every 12 to 24 hours, with improvement usually noticed within 6 weeks. If improvement is evident, an attempt can be made to decrease the dosage to 1 mg/kg PO every 24 to 48 hours for another 6 weeks. If improvement continues, the long-term goal is to control the disease with either 1 mg/kg PO every 48 hours or 0.5 mg/kg every 24 hours. However, systemic retinoids are increasingly unavailable for use by veterinarians in the treatment of diseases for animals. This is due to stricter regulations regarding the release of the drug by only registered physicians and the required use of a human patient consent form when prescribing systemic retinoids. For management of refractory cases of sebaceous adenitis in long-coated breeds of dogs (primarily standard poodles and Akitas), either isotretinoin or acitretin (Soriatane) can be recommended. One study indicated that it could not be predicted as to whether isotretinoin or etretinate would be more effective in the treatment of sebaceous adenitis in any long-coated dog breeds (White et al, 1995). Therefore these dogs can be treated initially with either isotretinoin (1 mg/kg PO q12-24h) or etretinate (1 mg/kg PO q12-24h) for an observation period of 6 weeks. Because etretinate is no longer commercially available, acitretin is being considered as the alternative and similarly acting retinoid. If there is a poor response to therapy on the first chosen retinoid, the dog should be switched to the second retinoid for an observation period of 6 weeks. If improvement is noted using either of these retinoids, an attempt can be made to decrease the dosage to 1 mg/kg PO every 24 to 48 hours for another 6 weeks. If improvement continues, the longterm goal is to control the disease using either retinoid at a dosage of 1 mg/kg every 48 hours or 0.5 mg/kg PO every 24 hours. A treatment option in the management of sebaceous adenitis that has been nonresponsive to retinoid therapy is the use of cyclosporine (Atopica) at a dosage of 5 mg/ kg PO every 12 to 24 hours (Carothers et al, 1991; Linek et al, 2005; see the previous edition of Current Veterinary Therapy, p. 386 for a discussion of the side effects and toxicities in the use of cyclosporine in dogs). This has become the author’s systemic drug of choice for the longterm treatment of sebaceous adenitis in the standard poodle with the concurrent use of a bath oil followed by Dermoscent Essential 6 (see earlier). Recent examination of skin biopsies in this breed indicates that the earliest inflammatory change targeted against the sebaceous glands is a lymphoplasmacytic infiltrate, followed by the granulomatous to pyogranulomatous infiltrate. A lymphoplasmacytic infiltrate has also been reported to occur in the Havanese with sebaceous adenitis (Frazer et al, 2010). This would help explain the responses to cyclosporine observed by other authors (Linek et al, 2005; Lortz

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et al, 2010), as the major action of this drug is the suppression of T-lymphocytes. Most recently, cyclosporine has been applied as a topical solution, using a microemulsified cyclosporine oral solution (Neoral; 100 mg/ml concentration), and mixing 25 ml of the oral solution with 250 ml of water (1 : 10 dilution), which is then sprayed over the alopecic areas once daily (Patterson, 2005). A response to treatment with evidence of hair regrowth usually occurs within 2 weeks if this regimen is to be effective. If hair regrowth is observed, the treatment may be decreased from once-daily application to twice-weekly therapy as maintenance in some cases. In long-coated breeds of dogs, the hair should be clipped and kept short to facilitate application of the spray down to the skin. The owners should be instructed to wear gloves during the application process; let the dogs dry for 10 minutes after each application before handling the dog; and apply the spray in the late evening to minimize the handling of the dogs. To date, no adverse reactions or toxicities to this treatment have been reported. A conditioner or humectant in a spray form (HyLyt, Humilac, HydraPearls) should be used following each treatment with the topical cyclosporine. Alternatively, cyclosporine may be applied as a topical solution mixing 2 ml of cyclosporine oral solution (Neoral; 100 mg/ml concentration) with 100 ml of oil and applied as a rinse twice weekly (Cantagallo et al, 2009). A more recently recommended systemic therapy involves use of either tetracycline (22 mg/kg PO q8h, not to exceed 500 mg PO q8h) or doxycycline (5 to 10 mg/ kg PO q12-24h) with or without concurrent niacinamide (22 mg/kg PO q8h, not to exceed 500 mg PO q8h); however, responses to therapy have only been anecdotal to date, without any referenced publications. Sebaceous adenitis appears to be relatively refractory to either antiinflammatory or immunosuppressive dosages of corticosteroids. When a secondary bacterial folliculitis is present, the treatment should include the use of an appropriate systemic antibiotic along with a keratolytic, antibacterial, and follicular flushing (comedolytic) shampoo (Pyoben, Allerderm).

References and Suggested Reading Blair GL: Home therapy of sebaceous adenitis, Prog SA Research Winter/Spring, 1993, p 4. Cantagallo KL et al: Sebaceous adenitis: a new therapy option, case report, WSAVA World Congress Proceedings, 2009. Carothers MA, Kwochka KW, Rojko JL: Cyclosporine-responsive granulomatous sebaceous adenitis in a dog, J Am Vet Med Assoc 198:1645, 1991. DeManuelle T, Rothstein E: Food allergy and nutritionally related skin disease, Adv Vet Dermatol 4:224, 2002. Dunstan DW, Hargis AM: The diagnosis of sebaceous adenitis in standard poodle dogs. In Bonagura JD, editor: Kirk’s current veterinary therapy XII, Philadelphia, 1995, WB Saunders, p 619. Frazer MM et al: Sebaceous adenitis in Havanese dogs: a retrospective study of the clinical presentation and incidence, Vet Dermatol 22:267, 2010. Gates AH, Karasek M: Hereditary absence of sebaceous glands in the mouse, Science 148:1471, 1965. Griffin CE: Common dermatoses of the Akita, Shar Pei, and chow chow, Annual meeting of the American Academy of Veterinary Dermatology, Washington, DC, 1988, p 31.

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Gross TL et al: Skin diseases of the dog and cat: clinical and histopathologic diagnosis, Oxford, 2005, Blackwell Publishing, p 186. Lam ATH et al: Oral vitamin A as an adjunct treatment for canine sebaceous adenitis, Vet Dermatol 22:305, 2011. Linek M et al: Effects of cyclosporine A on clinical and histologic abnormalities in dogs with sebaceous adenitis, J Am Vet Med Assoc 226:59, 2005. Lortz J et al: A multicenter placebo-controlled clinical trial on the efficacy of oral ciclosporin A in the treatment of canine idiopathic sebaceous adenitis in comparison with conventional topical treatment, Vet Dermatol 21:593, 2010. Patterson S: Topical cyclosporine in sebaceous adenitis. In Kwochka KW, Rosenkrantz WS, editors: Shampoos and topical therapy, Oxford, 2005, Blackwell Publishing, p 382. Power HT, Ihrke PJ: Synthetic retinoids in veterinary dermatology, Vet Clin North Am Small Anim Pract 20:1525, 1990. Reichler IM et al: Sebaceous adenitis in the Akita: clinical observations, histopathology and heredity, Vet Dermatol 12:243, 2001. Rosser EJ: Sebaceous adenitis. In Kirk RW, Bonagura JD, editors: Current veterinary therapy XI, Philadelphia, 1992, WB Saunders, p 534.

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Rosser EJ et al: Sebaceous adenitis with hyperkeratosis in the standard poodle: a discussion of 10 cases, J Am Anim Hosp Assoc 23:341, 1987. Rosser EJ: Sebaceous adenitis: current thoughts? Workshop on Sebaceous Adenitis, North American Veterinary Dermatology Forum, Portland, Oregon, 2010. Scott DW: Granulomatous sebaceous adenitis in dogs, J Am Anim Hosp Assoc 22:631, 1986. Sousa CA: Sebaceous adenitis, Vet Clin North Am Small Anim Pract 36:243, 2006. Spaterna A et al: Sebaceous in the dog: three cases, Vet Res Comm 27(suppl 1):441, 2003. Stenn KS et al: Hair follicle biology, the sebaceous gland, and scarring alopecias, Arch Dermatol 135:973, 1999. Stewart LJ, White SD, Carpenter JL: Isotretinoin in the treatment of sebaceous adenitis in two vizslas, J Am Anim Hosp Assoc 27:65, 1991. Tevell EH, Bergvall K, Egenvall A: Sebaceous adenitis in Swedish dogs: a retrospective study of 104 cases, Acta Vet Scand 50:11, 2008. White SD et al: Sebaceous adenitis in dogs and results of treatment with isotretinoin and etretinate: 30 cases (1990-1994), J Am Vet Med Assoc 207:197, 1995.

44 

Malassezia Infections DANIEL O. MORRIS, Philadelphia, Pennsylvania

M

alassezia dermatitis (MD) and Malassezia otitis (MO) are superficial fungal (yeast) infections occurring on and within the stratum corneum of the epidermis of many mammalian species. Canine Malassezia hypersensitivity (MH) is a type I (immediate) hypersensitivity reaction to soluble allergens produced by the yeast; these allergens are recognized by the host’s immune system in a manner similar to aeroallergens and contribute to the pathogenesis of atopic dermatitis (AD). In dogs and cats Malassezia pachydermatis colonizes the skin during the immediate perinatal period and is the primary yeast species associated with skin and ear canal disease.

Pathogenesis Malassezia yeast colonizes the skin and external ear canals of animals in very low numbers. Overt “infection,” sometimes referred to as “overgrowth,” is defined by increased numbers of the yeast on the skin surface in conjunction with inflammation. In a diseased state alterations in the

microclimate of the surface of the skin contribute to increased susceptibility to yeast infection. Primary diseases that cause increased moisture, altered surface lipids, or disruption of stratum corneum barrier function encourage secondary overgrowth of the organism. Pruritic inflammatory diseases (allergic and parasitic) result in microclimate changes caused by scratching (disruption of barrier function), licking (added moisture), and increased production of sebum. Endocrinopathies, especially hyperadrenocorticism, directly cause alterations in sebum characteristics and stratum corneum function. Metabolic diseases that result in hyperkeratosis (such as zinc-responsive dermatosis, hepatocutaneous syndrome/ superficial necrolytic dermatitis of dogs, and thymomaassociated dermatosis of cats) also appear to be risk factors. Secondary MD also is associated with primary (idiopathic) seborrhea of dogs and cats and paraneoplastic alopecia caused by internal carcinomas in cats. In some dogs with AD, antigens produced by M. pachydermatis may be recognized by the immune system as allergens (i.e., MH), in which case a highly inflammatory

WEB CHAPTER  44  and pruritic response can be mounted to relatively low numbers of yeast organisms, so that the line between cytologic definitions of colonization and infection is blurred. However, many dogs with MH also have overt infection, as defined cytologically by overgrowth of yeast on the skin surface (see the section on cytologic analysis later in the chapter for guidelines). MH has not yet been studied or defined in cats with allergic skin disease, although MD does appear to contribute to the pruritic threshold of some cats with AD.

Zoonosis M. pachydermatis has been documented to cause lifethreatening fungemia in people, especially in patients in critical condition receiving parenteral lipid infusions, such as neonates in the intensive care unit (ICU). In one case, the source of infection was shown to be a pet dog owned by a nurse who worked in the ICU (Chang et al, 1998). This observation suggested that M. pachydermatis could represent an emerging infectious zoonotic pathogen. An epidemiologic survey conducted by the author’s clinical research group has shown that M. pachydermatis can be isolated very commonly from the hands of dog owners, regardless of whether their dogs have MD or healthy skin (Morris et al, 2005). However, the public health significance appears to be extremely low, considering the commonness of mechanical carriage by dog owners coupled with the paucity of fungemia cases reported in the human literature.

Clinical Signs Several excellent reviews describing the clinical presentations of MD and MO in dogs and cats are available (Matousek and Campbell, 2002; Morris, 1999; Muse, 2000). Some key points are included here. Although MD usually is intensely pruritic, the only primary lesion produced is erythema. Secondary lesions, including alopecia, excoriations, seborrheic plaques, lichenification, maceration, and hyperpigmentation, are common and cannot be distinguished reliably from staphylococcal pyoderma without cytologic examination. Therefore one should look for the yeast on the surface of any pruritic skin lesion. The clinical appearance of the skin in cases of MD is highly variable. It may be either dry and flaky (seborrhea sicca) or tacky or greasy (seborrhea oleosa). In rare cases M. pachydermatis can cause a folliculitis that mimics staphylococcal folliculitis, dermatophytosis, and demodicosis. The distribution pattern of canine MD is variable, but MD most commonly affects some combination of the face (especially periocular and perioral skin), feet (interdigital spaces and claw folds), intertriginous areas (axillae, groin-inguinal area, facial folds, vulvar and mammary folds), and perineum. Generalized cases of MD may occur in chronic cases of allergic dermatitis. Similar distributions occur in cats. Malassezia overgrowth can provoke an overwhelming pruritic response in atopic dogs that can occur acutely and be misconstrued as increased exposure to aeroallergens. Resolution of the yeast infection

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can reduce the pruritic threshold of an atopic dog by as much as 75% to 100% in some cases, depending on concurrent exposure to other allergens. Therefore undiagnosed MD is one of the most common reasons for perceived failure in the management of atopic dogs. Malassezia pododermatitis may occur with or without more widespread MD. The feet are the most common single body area affected in allergic dogs. Patients with interdigital Malassezia pododermatitis are brought to the veterinarian because of paw licking or chewing. Paronychia (inflammation of the claw beds) also may occur as the sole presenting sign of MD and often causes claw biting. Physical examination usually reveals a reddishbrown staining of the proximal claw or a waxy exudate in the claw fold, with inflammation of the surrounding soft tissue. In any dog with a known endocrine or metabolic disease, MD must be ruled out (by surface cytologic analysis) if pruritus, cutaneous inflammation, or even noninflammatory seborrhea is present. Malassezia yeast also play an important role in cases of ceruminous otitis externa, in which it is highly proinflammatory. Some cases appear to be primary and associated only with moisture trapping (especially in swimming dogs).

Diagnosis Diagnosis of MD and MO is made by microscopic examination of surface cytologic specimens. Diagnosis of MH in dogs is made by intradermal testing with a commercial M. pachydermatis extract.

Cytologic Analysis Because of its unipolar budding process, M. pachydermatis appears on cytologic examination as an oval, peanutshaped, or bowling pin–shaped organism (depending on the state of budding), with a size ranging from 2 to 2.5 µm × 4 to 5 µm (Gueho et al, 1996). Although this is the species most commonly isolated from normal and inflamed skin of dogs and cats, occasionally other species are identified. Malassezia globosa, which sometimes is associated with ceruminous otitis in cats (and less commonly in dogs), has a more spherical shape with tiny budding heads. Methods of collection include dry skin scraping, adhesive tape stripping, wiping with cottontipped swabs, and making direct-impression smears with glass slides. For dry skin, scrapings and adhesive tape stripping (or direct skin impression using adhesive-coated slides [e.g., Duro-Tak] work best. Stripping with clear adhesive tape (e.g., Scotch Tear-by-Hand Tape), which is my favorite method, works well in tight spaces and is very economical. The slide or adhesive tape should be applied to the area of interest two or three times in succession. Impression smears and tape-stripped samples allow quantification of yeast per microscopic field. With scrapings it may be necessary to mix the material with saline and heatfix the material until dry (to adhere the material to the slide). For greasy skin, direct-impression smears (without adhesive) often work better. In cases of paronychia

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(inflammation of the claw bed) a cotton-tipped swab, the broken end of its wooden handle, or a metal spatula can be used to scrape the claw fold; exudate is pressed or rolled firmly onto a glass slide. For examination of ear exudate in dogs with ceruminous or exudative otitis externa, rolling exudate in a thin layer on glass slides with a cotton-tipped swab is the preferred method. It often is useful to sample the skin of the concave pinna separately from the ear canal if pinnal dermatitis is present. Preparation of Samples for Microscopic Examination When material is applied to a glass slide, a modified Wright stain (e.g., Diff-Quik) is used. Many dermatologists heat-fix the slide before staining, but a study has shown it generally to be unnecessary (Griffin et al, 2007). When adhesive tape is used, it may be dipped in the final stain only (there is no need to use a fixative), rinsed, and dried with a warm air dryer. The tape is applied to a glass slide while it is still warm and sticky for best adhesion. Some clinicians prefer wet mounts: a drop of new methylene blue stain is placed on a glass slide, and the tape strip is laid on top. Cytologic specimens should be examined under oil immersion (1000×) or high-power dry (400×) for oval or budding yeast. I prefer oil immersion for more reliable identification of bacteria and yeast cells. Interpretation of Cytologic Results: How Many Is Too Many? For skin, 1 yeast organism per high-power (1000×) oil immersion field (hpoif) is a general guideline used by many dermatologists to indicate pathologic overgrowth. For ear canals a study semiquantitatively evaluated the expected (commensal) populations of Malassezia spp. yeast residing in normal and diseased canals. It showed that normal dogs routinely may exhibit up to 5 organisms per high-power dry (400×) field (roughly equivalent to 2 organisms per hpoif), whereas cats may harbor up to 12 organisms per high-power dry field (roughly 5 per hpoif) (Ginel et al, 2002). These numbers are guidelines only. Since dogs may mount a hypersensitivity response to M. pachydermatis, some individuals may experience a pathologic effect from what otherwise would be considered a normal population of yeast colonizing the skin or ear canals. For example, a study examining yeast numbers on healthy and atopic canine skin suggested that 1 yeast organism per 27 hpoif may be sufficient to correlate with hypersensitivity (Morris et al, 1998). Since a threshold this low is almost impossible to quantify and appreciate clinically during routine practice, I generally recommend antifungal therapy when more than 1 yeast per 5 hpoif is identified on samples from inflamed skin or more than 1 yeast per hpoif is identified on swabs from an inflamed ear canal.

Intradermal Testing for Malassezia Hypersensitivity A commercial M. pachydermatis extract is available for intradermal testing and subcutaneous immunotherapy. This allergenic extract is available in concentrations of

20,000 protein nitrogen units (PNU)/ml and 40,000 PNU/ ml. A study conducted in healthy dogs with normal skin and dogs with AD (both with and without overt MD based on cytologic evaluation) has demonstrated a threshold concentration of 1000 PNU/ml for use in intradermal testing (Farver et al, 2005). The threshold concentration of an allergen is that to which 90% of the nonallergic population is nonreactive (i.e., ceases to develop an irritant reaction). Ideally the threshold concentration also should correctly identify at least 90% of sensitized individuals, although this is difficult to assess because of lack of a validated gold standard. This extract is now included in the battery of allergens used for intradermal testing in my group practice for evaluation of dogs with a clinical diagnosis of AD. To date, a validated in vitro commercial assay for antiMalassezia immunoglobulin E has not been reported in the scientific literature. Owing to great discrepancies in the results reported by different laboratories, any commercial offering of an enzyme-linked immunosorbent assay for detection of anti-Malassezia antibodies in canine serum should be scrutinized carefully using rigorous scientific methods before it is recommended for routine clinical use.

Treatment The antifungal regimen chosen for treatment of MD or MO should be based on the distribution of the infection, the general health status of the patient, and expectations of the pet owner concerning the commitment of time and effort (relevant to topical therapy) and adverse effects (most relevant to systemic therapy). Diagnosing and eliminating (or controlling) underlying diseases are also paramount for long-term prevention of recurrence. Since M. pachydermatis is part of the normal cutaneous microflora, complete elimination of the organism is likely to be impossible.

Systemic Therapy Unless there is a specific contraindication to using an oral antifungal drug, I prefer to treat all cases of generalized and regional MD (e.g., pododermatitis) systemically. Otitis media also requires systemic therapy (presumably) to achieve therapeutic drug levels within the tympanic cavity. Oral ketoconazole, itraconazole, fluconazole, or terbinafine is most commonly recommended (Web Table 44-1). Griseofulvin is ineffective against Malassezia spp. Ketoconazole (Nizoral and generics) is an imidazole antifungal with proven efficacy for treatment of canine MD. This drug always should be administered with food for maximum absorption. It undergoes extensive metabolism by the liver, and its use is contraindicated in patients with hepatic disease. In aged or debilitated dogs, liver enzyme levels should be evaluated before use of ketoconazole. I do not routinely perform screening tests in young healthy dogs. With long-term or repeated use, monitoring of hepatic function is performed on a caseby-case basis as dictated by clinical signs (some dermatologists recommend monthly monitoring). The risk of

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WEB TABLE 44-1  Systemic Drugs for Treatment of Malassezia Dermatitis and Otitis Media Drug

Formulation

Dosage

Species

Ketoconazole

200-mg tablets

5-10 mg/kg daily × 21-28 days, or (low-dose regimen) 5 mg/kg daily × 10 days, then every other day × 10 Pulse-dose regimen for prophylaxis: 5-10 mg/kg on 2 consecutive days/wk

Dogs Dogs

Itraconazole

100-mg capsules or 10-mg/ml elixir

5 mg/kg daily × 21-28 days, or 5 mg/kg 2 days/wk × 3 wk

Dogs and cats

Fluconazole

50-, 100-, 150-, 200-mg tablets and oral powder for 10-mg/ml suspension

2.5-10 mg/kg daily × 21-28 days

Dogs and cats

Terbinafine

200-mg tablets

30 mg/kg daily × 21-28 days 30-40 mg/kg daily × 21-28 days

Dogs Cats

hepatotoxicity is greater in cats, and the use of ketoconazole in feline MD is not recommended. The most common adverse effect in dogs is gastrointestinal upset (anorexia, vomiting, diarrhea), which occurs in approximately 10% of dogs. Finally, ketoconazole is a known teratogen and should not be used in breeding animals. Itraconazole (Sporanox) and fluconazole (Diflucan and generics) are triazole antifungals that pose less risk of hepatotoxicity than ketoconazole. Both have teratogenic potential and should not be used in pregnant animals. Fluconazole has become a popular treatment option for canine MD now that generic formulations have reduced the cost of therapy to a level comparable to that of ketoconazole. A clinical trial in dogs has proven it to be noninferior to ketoconazole for the treatment of MD, and I have used it successfully for the treatment of feline MD. However, fluconazole is excreted by the kidneys and should not be used in patients with significant renal impairment. Dosage adjustments should be made in animals with renal insufficiency and a specialist should be consulted. The relatively high cost of itraconazole makes it an unpopular choice for the treatment of canine MD, although it continues to be the most common choice for treatment of superficial fungal infections in cats. Itraconazole always should be administered with food because the most common adverse effects are gastrointestinal. Caution should be exercised in both species when hepatic disease is present. Terbinafine (Lamisil and generics) is an allylamine antifungal with a high margin of safety for use in mammals. Results of a pilot study comparing the efficacy of terbinafine with that of ketoconazole suggest that it is effective for the treatment of canine MD. Because terbinafine is effective for the treatment of dermatophytosis in cats, efficacy for feline MD also should be expected. The cost of therapy has been reduced significantly by the recent availability of generic formulations. Lufenuron (Program) is a benzoylphenylurea drug that disrupts chitin synthesis in the cell wall of insects and perhaps of some fungi. There is no evidence at this time to suggest that this drug is effective in the treatment of MD.

Topical Therapy Topical antifungals are most useful for treatment of localized infections or as adjunctive therapy along with oral drugs. Topicals also are quite valuable for prophylaxis in chronic or relapsing MD. For regional or generalized disease, shampoos containing miconazole, ketoconazole, chlorhexidine, climbazole, or selenium sulfide are available and have achieved variable success, depending on client compliance, frequency and technique of application, and severity of disease. In animals with frequent relapse, shampoo therapy (once or twice weekly, 10 minutes’ minimum contact time) may be adequate for prophylaxis. A leave-on conditioner containing ketoconazole and chlorhexidine also is available and provides for more residual action than shampoos. Rinses such as lime sulfur dip and enilconazole can be quite effective; however, lime sulfur dip is not available in the United Kingdom, and enilconazole is available in Canada but not in the United States. Miconazole, clotrimazole, climbazole, or ketoconazole sprays, lotions, wipes, or creams may be used for spot treatment of the skin. Ointments and lotions containing nystatin, thiabendazole, miconazole, or clotrimazole commonly are used for otitis externa. Some products also contain glucocorticoids and antibacterials. An in vitro study comparing the efficacy of the azoles against Malassezia spp. yeast indicated that thiabendazole is the least effective, followed by clotrimazole (with efficacy comparable to that of nystatin), miconazole (with 10 times the potency of nystatin), ketoconazole, and itraconazole (Lorenzini et al, 1985). My clinical bias is that miconazole is the most effective topical therapy on a per-case basis, and poor clinical responses to nystatin, thiabendazole, and clotrimazole have been common in my practice population.

Immunotherapy for Malassezia Hypersensitivity The M. pachydermatis extract has been evaluated in a multicenter study to determine its usefulness as an immunotherapeutic extract. Atopic dogs that had been

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receiving allergen-specific immunotherapy for a minimum of 12 months but that continued to have chronic or recurrent MD and required antifungal prophylaxis were enrolled. A dose of 2000 PNU was administered weekly by subcutaneous injection, and cases were followed for 12 months. Although data were not published in a peerreviewed format, clinical evaluations suggested good to excellent efficacy in preventing chronic or recurrent MD, even after discontinuation of antifungal drugs. Anecdotal reports from practicing dermatologists support these preliminary conclusions. Therefore I currently recommend the use of M. pachydermatis immunotherapy for all atopic dogs with chronic or recurrent MD, either as monotherapy or in combination with other allergens in immunotherapy treatment sets, at a concentration of 2000 PNU/ml.

References and Suggested Reading Chang HJ et al: An epidemic of Malassezia pachydermatis in an intensive care nursery associated with colonization of health care workers’ pet dogs, N Engl J Med 338:706, 1998. Farver K et al: Humoral measurement of type-1 hypersensitivity reactions to a commercial Malassezia pachydermatis allergen, Vet Dermatol 16:261, 2005.

WEB CHAPTER 

Ginel PJ et al: A semiquantitative cytological evaluation of normal and pathological samples from the external ear canal of dogs and cats, Vet Dermatol 13:151, 2002. Griffin JS, Scott DW, Erb HN: Malassezia otitis externa in the dog: the effect of heat-fixing otic exudate for cytological analysis, J Vet Med Series A 54(8):424, 2007. Gueho E, Midgley G, Guillot J: The genus Malassezia with description of four new species, Antonie van Leeuwenhoek 69:337, 1996. Lorenzini R, Mercantini R, De Bernardis F: In vitro sensitivity of Malassezia spp. to various antimycotics, Drugs Exp Clin Res 11(6):393, 1985. Matousek JL, Campbell KL: Malassezia dermatitis, Compend Contin Educ Small Anim Pract 24:224, 2002. Morris DO: Malassezia dermatitis and otitis. Vet Clin North Am Small Anim Pract 29(6):1303, 1999. Morris DO: Malassezia dermatitis. In Birchard SJ, Sherding RG, editors: Saunders manual of small animal practice, ed 3, St Louis, 2006, Saunders, p 445. Morris DO et al: Malassezia pachydermatis carriage in dog owners, Emerg Infect Dis 11(1):83, 2005. Morris DO, Olivier NB, Rosser EJ: Type-1 hypersensitivity reactions to Malassezia pachydermatis extracts in atopic dogs, Am J Vet Res 59:836, 1998. Muse R: Malassezia dermatitis. In Bonagura JD, editor: Kirk’s current veterinary therapy XIII, Philadelphia, 2000, Saunders, p 574.

45 

Topical Immunomodulators JOEL D. GRIFFIES, Marietta, Georgia

I

mmunomodulators have been defined as drugs used for their effect on the immune system. This effect may be immunosuppressant as in the case of corticosteroids and calcineurin inhibitors or immunostimulatory as occurs with the use of vaccines or drugs such as imiquimod. When applied topically these drugs have a focused effect at the site of disease with, in many cases, significantly decreased or no systemic effects. Although a large body of research has developed on the use of these compounds in humans, the indications for topical immunomodulators in animals are just emerging. However, the mechanism of activity, minimal absorption, and increased potency of these drugs, as well as early clinical and anecdotal evidence, make them attractive and suggest that a number of applications likely will be adapted to veterinary medicine, making them useful tools for the practitioner.

Calcineurin Inhibitors Calcineurin inhibitors, including drugs such as cyclosporine, tacrolimus, and pimecrolimus, are an important class of immunomodulators that have been at the forefront of this genre in the last few years (see Chapter 59). Calcineurin is a key enzyme in the activation of T lymphocytes. It functions in the induction of gene transcription for a number of inflammatory mediators, including many interleukins (e.g., interleukin-2, interleukin-3, interleukin-4), granulocyte-macrophage colony-stimulating factor, tumor necrosis factor-α, and interferon-γ (IFN-γ). Calcineurin inhibitors function by binding to a carrier protein with a high affinity for calcineurin, preventing its activity (Web Figure 45-1). They also have been shown to inhibit the activation of mast cells, basophils, eosinophils, keratinocytes, and Langerhans cells. Both cyclosporine and tacrolimus decrease

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Calcineurin

Cyclophilin Cyclosporine Tacrolimus

FK binding protein

Cytoplasm

Pimecrolimus Macrophilin NFATc

P

NFATc

Nucleus

IL-2 IL-3 IL-4 IFN- TNF- GMCSF

Web Figure 45-1  Mechanism of action of calcineurin inhibitors. GMCSF, Granulocyte-

macrophage colony-stimulating factor; IFN, interferon; IL, interleukin; NFATc, nuclear factor of activated T cells; P, phosphorylation; TNF, tumor necrosis factor.

the number and activity of epidermal dendritic cells and down-regulate the expression of the high-affinity immunoglobulin E receptor (FcεRI) on Langerhans cells. Calcineurin inhibitors have been used in humans and animals for many years. Specifically, the use of oral cyclosporine for treatment of atopic dermatitis (AD) has received much interest recently in veterinary medicine, whereas topical calcineurin inhibitors have been a hot topic in human dermatology literature.

Cyclosporine Oral cyclosporine has been well studied for its role in managing AD and a number of other dermatologic diseases (see Chapter 92). It is a highly lipophilic cyclic polypeptide with a molecular weight of 1202 kD. Because of its molecular size and structural and biologic differences from the other calcineurin inhibitors, its use as a topical treatment for inflammatory skin disease has been unrewarding and limited to only anecdotal reports of success.

Tacrolimus Since the discovery of tacrolimus in 1984, intravenous and oral formulations of the drug have been used worldwide in the prevention of organ rejection following allogeneic transplantation in humans. Although similar to cyclosporine in its mechanism of activity, it is structurally

different. Tacrolimus is a hydrophobic macrolide lactone with an atomic weight of 822 kD (smaller than cyclosporine) and is well absorbed into the epidermis via topical administration. The potency of tacrolimus has been estimated to be 10 to 100 times greater than that of cyclosporine. It is currently approved in the United States for use in humans with moderate to severe AD. In numerous large multicenter studies it has been found to have significant benefit in the treatment of both pediatric and adult atopic patients. More recently, additional applications, including treatment of actinic (solar) dermatosis, psoriasis, chronic noninfectious otitis, and early stages of cutaneous T-cell lymphoma have been reported. In veterinary medicine, data on the use of topical tacrolimus are much more limited but show promising findings in a number of applications. Canine Atopic Dermatitis Marsella and Nicklin (2002) performed early studies on the topical use of tacrolimus for treatment of AD in dogs. In the initial pilot study, which used a 0.3% lotion formulated from the oral product, investigator scores for erythema were lower (indicating less erythema) in tacrolimus-treated dogs than in placebo-treated dogs, but owner scores for pruritus were not significantly different for the two groups. However, a subsequent randomized, double-blind, placebo-controlled crossover study using commercially available 0.1% tacrolimus ointment (Protopic) found more encouraging results (Marsella et al,

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2004). In this study, treatment with topical tacrolimus was evaluated in 12 dogs that were diagnosed with AD. After 4 weeks of once-daily application, investigator scores improved significantly in the tacrolimus-treated group, whereas no significant differences between pretreatment and posttreatment signs were detected in the placebo group. When the dogs were divided based on severity of disease, those with localized disease were found to show significantly greater improvement than those with generalized disease according to both owner and investigator assessments. In conclusion, this study found that tacrolimus ointment decreased clinical signs of AD over a 4-week period with minimal adverse effects or safety concerns. A third study investigated the efficacy of 0.1% tacrolimus ointment in the treatment of localized lesions of AD on the front paws of dogs (Bensignor and Olivry, 2005). All dogs had lesions at other sites, but these were not included in either treatment or evaluation. At the end of the 6-week study the primary investigator found that all dogs that completed the study showed a more than 50% decrease in lesional scores for the evaluated areas (based on grading of erythema, lichenification, oozing, and excoriations). This study did not evaluate pruritus. Although the results of these studies showed benefit from topical application of tacrolimus, especially for localized AD, I have noted only limited benefit in the treatment of this disease. My experience corresponds with the observation that localized lesions may improve, but progress generally is limited to decreases in erythema with less effect on pruritus. As a result, owners have not perceived a benefit substantial enough to warrant continued administration in most cases. Tacrolimus remains a potential option for treatment of localized AD, especially when the practitioner is trying to minimize the use of other treatments that raise greater concern for adverse effects (e.g., topical or systemic glucocorticoids), but at least in my practice it is not used as a sole therapy. A recent study evaluated the tolerability and safety of a 0.1% compounded tacrolimus solution (in olive oil) applied to the external ear canals of atopic dogs with normal otoscopic findings, including intact tympanic membranes (Kelley et al, 2010). In this prospective, double-blind, placebo-controlled trial a colony of high IgE–producing beagles validated as a model for AD were studied. This tacrolimus solution was well tolerated by these dogs, with no adverse topical reactions noted and no evidence of hearing loss. However, the olive oil vehicle may have predisposed to an increase in Malassezia overgrowth and mild otitis. These results, along with favorable outcomes reported with the use of an ear wick containing 0.1% tacrolimus ointment to treat chronic noninfectious otitis in human patients, suggests that further investigation of this therapy is warranted (Harth et al, 2007). Immune-Mediated Diseases An open-label study was performed by my practice evaluating 0.1% topical tacrolimus in the management of immune-mediated diseases such as discoid lupus erythematosus (DLE) and pemphigus erythematosus (PE). In this study 10 dogs with DLE and 2 dogs with PE were

treated with a commercially available 0.1% tacrolimus ointment (Griffies et al, 2004). All dogs had lesions localized to the nasal planum and adjacent regions of the muzzle. Owners applied 0.1% tacrolimus ointment to the affected areas every 12 hours. Each dog’s lesions were assessed for degree of erythema, crust, ulceration or erosion, depigmentation, and scarring and were evaluated 2, 4, and 8 weeks after the start of therapy. Ten of 12 dogs exhibited improvement in clinical lesions associated with PE or DLE (5 with excellent response, 5 with partial response) over the 8-week trial. Of the dogs that showed progress, 8 of 10 were treated with tacrolimus alone by the end of the study and remained in remission at 12 weeks. Two of these dogs followed for an additional 2 years continued to do well with topical tacrolimus alone. In my practice 0.1% tacrolimus has become a first-line drug for mild to moderate DLE. In mild cases it often is used alone every 12 hours for the first 2 weeks and then decreased to every 24 hours, depending on progress. Once clinical lesions have resolved, drug application can be tapered to every other day or twice weekly in many cases. In moderate to severe cases 0.1% tacrolimus ointment often is used as adjunctive therapy in combination with tetracycline and niacinamide, vitamin E, or oral corticosteroids. In these cases the use of topical tacrolimus may allow reduction of systemic therapies and can become part of the longer-term maintenance for this chronic disease. Similarly, I use topical tacrolimus as an adjunct in managing localized lesions of pemphigus foliaceus. Topical tacrolimus is not considered a successful primary or exclusive therapy for this disease; however, it may assist in managing localized lesions, such as those remaining on the nasal planum, without necessitating an increase in or modification of systemic medications such as corticosteroids or azathioprine, provided the majority of other lesions have resolved. Cutaneous Vasculitis Cutaneous vasculitis may have a variety of clinical manifestations, including purpura, wheals, edema, papules, plaques, nodules, alopecia, scarring, necrosis, and ulceration, often involving the extremities. One of the most common presentations seen by general practitioners and veterinary dermatologists is an ischemic dermatopathy often linked to vaccine administration. The lesions observed result from the loss of blood supply due to vasculitis or a vasculopathy. The prototypical form is that seen following rabies vaccination, usually 1 to 3 months after administration. A classic postvaccinal lesion may occur, characterized by an annular hypopigmented or hyperpigmented area of alopecia that also may be indurated, erythematous, or scaly. Multiple distal lesions may occur with or without the presence of an injection site reaction. These commonly include lesions at the apex and often the concave aspect of the pinnae, especially at the margins, but other areas such as the paw pads, tip of the tail, periocular region, and junction of the nasal planum and haired skin may also be involved. Topical tacrolimus has been especially useful in managing the mild to moderate pinnal lesions associated with this disease. Twice-daily application of the 0.1% ointment to

WEB CHAPTER  45  Topical Immunomodulators crusted, indurated, and erythematous lesions typically produces improvement in these lesions within 2 to 4 weeks. Because of the ischemic nature of the lesions, some scarring, alopecia, or hyperpigmentation may be expected to remain even after the lesions are no longer active. In more severe cases topical tacrolimus therapy often is combined with other systemic therapies. Similar benefit has been seen in decreasing edema and erythema associated with early lesions related to rabies vaccine injection site reactions. Alopecia again is expected to persist. Topical tacrolimus has been less effective in treating the more aggressive proliferative thrombovascular necrosis of the pinnae, and these cases typically need a more aggressive systemic therapeutic approach. Perianal Fistulas Perianal fistulas are chronic, painful, often progressive inflammatory lesions of the perianal, anal, and perirectal tissues (see Web Chapter 36). This condition has been reported most commonly in German shepherd dogs but also has been observed in Irish setters, Labrador retrievers, Old English sheepdogs, Border collies, bulldogs, and others. Lesions vary from superficial microscopic fistulas to large ulcerations and sinus tracts and often are complicated by secondary bacterial infection. Although a specific etiopathogenesis has not been recognized, most recent efforts suggest an immune-mediated component. Clinical signs may include tenesmus, dyschezia, constipation, excessive perianal licking, and increased frequency of defecation. Previous therapies have included a variety of surgical procedures, including excision, cryotherapy, chemical cauterization, and laser surgery. There is great variability in the reported rates of remission (48% to 97%), complications (13% to 100%), and recurrences (13% to 56%) with surgical treatment. More recently medical therapies for this disease have produced more encouraging results. Most notably, the use of cyclosporine with or without ketoconazole has shown substantial success in improving and resolving the lesions and clinical signs associated with perianal fistulas. As noted earlier, topical tacrolimus has a mechanism of action similar to that of systemic cyclosporine, which makes it a good choice for this disease. Misseghers and colleagues (2000) reported clinical observations on 10 dogs treated with a 0.1% topical tacrolimus ointment formulated from the oral product before the release of the commercial ointment. When treated with the tacrolimus ointment as sole therapy in this case series, 5 of 10 dogs experienced a complete response, and 4 of 10 showed a partial response. In my practice I have found the 0.1% commercially available tacrolimus ointment to be a useful agent for the treatment of perianal fistulas. However, because of the discomfort often associated with these lesions, the use of any topical medication as an initial therapy is less successful. A more practical protocol is to use oral cyclosporine alone (5 to 7 mg/kg daily) or oral cyclosporine (1 to 3 mg/kg daily) in combination with ketoconazole (5 to 10 mg/kg daily) initially. Once lesions are seen to improve, tacrolimus may be added once or twice daily. This allows reduction of the dose of cyclosporine, an expensive drug, while maintaining control of the disease. In my experience long-term maintenance has

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been possible using only tacrolimus applied daily to two or three times per week. Emerging Therapies Metatarsal Fistulation of German Shepherd Dogs.  Metatarsal fistulation is an uncommon condition reported in German shepherd dogs. It has been suggested to be a familial disorder of collagen caused by similar ancestry and antibodies against types I and II collagen found in the dogs studied. Affected dogs develop fistulous tracts proximal to the metatarsal pads that typically have a serous or serosanguineous discharge. Treatments described for the management of this condition include antibiotic therapy along with oral immunomodulators such as corticosteroids. Researchers reported in a workshop that 0.1% topical tacrolimus was useful in these cases in an open clinical trial. At the end of 6 weeks of therapy, treated lesions were in complete remission in four of seven cases, and in three cases lesions were palpable but not visible (Kwochka and Rosenkrantz, 2005). These cases were followed for an additional 2 years, during which improvement was maintained with intermittent topical tacrolimus therapy. My own experience has been similar to these findings, and I have had positive results in achieving and maintaining improvement in plantar fistulas with intermittent topical tacrolimus therapy, along with oral antibiotic therapy for secondary bacterial infections. Other Applications.  As a new topical tool for treatment of veterinary dermatologic conditions, tacrolimus has been used in a number of different types of cases. Anecdotal reports of success with topical tacrolimus include its use as an adjunct in the treatment of acral pruritic nodules in combination with systemic antibiotics. I have found it only mildly useful in this application. Other areas of application may include assistance in the management of actinic dermatosis and feline eosinophilic granuloma/plaque lesions.

Pimecrolimus Although pimecrolimus (Elidel) has a mechanism of action virtually identical to that of tacrolimus and cyclosporine, no reports of its efficacy in veterinary dermatology have been published. It is produced commercially as a topical hydrophilic cream. In the human medical literature side-by-side comparisons of pimecrolimus and tacrolimus found tacrolimus to be superior for the treatment of AD, although both drugs showed benefit. In my limited experience pimecrolimus has been less successful in the management of the diseases mentioned previously. Anecdotal reports suggest that the pimecrolimus molecule is not well absorbed when applied topically, which may explain these observations. Until more positive experience is obtained with this calcineurin inhibitor, I cannot recommend it.

Safety Concerns Regarding Topical Calcineurin Inhibitors In 2002 the Food and Drug Administration required a black box label to be applied to the packaging of topical

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calcineurin inhibitors, including tacrolimus and pimecrolimus. Unfortunately, based on a number of independent reviews, these concerns are largely unfounded. The potential risk of malignancies, especially lymphoma, with the use of systemic immunosuppressive drugs has been well studied. This risk has been noted with oral administration of cyclosporine, tacrolimus, azathioprine, and others. Studies supporting these concerns for topical immunomodulators have used quantities of these drugs that are overwhelmingly higher than those typically used in human medicine and than those suggested for animals in this chapter and in other publications. Although the validity of this concern can be determined only by continued surveillance, most expert opinions express only minor concern in this area. Of the handful of veterinary studies using topical tacrolimus for dermatoses, none has noted significant systemic or topical adverse effects. Absorption of tacrolimus has been confirmed in some studies by the detection of measurable blood levels in treated patients. However, these levels have remained far below previously established toxicity levels and have had no effect on routine complete blood counts and biochemical parameters. These findings suggests that the use of topical calcineurin inhibitors is unlikely to predispose veterinary patients or their owners to lymphoma. However, I still recommend that these products be applied with gloves and that owners wash their hands after handling them.

Imiquimod In contrast to the calcineurin inhibitors, imiquimod is an immune response modifier that functions by stimulating or enhancing local innate immune response. An imidazoquinoline amine, imiquimod (Aldara) demonstrates potent antiviral and antitumor activity in animal research models. It has been shown to be a ligand for Toll-like receptor 7 (TLR-7). Activation of TLR-7 results in cellmediated immunity facilitated by helper T lymphocytes and can result in tissue-specific apoptosis. Imiquimod is approved for the topical treatment of external genital and perianal warts in humans (commonly caused by human papillomavirus) as well as superficial basal cell carcinoma and actinic keratosis. Topically applied imiquimod can induce cells, including keratinocytes, to synthesize and release cytokines, including IFN-α, interleukin-6, and tumor necrosis factor-α among others. Although imiquimod is not antiviral itself, the induction of these cytokines, specifically IFN-α, inhibits viral replication and promotes stronger cell-mediated immune responses. A component of the innate immune system, IFN-α helps infected cells and their neighbors eliminate virus without a specific cell-mediated immune response. The cells respond as though they have been infected and begin making IFN-γ and other cytokines, which help to clear viral pathogens and the lesions caused by them. As a biologic response modifier and an agent fostering a cellmediated immune response, imiquimod also may help treat other dermatologic disorders, infections, and neoplasms. In this regard, imiquimod has been reported to aid in the treatment of a variety of human diseases, including squamous cell carcinoma in situ (Bowen’s disease),

basal cell carcinoma, molluscum contagiosum, actinic keratosis, and various forms of cutaneous lymphoma. In animal models imiquimod also stimulates innate immune response by increasing natural killer cell activity, activating macrophages to secrete cytokines and nitric oxide, and inducing proliferation and differentiation of B lymphocytes (Sauder, 2000). Reports of imiquimod use in veterinary patients are limited but again show promise. As in humans, imiquimod has been a useful tool in managing localized disease associated with viral infection.

Squamous Cell Carcinoma in Situ (Bowen’s Disease) Squamous cell carcinoma in situ (Bowen’s disease) is an uncommon disorder in cats linked to a papillomavirus. Lesions often are found on the head, neck, and forelimbs. Topical use of imiquimod has shown success in managing localized lesions. It has been my experience on occasion that sites distant to those treated may improve or resolve while other lesions are being treated. Because of concern about inflammation and irritation at the site of application, a protocol of intermittent application typically is used. This may include alternate-day or three-timesweekly application or application on 2 to 3 consecutive days followed by 2 to 4 days off. Limitations of this therapy include the high cost of imiquimod and the small surface area that can be treated with the small volume of medication per packet. I commonly reseal an open packet and use it repetitively to treat smaller lesions. However, even for larger lesions, the cost of repeated topical application may be less than that of traditional or carbon dioxide laser surgery.

Feline Herpesvirus Infection Feline herpesvirus type 1 (FHV-1) is a common cause of upper respiratory tract disease in domestic cats and an uncommon cause of cutaneous erosion and ulceration (see Chapter 152). The localized nature of cutaneous lesions when present makes FHV-1–related dermatologic disease an excellent candidate for topical imiquimod. As in other conditions, application of imiquimod often incites an initial inflammatory response that appears to worsen clinical lesions. However, following the initial inflammation, lesions may heal and be replaced by localized scarring. In at least one unpublished case polymerase chain reaction testing for FHV-1 yielded positive results for both the cutaneous lesion and the conjunctival sac (a known site of FHV-1 sequestration) before treatment and negative results after treatment with imiquimod. This suggested that not only did lesions resolve but the immune response stimulated may have been able to clear the virus entirely. Whether this was a true finding or a temporary change is difficult to ascertain and warrants further investigation.

Canine Cutaneous Papillomatosis Clinical syndromes associated with papillomavirus infection in the dog include oral papillomatosis, cutaneous

papillomas, cutaneous inverted papillomas, and papillomavirus-associated canine pigmented plaques. Of these, cutaneous inverted papillomas and cutaneous papillomas have been managed successfully with imiquimod. In most cases reported, topical imiquimod has been used following recurrence after surgical excision of solitary lesions. Unlike after the surgical procedures, when the recurrent lesions are cleared via topical imiquimod treatment, further relapse has not been observed.

Other Potential Uses Because of its innovative mechanism of action and the induction of an immune response by local cells, imiquimod is very likely to have a number of additional uses. Based on applications in human medicine, these may include management of actinic keratosis lesions in dogs and cats. Recent reports of success in the use of topical imiquimod to treat equine sarcoid also have been published (Nogueira et al, 2006).

References and Suggested Reading Beck LA: The efficacy and safety of tacrolimus ointment: a clinical review, J Am Acad Dermatol 53:S165, 2005. Bensignor E, Olivry T: Treatment of localized lesions of canine atopic dermatitis with tacrolimus ointment: a blinded randomized controlled trial, Vet Dermatol 16:52, 2005.

Griffies JD et al: Topical 0.1% tacrolimus for the treatment of discoid lupus erythematosus and pemphigus erythematosus in dogs, J Am Anim Hosp Assoc 40:29, 2004. Harth W et al: Topical tacrolimus treatment for chronic dermatitis of the ear, Eur J Dermatol 17(5):405, 2007. Kelley LS et al: Safety and tolerability of 0.1% tacrolimus solution applied to the external ear canals of atopic beagle dogs without otitis, Vet Dermatol 21:6, 2010. Kwochka KW, Rosenkrantz WS: Shampoos and topical therapy. In Hillier A, Foster A, Kwochka K, editors: Advances in veterinary dermatology, Oxford, UK, 2005, Blackwell Publishing, p 378. Marsella R et al: Investigation on the clinical efficacy and safety of 0.1% tacrolimus ointment (Protopic) in canine atopic dermatitis: a randomized, double-blinded, placebo-controlled, cross-over study, Vet Dermatol 15:294, 2004. Marsella R, Nicklin CF: Investigation on the use of 0.3% tacrolimus for atopic dermatitis, Vet Dermatol 13:203, 2002. Misseghers BS, Binnington AG, Mathews KA: Clinical observations of the treatment of canine perianal fistulas with topical tacrolimus in 10 dogs, Can Vet J 41:623, 2000. Nogueira SA et al: Efficacy of imiquimod 5% cream on the treatment of equine sarcoid: a pilot study, Vet Dermatol 17:259, 2006. Patel GK et al: Imiquimod 5% cream monotherapy for cutaneous squamous cell carcinoma in situ (Bowen’s disease): a randomized, double-blind, placebo-controlled trial, J Am Acad Dermatol 54:1025, 2006. Sauder DN: Immunomodulatory and pharmacologic properties of imiquimod, J Am Acad Dermatol 43:S6, 2000.

SECTION VI Gastrointestinal Diseases Chapter Chapter Chapter Chapter Chapter Chapter Chapter Chapter Chapter Chapter Chapter Chapter Chapter Chapter Chapter Chapter Chapter Chapter Chapter Chapter Chapter Chapter Chapter Chapter Chapter Chapter Chapter Chapter Chapter Chapter Chapter

120: 121: 122: 123: 124: 125: 126: 127: 128: 129: 130: 131: 132: 133: 134: 135: 136: 137: 138: 139: 140: 141: 142: 143: 144: 145: 146: 147: 148: 149: 150:

Feline Caudal Stomatitis Oropharyngeal Dysphagia Gastroesophageal Reflux Antacid Therapy Gastric Helicobacter spp. and Chronic Vomiting in Dogs Gastric and Intestinal Motility Disorders Current Veterinary Therapy: Antibiotic Responsive Enteropathy Cobalamin Deficiency in Cats Probiotic Therapy Protozoal Gastrointestinal Disease Canine Parvoviral Enteritis Inflammatory Bowel Disease Protein-Losing Enteropathies Feline Gastrointestinal Lymphoma Canine Colitis Laboratory Testing for the Exocrine Pancreas Exocrine Pancreatic Insufficiency in Dogs Treatment of Canine Pancreatitis Feline Exocrine Pancreatic Disorders Diagnostic Approach to Hepatobiliary Disease Drug-Associated Liver Disease Acute Liver Failure Chronic Hepatitis Therapy Copper Chelator Therapy Ascites and Hepatic Encephalopathy Therapy for Liver Disease Portosystemic Shunts Portal Vein Hypoplasia (Microvascular Dysplasia) Extrahepatic Biliary Tract Disease Idiopathic Vacuolar Hepatopathy Feline Hepatic Lipidosis Feline Cholangitis

492 495 501 505 508 513 518 522 525 528 533 536 540 545 550 554 558 561 565 569 575 580 583 588 591 594 599 602 606 608 614

The following web chapters can be found on the companion website at www.currentveterinarytherapy.com Web Web Web Web Web Web Web Web Web Web

Chapter Chapter Chapter Chapter Chapter Chapter Chapter Chapter Chapter Chapter

46: 47: 48: 49: 50: 51: 52: 53: 54: 55:

Canine Biliary Mucocele Canine Megaesophagus Copper-Associated Hepatitis Esophagitis Evaluation of Elevated Serum Alkaline Phosphatase in Dogs Flatulence Gastric Ulceration Hepatic Support Therapy Oropharyngeal Dysphagia Tylosin-Responsive Diarrhea

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Feline Caudal Stomatitis LINDA J. DEBOWES, Seattle, Washington

T

he most common cause of oral inflammation in cats is periodontal disease (gingivitis, periodontitis). Inflammation of the buccal mucosa (stomatitis) also may be associated with severe periodontal disease. Eosinophilic complex–related disorders, neoplasia, trauma, irritation caused by ingestion of noxious materials, immune-mediated diseases, and metabolic abnormalities also are potential causes of oral inflammation. Caudal  stomatitis is a problem seen in cats and should not be  confused with inflammation in other areas of the mouth. Infectious diseases have been associated with oral inflammation. Cats with altered immune function from infection with feline leukemia virus or feline immunodeficiency virus may have more severe periodontal disease or oral inflammation. Chronic calicivirus infection has been implicated as a factor in severe oral inflammation, especially in cats with inflammation in the area of the palatoglossal fold (caudal stomatitis). In one study, 81% of 25 cats with caudal stomatitis were shedding both feline calicivirus and feline herpesvirus 1 compared with 21% of a similar number of cats with periodontal disease (Lommer and Verstraete, 2003). The role of bacteria in caudal stomatitis is unknown. Pasteurella multocida subsp. multocida was identified more frequently in cats with caudal stomatitis than in normal cats in one study, which suggests that it may play a role in the disease (Dolieslager et al, 2011). Bartonella henselae infection has been suggested as a possible factor in the development of feline caudal stomatitis (Hardy et al, 2002). However, there is a high prevalence of B. henselae antibody positivity in healthy cats, which makes it difficult to determine the significance of an antibody-positive test result in a cat with caudal stomatitis. A recent study of 34 cats with chronic stomatitis and 34 age-matched healthy control cats reported no significant differences between the two groups in the prevalence of positivity for Bartonella spp. by polymerase chain reaction testing and antibody positivity for B. henselae. More recent studies evaluating potential causative agents have found that calicivirus and not Bartonella is associated with caudal stomatitis in cats (Belgard et al, 2010; Dowers et al, 2010). Cats with chronic caudal stomatitis have decreased salivary immunoglobulin A (IgA) levels compared with healthy cats; however, the significance of this in the development of disease is unknown (Harley et al, 2003). Cats with chronic caudal stomatitis also have higher serum IgG, IgM, and IgA concentrations than healthy cats. Oral inflammatory disease of unknown cause is a common problem in cats. The degree of inflammation is 492

variable and may be severe. These cats present a diagnostic and therapeutic challenge, and management frequently is frustrating for both the veterinarian and owner. Inflammation may involve the gingiva (gingivitis), buccal mucosa (stomatitis), or tissues of and adjacent to the palatoglossal fold (caudal stomatitis) or pharyngeal area (pharyngitis). Current knowledge about the cause of caudal stomatitis unrelated to periodontal disease in  cats is limited. The condition has been referred to as lymphocytic-plasmacytic stomatitis based on the major cellular infiltrate present on histologic examination. The histologic features are compatible with a chronic inflammatory or immunologic response but do not provide a definitive diagnosis as to the primary cause. Immunohistochemical studies have demonstrated a predominance of CD8+ cells over CD4+ cells, which could be consistent with a viral cause (Harley et al, 2011). Cats with severe caudal stomatitis often are grouped together as all having the same unknown problem; yet based on clinical presentation and variable response to treatment, it is more likely that multiple factors are involved.

Historical and Clinical Signs Cats with caudal stomatitis frequently have a history of dysphagia, inappetence, or anorexia and of pain when eating is attempted. The cat may appear interested in food but is unwilling to eat or may attempt to eat but drops the food from its mouth or paws at its muzzle. The affected cat usually is reluctant to eat hard food but may eat soft food. As the severity of the inflammation increases, the cat becomes pickier about what it will eat, or bloodtinged saliva may be noted after eating. In severe cases the cat may be in a great deal of pain, which causes a reluctance to swallow and drooling (pseudoptyalism). Weight loss may be a significant problem, depending on the severity and duration of inflammation. Affected cats may exhibit altered behavior such as reduced activity, demonstrate aggressive behavior toward other pets or persons, or show an aversion to having the face or head touched. These cats may have an unkempt appearance resulting from a reluctance to groom because of oral pain. Owners may notice that the cat no longer yawns.

Oral Examination Before the oral cavity is examined, the regional lymph nodes should be palpated and the mandible and maxilla examined for swelling or pain. It may not be possible  to complete the initial oral examination if the cat has 

CHAPTER  120  Feline Caudal Stomatitis severe oral pain. In severe cases the inflamed tissues may be ulcerated and bleed readily. Proliferation of oral tissues may make it difficult to visualize the teeth. Cats with severe caudal stomatitis may have extreme pain on opening the mouth; thus the initial examination should be performed with the mouth closed while the lips  are gently retracted. This examination is performed slowly to minimize pain. The mouth then is opened gently if possible. Lesions of the oral cavity may include inflammation of the gingiva (gingivitis), oral buccal mucosa (stomatitis), and tissues lateral to the palatoglossal fold (caudal stomatitis). Often a complete oral examination  is not possible without benefit of sedation or general anesthesia.

Diagnostic Evaluation A complete blood count, biochemical panel, and urinalysis are performed to identify concurrent or contributory diseases. The complete blood count usually is unremarkable. Hyperglobulinemia has been identified in some cats with chronic caudal stomatitis. Serologic evaluation for feline leukemia virus antigen and feline immunodeficiency virus antibody should be performed. It is ideal to include virus isolation studies on specimens obtained from oral swabs of inflamed tissues in cats with caudal stomatitis. Although bacterial cultures are not part of  a basic evaluation in most cases, bacterial culture and  sensitivity testing may be helpful in chronic cases that  do not respond to the antibiotics commonly used for  oral infections. A biopsy specimen should be obtained from any lesion that appears neoplastic or is of unknown cause and should be submitted for histopathologic examination. A complete oral and dental examination is performed with the cat under general anesthesia. The animal is evaluated for periodontal disease, tooth resorption, and other problems that may cause oral inflammation. Dental radiographs are obtained to evaluate for alveolar bone loss (indicating periodontitis), tooth resorption, and retained roots.

Management The goals of management are to control plaque bacteria and decrease the inflammatory and immunologic response. Control of plaque bacteria can be attempted by several methods, including scaling, topical antimicrobial application, systemic antimicrobial therapy, and tooth removal. Cats with caudal stomatitis are best treated with extraction of all premolars and molars. This includes the extraction of any retained roots. Extraction of the teeth removes the surfaces that are available for plaque retention and consequently decreases plaque and the associated inflammation. Extractions are successful in decreasing inflammation when the plaque is initiating the excessive inflammatory response. Retained roots may be a source of residual bacteria and, if found in association with oral inflammation, should be extracted as well. When an owner is not willing or able to proceed with extractions of premolars and molars, the cat should be

493

managed with plaque removal, plaque control, and medications to suppress the inflammatory response. The first step is a complete scaling and polishing along with extraction of teeth that show evidence of periodontitis or tooth resorption. Oral antibiotic administration for 4 to 6 weeks following the dental surgery is recommended. In severe cases, when the patient is not eating, it is necessary to decrease the inflammation quickly so the patient will resume eating. To manage the inflammation and maintain appetite initially, most cats require methylprednisolone administration every 4 to 6 weeks and over time possibly as frequently as every 3 weeks. Potential complications including diabetes mellitus are a concern with long-term glucocorticoid administration; therefore oral triamcinolone 1.5 mg administered every day for 3 to 5 days during acute flare-ups then decreased to every second or third day is recommended rather than injections of methylprednisolone. Alternatively, other antiinflammatory or immunosuppressive drugs can be considered. Once the inflammation has decreased and the cat is eating, toothbrushing or wiping the teeth with a gauze pad is instituted if the owners are able to adequately perform this and the cat is cooperative. Many owners are not able to brush the cat’s teeth sufficiently to decrease plaque accumulation and prevent inflammation. A topical rinse using a 0.12% chlorhexidine product is an adjunctive treatment in management of plaque accumulation. The author informs the owners on the initial visit that extractions of all premolars and molars provides the best long-term results. Medical management with antibiotics and glucocorticoids generally loses effectiveness over time, and severe clinical signs return, requiring more aggressive medical management or extractions. For these reasons, the author believes that extraction of all premolars and molars provides the best long-term management for the majority of affected cats.

Extractions Extractions are indicated when there is severe periodontitis or when teeth have type 1 tooth resorption. In addition to extractions for treatment of related periodontal disease and tooth resorption, removal of healthy teeth is an option for cats with caudal stomatitis. Plaque bacteria attach to the tooth surfaces (crowns and roots), eliciting an inflammatory response. Oral hygiene directed at plaque control is difficult in cats with severe inflammation and oral pain. Extraction of the premolars and molars removes the surfaces to which plaque attaches and therefore decreases the plaque in the cat’s mouth. Dental radiographs are needed to confirm removal of all premolar and molar roots in these cats. When inflammation is present adjacent to the incisors, they also should be extracted. It is rarely necessary to extract the canine teeth unless they have severe periodontitis or resorptive lesions. The response to extractions is variable, ranging from complete resolution of the inflammation to no improvement, and clients should be so advised. Cats tolerate extractions, even full-mouth extractions, very well and can eat dry and moist cat food without teeth. After extractions some cats may show significant improvement, and medical management may

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SECTION  VI  Gastrointestinal Diseases

not be required to keep the cat free of clinical signs.  Other cats may exhibit a partial response, requiring less aggressive medical management than that required  before extractions. Another group of cats appears to have minimal response to extractions, and medical management is continued as before the extractions. In the author’s practice cats that responded poorly to full-mouth extractions often were those in which calicivirus was  isolated from the oral cavity or cats that had received long-term (months to years) medical management. In a report of 30 cats with gingivitis, stomatitis, and caudal stomatitis, the response to periodontal treatment and extraction of selected teeth, including retained root tips, generally was favorable (Hennet, 1994). Oral inflammation resolved completely in 60% (18 of 30 cats), with an additional 20% (6 of 30 cats) responding with minimal residual inflammation and no oral pain. None of these 24 cats required medical therapy to manage oral inflammation after the treatment. Initial improvement requiring continued medical therapy to control clinical signs was seen in 13% (4 of 30 cats), and no improvement occurred in 7% (2 of 30 cats). When long-term medical management becomes ineffective, or when the adverse effects of drug therapy are unacceptable, extractions of the premolars and molars offer the next option. The maximal clinical improvement may not be reached for several weeks in cats with severe and chronic inflammation. Some of these cats may benefit from enteral feeding to maintain an adequate caloric intake and balanced nutrition. Appropriate pain management also should be provided. Buprenorphine HCL at 0.01 to 0.03 mg/kg administered in the cheek (buccal mucosal absorption) q6-12h for 3 days usually is adequate for postoperative pain control. Buprenorphine also may be beneficial for pain control in cats with owners who have chosen medical management.

Scaling and Polishing The teeth should be scaled to remove plaque bacteria and calculus. Plaque bacteria may be a factor in the excessive inflammatory response present in these cats. The teeth should be polished after any scaling to smooth the tooth surface. Plaque attaches and becomes established on the tooth surfaces within several hours after the scaling and polishing procedures; therefore continued control measures should be undertaken. Cats with severe oral inflammation are usually in too much pain for toothbrushing to be practical; thus plaque control must be maintained initially with topical or systemic antimicrobial therapy. Once the oral inflammation is well controlled, the owner may attempt plaque control with toothbrushing. A finger toothbrush or small toothbrush designed for cats is used with an acceptably flavored veterinary dentifrice.

Antimicrobial Therapy Antimicrobial therapy is best accomplished with systemic antibiotic administration. A variable response is observed with antibiotic therapy, although treatment for 4 to 6 weeks may result in improvement of clinical signs in

some cats. Antibiotics as a single treatment rarely are effective in the initial management of inflammation, and combined treatment with both antibiotics and glucocorticoids usually is required. Amoxicillin/clavulanic acid (Clavamox), clindamycin (Antirobe), and metronidazole are useful antibiotics in managing inflammation in these cats. Repeated treatment with antibiotics may be necessary. Complete resolution of clinical signs is unlikely, and relapses are common. Topical chlorhexidine may be used for adjunctive antimicrobial therapy.

Antiinflammatory and Immunosuppressive Therapy Immunosuppressive doses of glucocorticoids are required in most cats to decrease the inflammation and reduce pain sufficiently so that the cat will eat. Methylprednisolone acetate (Depo-Medrol) at 15 to 20 mg total dosage intramuscularly or subcutaneously, or triamcinolone 1.5 mg once daily for 3 to 5 days generally is adequate, and cats usually demonstrate a decrease in oral inflammation and a willingness to eat within 1 to 2 days. Triamcinolone 1.5 mg every second or third day generally is adequate following the initial daily dose. Satisfactory results are less common with oral prednisone administration in cats with severe inflammation. For cats demonstrating moderate improvement after extractions and requiring further control of residual inflammation, triamcinolone 1.5 mg every third day may be sufficient; however, higher dosages may be required, and the ultimate dosage is determined by the response. Clients should be cautioned about potential adverse effects of corticosteroid use in cats, including diabetes mellitus and precipitation of congestive heart failure in cats with cardiomyopathy. Recombinant feline interferon-ω administered orally for 90 days has been shown to improve clinical lesions and decrease pain in cats that have undergone extractions and have refractory chronic caudal stomatitis (Hennet et al, 2011). Oral administration of cyclosporine to cats with a poor response to extractions also has been show to improve oral inflammation significantly when trough whole blood levels are greater than 300 ng/dl (Lommer, 2013). The initial recommended dose of cyclosporine is 2.5 mg/kg twice daily PO; however, there is significant variability in absorption so the trough whole blood levels must be measured so the dose can be adjusted to maintain the level above 300 ng/dl.

Miscellaneous Treatments A trial treatment of coenzyme Q10 (CoQ10) supplementation at 30 to 100 mg daily for 4 months is recommended in cats with residual inflammation following extractions or as a supplement to medical management. There is anecdotal evidence of improvement in cats with caudal stomatitis and humans with chronic periodontitis after 3 to 4 months of supplementation with CoQ10. Prospective studies are needed to prove efficacy.

References and Suggested Reading Belgard S, Truyen U, Thibault JC: Relevance of feline calicivirus, feline immunodeficiency virus, feline leukemia virus, feline

CHAPTER  121  Oropharyngeal Dysphagia herpesvirus and Bartonella henselae in cats with chronic gingivostomatitis, Berl Munch Tierarztl Wochenschr 123:369, 2010. Dolieslager SM et al: Identification of bacteria associated with feline chronic gingivostomatitis using culture-dependent and culture-independent methods, Vet Microbiol 148(1):93, 2011. Dowers KL et al: Association of Bartonella species, feline calicivirus, and feline herpesvirus 1 infection with gingivostomatitis in cats, J Feline Med Surg 12:314, 2010. Hardy WD, Zuckerman E, Corbishley J: Serological evidence that Bartonella causes gingivitis and stomatitis in cats. In Proceedings of the 16th Annual Veterinary Dental Forum, Savannah, Ga, October 3-6, 2002, p 79. Harley R, Gruffydd-Jones TJ, Day MJ: Salivary and serum immunoglobulin levels in cats with chronic gingivostomatitis, Vet Rec 152:125, 2003.

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Harley R, Gruffydd-Jones TJ, Day MJ: Immunohistochemical characterization of oral mucosal lesions in cats with chronic gingivostomatitis, J Comp Pathol 144(4):239, 2011. Hennet P: Results of periodontal and extraction treatment in cats with gingivo-stomatitis. In Proceedings of the World Veterinary Dental Congress, Philadelphia, 1994, p 49. Hennet PR et al: Comparative efficacy of a recombinant feline interferon omega in refractory cases of calicivirus-positive cats with caudal stomatitis: a randomised, multi-centre, controlled, double-blind study in 39 cats, J Feline Med Surg 13:577, 2011. Lommer MJ: Efficacy of cyclosporine for chronic, refractory stomatitis in cats: a randomized, placebo-controlled, doubleblinded clinical study, J Vet Dent 30:8, 2013. Lommer MJ, Verstraete FJ: Concurrent oral shedding of feline calicivirus and feline herpesvirus 1 in cats with chronic gingivostomatitis, Oral Microbiol Immunol 18:131, 2003.

121 

Oropharyngeal Dysphagia STANLEY L. MARKS, Davis, California

O

ropharyngeal dysphagia (OPD) occurs when the elaborate mechanism of bolus transit from the oral cavity into the esophagus becomes com­ promised. The swallowing mechanism is complex and involves the action of 31 paired striated muscles and five cranial nerves (sensory and motor fibers of the trigeminal, facial, glossopharyngeal, and vagus nerve, and motor fibers of the hypoglossal nerve), their nuclei in the brain­ stem, and the swallowing center in the reticular forma­ tion of the brainstem. The normal swallowing reflex is a four-stage process, characterized by the oral preparatory phase, oral phase, pharyngeal phase, and esophageal phase. Esophageal and gastroesophageal dysphagias are described elsewhere (see Web Chapter 54). Dysphagia is relatively common in dogs, and the list of possible causes is extensive (Box 121-1). Dysphagia  is far less common in cats, and most of the causes of  OPD in this species are structural (oral tumors, ulcers, stomatitis).

Phases of Swallowing The oral preparatory phase is voluntary and begins as food or liquid enters the mouth. Mastication and lubrication of food are the hallmarks of this phase, as the bolus is modified and prepared for swallowing. Abnormalities of the oral preparatory phase usually are associated with dental disease, xerostomia, weakness of the lips (cranial

nerves V and VII), tongue (cranial nerve XII), and cheeks (cranial nerves V and VII). The oral phase of swallowing consists of the muscular events responsible for movement of the bolus from the tongue to the pharynx and is facili­ tated by the tongue, jaw, and hyoid muscle movements. The pharyngeal phase begins as the bolus reaches the tonsils and is characterized by elevation of the soft palate to prevent the bolus from entering the nasopharynx, elevation and forward movement of the larynx and hyoid, retroflexion of the epiglottis and closure of the vocal folds to close the entrance into the larynx, synchro­ nized contraction of the middle and inferior constrictor muscles of the pharynx, and relaxation of the cricopha­ ryngeus muscle that makes up much of the proximal esophageal sphincter (PES) to allow passage of the bolus into the esophagus (Figure 121-1). Respiration is briefly halted (apneic moment) during the pharyngeal phase. Abnormalities of the pharyngeal phase of swallowing are associated with pharyngeal weakness secondary to neu­ ropathies or myopathies, pharyngeal tumors or foreign bodies, and obstruction of the PES secondary to hypertro­ phy of the cricopharyngeus muscle. Synchrony between constriction of the pharyngeal muscles and relaxation of the cricopharyngeus muscle is essential to allow passage of the bolus into the esophagus. The esophageal phase is involuntary and begins with the relaxation of the PES and movement of the bolus into the esophagus. Despite the myriad causes of OPD, the pathophysiologic end results

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SECTION  VI  Gastrointestinal Diseases

BOX 121-1  Causes of Oropharyngeal Dysphagia in Dogs 1

Central Nervous System Cerebrovascular accident Brainstem tumor Iatrogenic Antihistamines Anticholinergics Phenothiazines Chemotherapy Postsurgical muscular or neurogenic damage Radiation exposure Ingestion of a corrosive substance Infectious Botulism Tetanus Candidiasis Rabies Abscess Calicivirus infection (cats) Rhinotracheitis virus infection (cats) Metabolic Cushing’s disease Thyrotoxicosis-associated myopathy (humans) Myopathic/Neuropathic Peripheral neuropathies Inflammatory myopathies Polymyositis Dermatomyositis Muscular dystrophies Myasthenia gravis Structural Oropharyngeal tumor Cricopharyngeal bar Proximal esophageal webs Foreign body Congenital anomaly (cleft palate, diverticula) Fracture of the mandible Tooth fracture Glossal ulcer or inflammation Glossal hypertrophy (muscular dystrophy)

fall into one of two interrelated categories: (1) abnormali­ ties of bolus transfer and (2) abnormalities of airway pro­ tection. Abnormalities of bolus transfer can be further grouped into those caused by (a) oropharyngeal pump failure (pharyngeal weakness), (b) oropharyngeal and pharyngo-PES discoordination (neuropathies), and (c) pharyngeal outflow obstruction (cricopharyngeal achala­ sia, tumors of the pharynx, foreign bodies).

Diagnostic Approach The diagnosis of disorders affecting the oropharyngeal phase of swallowing can be extremely challenging in dogs; however, a history of repetitive swallowing, gagging,

2

6 4 7

3

5

Figure 121-1  Normal lateral fluoroscopic view of the pharynx

at rest. Note that the radiodensity is reversed on fluoroscopic images compared with conventional radiographic images (i.e., air is white, bone is black). 1, Nasopharynx. 2, Soft palate. 3, Base of tongue. 4, Epiglottis. 5, Trachea. 6, Proximal esophageal sphincter. 7, Proximal esophagus with barium in the lumen. (From Pollard RE et al: Quantitative videofluoroscopic evaluation of pharyngeal function in the dog, Vet Radiol Ultrasound 41[5]:409, 2000.)

BOX 121-2  Clinical Signs of Oropharyngeal Dysphagia Difficulty swallowing water or solids Nasal regurgitation Frequent repetitive swallowing Falling of food from the mouth Dysphonia Coughing Gagging Retching Syncope

and retching associated with meals, nasal regurgitation with meals, swallow-related coughing, falling of food from the mouth during swallowing, and recurrent pneu­ monia should cause the clinician to suspect OPD (Box 121-2). Dysphagia may be the sole presenting sign in  an animal or may be associated with myriad clinical  abnormalities. It should be emphasized that OPD may  be part of a systemic disease in dogs manifesting signs  of dysphagia only, which underscores the importance of a comprehensive systemic evaluation in affected animals. The assessment of dogs with signs of OPD encompasses multiple dimensions that include (1) review of the signal­ ment, (2) review of medication history and inquiry regard­ ing recent anesthesia (Box 121-3), (3) physical examination (prefeeding assessment), (4) neurologic examination, (5) clinical feeding and swallowing evaluation, and (6) labo­ ratory and other testing to provide a basic data set for neurologic evaluation, including imaging studies and endoscopic evaluation of swallowing.

CHAPTER  121  Oropharyngeal Dysphagia

BOX 121-3  History-Based Evaluation of the   Dysphagic Animal Age of onset? Sudden onset or gradual onset? Dysphagia while eating or between meals? Difficulty with solids or liquids or both? Intermittent or progressive dysphagia? Temporal pattern of dysphagia (OPD occurs within seconds following swallowing)? History of coughing? History of medication administration? Dysphonia? Recent general anesthesia? Odynophagia?

Signalment Age and breed associations with OPD have been well documented in dogs. Causes of OPD in puppies include cleft palate, cricopharyngeal achalasia, glossal hypertro­ phy secondary to muscular dystrophy, and pharyngeal weakness. Breeds that have a hereditary predisposition or a high incidence of OPD include the golden retriever (pharyngeal weakness), cocker and springer spaniels  (cricopharyngeal dysphagia), Bouvier des Flandres and cavalier King Charles spaniel (muscular dystrophy), and boxer (inflammatory myopathy). In addition, large-breed dogs are predisposed to masticatory muscle disorders.

Physical and Neurologic Examination Physical examination of the animal must include careful examination of the oropharynx using sedation or anes­ thesia if necessary to help rule out morphologic abnor­ malities such as dental disease, foreign bodies, cleft palate, glossal abnormalities, and oropharyngeal tumors. The pharynx and neck should be palpated carefully for masses, asymmetry, or pain. The chest should be auscultated care­ fully for evidence of aspiration pneumonia. Evaluation of cranial nerves should be performed, including assessment of tongue and jaw tone, and abduction of the arytenoid cartilages with inspiration. A complete physical and neu­ rologic examination may identify clinical signs support­ ing a generalized neuromuscular disorder, including muscle atrophy, stiffness, or decreased or absent spinal reflexes. The gag reflex should be evaluated by placing a finger in the pharynx; however, the presence or absence of a gag reflex does not correlate with the efficacy of the pharyngeal swallow nor the adequacy of deglutitive airway protection.

Observation of Eating and Drinking The importance of the clinician’s carefully observing the dysphagic animal while it is eating (kibble and canned food) and drinking in the hospital cannot be overempha­ sized, and such observation helps to localize the problem to the oral cavity, pharynx, or esophagus. Dogs with an

497

abnormal oral phase of swallowing typically have diffi­ culty with prehension or aboral transport of a bolus to the tongue base, and these disorders often can be diag­ nosed by watching the animal eat. OPDs affecting the pharyngeal phase of swallowing can be more challenging to diagnose and often present with nonspecific signs such as gagging, retching, and the necessity for multiple swal­ lowing attempts before a bolus is moved successfully into the proximal esophagus. These patients have abnormal transport of bolus from the oropharynx to the hypophar­ ynx or from the hypopharynx to the proximal esophagus. Cricopharyngeal dysphagia is associated with the abnor­ mal transport of a bolus through the PES, and signs are similar to those seen with pharyngeal disorders.

Laboratory Testing to Provide a Minimum Neuromuscular Data Set Comprehensive laboratory testing is warranted in animals with OPD to provide a minimum neuromuscular data set and should consist of a complete blood count, serum chemistry panel including creatine kinase (CK) and elec­ trolyte concentrations, urinalysis, evaluation of thyroid function, and acetylcholine receptor (AChR) antibody titer for acquired myasthenia gravis. A persistently ele­ vated CK level could be an indication of an inflammatory myopathy, whereas markedly elevated CK concentrations may suggest a necrotizing or dystrophic myopathy. A normal CK level does not rule out a myopathy, particu­ larly when the myopathy is focal (masticatory muscle myositis) or in the chronic stage of disease. Acquired myasthenia gravis is an important neuromuscular cause of OPD and can be associated with focal signs including pharyngeal, esophageal, and laryngeal weakness without clinically detectable limb muscle weakness. Pharyngeal weakness as the only clinical sign of myasthenia gravis has been described in 1% of myasthenic dogs.

Cervical and Thoracic Radiography The pharynx of healthy animals is evident on radiographs because it is air filled. The size of the air-filled space can be decreased by local inflammation or neoplasia, laryn­ geal edema, or elongation of the soft palate. Pharyngeal size also can appear increased with dysfunction of the pharynx or upper esophageal sphincter, chronic respira­ tory (inspiratory) disease, and chronic severe megaesoph­ agus. The normal esophagus is not visible on survey radiographs. An exception occurs following aerophagia due to excitement, nausea, dyspnea, or anesthesia.

Videofluoroscopic Swallow Study Contrast videofluoroscopy involves real-time capture of images of the animal as it is swallowing liquid barium or barium-soaked kibble and is one of the most important procedures for assessing the functional integrity of the swallow reflex (Figure 121-2). Videofluoroscopy is used to determine the normal sequence of events that make up a swallow and to measure the timing of these events in relation to one another. Additionally, the movement of certain anatomic structures is measured in relation to a

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SECTION  VI  Gastrointestinal Diseases

A

* B

The timing of the swallow can be determined easily when the swallow video is viewed frame by frame, with each frame representing 1 30 th of a second in the National Television System Committee (NTSC) system, the analog television system used in the United States. The frame in which the epiglottis is observed to close over the larynx is considered as the starting point for all time measure­ ments, and frames are counted until the observation of maximal contraction of the pharynx, opening of the PES, and closing of the PES. The swallow is considered com­ pleted when the epiglottis is observed to reopen, which usually takes five or six frames in healthy dogs. More recently, a contrast videofluoroscopy method for quantifying pharyngeal contractility in the dog has been described (Pollard et al, 2007). The pharyngeal constric­ tion ratio is calculated by dividing the pharyngeal area at maximum contraction by the pharyngeal area at rest. As pharyngeal contractility diminishes, the ratio approaches 1.0. This simple procedure provides important informa­ tion regarding the strength of pharyngeal contraction in dysphagic dogs and facilitates the improved selection of dogs diagnosed with cricopharyngeal dysphagia for surgi­ cal intervention.

Laryngoscopy and Pharyngoscopy C Figure 121-2  Fluoroscopic swallow study in a 7-month-old

spayed female miniature dachshund with severe dysphagia  secondary to cricopharyngeal achalasia. A, Pharynx (arrow) filled with liquid barium. B, Hypertrophied cricopharyngeus muscle (cricopharyngeal bar) (asterisk) obstructing the movement of the bolus from the pharynx (arrow) into the proximal esophagus (arrowhead). Notice the attenuated column of barium being squeezed through the narrow opening of the proximal esophageal sphincter (PES). C, Retrograde movement of liquid barium into the oropharynx (arrow) caused by obstruction of the PES, and subsequent aspiration of barium into the trachea (arrowhead).

fixed point to assess function further. Swallowing events that occur out of sequence, at inappropriate times, or with reduced vigor can cause significant morbidity. One problem with videofluoroscopy is that animal positioning is not standardized in veterinary medicine. Alterations  in body position (sternal versus lateral recumbency) do  not appear to affect measurements of pharyngeal con­ striction ratio or the timing of swallowing in healthy dogs; however, cervical esophageal transit is significantly delayed when dogs are imaged in lateral recumbency. Swallow studies performed with the dog in sternal recum­ bency are significantly more likely to result in generation of a primary peristaltic wave for both liquid and kibble boluses. Thus it is important to recognize that the reten­ tion of liquid or kibble boluses in the cervical esophagus may not be considered abnormal when clinically ill dogs are imaged in lateral recumbency because this may be related to body position. The fluoroscopic swallow study typically involves assessment of five swallows each of 5 to 10 ml of liquid barium (60% weight per volume) fol­ lowed by five swallows of kibble soaked in barium.

Thorough laryngeal examination is important in all animals with OPD to rule out laryngeal paralysis associ­ ated with a polyneuropathy. Geriatric large-breed dogs can experience a progressive generalized neuropathy with associated pharyngeal weakness, OPD, and esophageal dysmotility. Pharyngoscopy and esophagoscopy provide anatomic information about the structures involved in the oropharynx and esophagus, but both procedures  are of limited diagnostic utility for evaluating functional disorders in anesthetized animals. Unsedated transnasal  videoendoscopy is an easily accomplished and useful pro­ cedure in people that often is performed as an outpatient procedure. The author has assessed the feasibility of fiber­ optic endoscopic evaluation of swallowing via transnasal intubation in fully awake dogs; however, the procedure is limited to larger dogs that can be restrained readily for the procedure.

Electrodiagnostic Testing Electrodiagnostic evaluation, including electromyogra­ phy and measurement of motor and sensory nerve con­ duction velocities, does not provide a specific diagnosis in most cases but can supply important information as to the severity, distribution, and character of a myopathic or neuropathic disease process and assist in selecting the optimal anatomic site for biopsy. Electrodiagnostic testing also should include evaluation of the pharyngeal muscles and tongue. The health status of the animal must be taken into consideration because the procedure is per­ formed under general anesthesia.

Muscle and Nerve Biopsies Muscle and nerve biopsies usually are integral to reaching a specific diagnosis. The biopsy procedure should be

CHAPTER  121  Oropharyngeal Dysphagia performed after the serum AChR antibody titer has been determined to be negative. If the onset of clinical signs is recent and the antibody test is negative, retesting in 4 to 6 weeks is suggested because a significant number of dogs with early clinical signs have antibody titers below the detection limits of the assay at initial testing but test posi­ tive 4 to 6 weeks later. Muscle biopsy specimens usually are obtained from a large proximal pelvic limb such as the vastus lateralis or a thoracic limb such as the triceps muscle; however, biopsy specimens from the pharynx and cricopharyngeus muscle also should be obtained in dogs with OPD. Muscle biopsy, when warranted, ideally should be performed relatively early in the disease process before irreversible muscle fibrosis and myofiber loss is extensive.

Magnetic Resonance and Computed Tomographic Imaging Magnetic resonance and computed tomographic imaging of the head and neck have been used to diagnose inflam­ matory myopathies, particularly masticatory muscle myositis in dogs, and the imaging can be used to help select sites for diagnostic muscle biopsy. Common find­ ings include changes in size (atrophy or swelling) of all masticatory muscles except the digastricus muscles and contrast enhancement with a predominantly inhomoge­ neous distribution pattern in the temporalis, masseter, and pterygoid muscles. Magnetic resonance imaging also can be used to detect neoplasia involving the cranial nerves.

Treatment The treatment of OPD depends on what the underlying cause is and whether the condition is structural or functional.

Functional Disorders Associated with Oropharyngeal Dysphagia Cricopharyngeal dysphagia is a swallowing disorder of the PES characterized by either cricopharyngeal dyssyn­ chrony (functional) or cricopharyngeal achalasia (struc­ tural). Cricopharyngeal dyssynchrony is essentially a pump problem in which the weak pharyngeal muscles are unable to propel the bolus through the PES (see Figure 121-2). Early evidence in the author’s laboratory points toward a neuropathy in these dogs. On videofluoroscopy, there is evidence of incoordination between the contrac­ tion of the dorsal cranial and middle pharyngeal contrac­ tor muscles (hyopharyngeus, pterygopharyngeus, and palatopharyngeus muscles) and opening of the PES (cri­ copharyngeus and thyropharyngeus muscles). A compre­ hensive workup should be completed in an effort to find a treatable cause of the suspected neuropathy (complete blood count and serum chemistry panel, AChR antibody titer, CK measurement, muscle and nerve biopsy). The prognosis for these dogs generally is extremely poor, and surgical intervention (cricopharyngeus myotomy or myectomy) is contraindicated because the procedure can exacerbate the dysphagia. An effort should be made to

499

identify the optimal consistency of food and water that these dogs will tolerate (by adding commercial food thick­ eners such as Thick-It), although these animals will ulti­ mately succumb to repeated bouts of aspiration pneumonia and malnutrition. Enteral feeding via a per­ cutaneous endoscopic gastrostomy tube is a viable alter­ native in these animals; however, silent aspiration and pneumonia can occur despite the use of enteral feeding devices. Pharyngeal weakness can be a primary disorder second­ ary to an underlying neuropathy (see earlier) or myopa­ thy, or it can be seen in association with an obstructing cricopharyngeal bar that prevents the pharynx from con­ tracting properly. Pharyngeal function usually can be restored following surgical correction of the obstructing bar (see later).

Structural Disorders Associated with Oropharyngeal Dysphagia Structural causes of OPD in dogs include penetrating foreign bodies, cleft palate, cricopharyngeal achalasia, and iatrogenically shortened soft palate. Cricopharyngeal achalasia is the inability of the cricopharyngeus muscle to open during the cricopharyngeal phase of swallowing. The exact underlying causes have not been determined, although the disorder can be reproduced by transection of the pharyngeal branch of cranial nerve X. Cricopha­ ryngeal dysphagia and achalasia are diagnosed via con­ trast videofluoroscopy. Cricopharyngeal achalasia has been well documented in miniature dachshunds and a variety of other small breeds in the author’s laboratory, and all dogs had marked hypertrophy of the cricopharyn­ geus muscle (cricopharyngeal bar) causing severe obstruc­ tion to propulsion of the bolus through the PES. In dogs with cricopharyngeal dysphagia a comprehen­ sive workup must be undertaken before surgical inter­ vention to ensure that systemic disorders (myopathies, polyneuropathies) are ruled out and aspiration pneumo­ nia is managed properly. A fluoroscopic swallow study must be performed in dogs suspected of having cricopha­ ryngeal dysphagia to assess pharyngeal function before surgical intervention. Dogs that are diagnosed with underlying neuropathies or myopathies are managed conservatively with alterations of feeding practice or the use of low-profile gastrostomy devices if specific manage­ ment of the underlying neuropathy or myopathy is not possible. Definitive treatment of cricopharyngeal achalasia involves surgical myotomy or myectomy of the cricopha­ ryngeal muscle. In veterinary medicine, the standard sur­ gical approach for myotomy or myectomy has remained constant over the years, and the cricopharyngeal and thyropharyngeal muscles are approached either by a stan­ dard ventral midline approach with 180-degree rotation of the larynx on its longitudinal axis or by a lateral approach with 90-degree rotation of the larynx. Crico­ pharyngeal myotomy involves transection of the crico­ pharyngeal muscle to the level of the pharyngeal mucosa. A closed endoscopic procedure employing a carbon dioxide laser increasingly is being used for cricopharyn­ geal myotomy in people and dogs and is associated with

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shorter anesthesia time and reduced morbidity compared with the more traditional transcervical cricopharyngeal myotomy. An alternative and less invasive procedure involves  the injection of botulinum toxin into the cricopharyn­ geus muscle. Botulinum toxin A is a neurotoxin synthe­ sized from the bacillus Clostridium botulinum. It acts at the presynaptic cholinergic nerve terminals to block  the release of acetylcholine at the myoneuronal junction. In a dose-related manner, it weakens contraction when injected into the target muscle. The toxin has been used successfully in people for the treatment of esophageal achalasia, a condition characterized by hypertonicity of the lower esophageal sphincter, and has been used  successfully in people and dogs for the management  of cricopharyngeal achalasia. Because of its short half-life (4 hours), the toxin is reconstituted shortly before  injection with 0.9% sterile saline to a concentration of  25 U/ml. The author uses a transbronchial needle to inject the cricopharyngeus muscle in three sites, admin­ istering a dose of 10 U per site. The limited duration of effect of botulinum toxin (approximately 3 to 4 months) is a benefit because animals that respond favorably to the toxin should do well following surgical myotomy or myectomy. In contrast, animals that do poorly following botulinum injection can be supported with an enteral feeding device until the effects of the toxin have worn off. These animals should not undergo surgical correction of their cricopharyngeal disease because the disorder will be exacerbated. The veterinary profession has made tremendous strides in our ability to evaluate and diagnose disorders causing OPD in dogs and has refined the surgical procedures for managing some of the structural disorders such as crico­ pharyngeal achalasia in dogs. The diagnostic utility of observing the dysphagic animal eating and drinking cannot be overemphasized because this approach will help localize the phase of swallowing affected. Future efforts should be concentrated on better understanding the functional disorders causing dysphagia because the

prognosis for these animals unfortunately is poor. The observed association between certain dog breeds and a variety of causes of dysphagia warrant a comprehensive effort to perform genetic screening and modify breeding practices to help eradicate these disorders.

References and Suggested Reading Cook IJ: Investigative techniques in the assessment of oralpharyngeal dysphagia, Dig Dis 16:125, 1998. Dauer E et al: Endoscopic laser vs. open approach for cricopha­ ryngeal myotomy, Otolaryngol Head Neck Surg 134:830, 2006. Davidson AP et al: Inheritance of cricopharyngeal dysfunction in Golden Retrievers, Am J Vet Res 65:344, 2004. Dodds WJ, Stewart ET, Logemann JA: Physiology and radiology of the normal oral and pharyngeal phases of swallowing, Am J Roentgenol 154:953, 1990. Dua KS et al: Coordination of deglutitive glottal function and pharyngeal bolus transit during normal eating, Gastroenterology 112:73, 1997. Moerman MBJ: Cricopharyngeal Botox injection: indications and technique, Curr Opin Otolaryngol Head Neck Surg 14:431, 2006. Pollard RE et al: Quantitative videofluoroscopic evaluation of pharyngeal function in the dog, Vet Radiol Ultrasound 41:409, 2000. Pollard RE et al: Preliminary evaluation of the pharyngeal con­ striction ratio (PCR) for fluoroscopic determination of pharyn­ geal constriction in dysphagic dogs, Vet Radiol Ultrasound 48:221, 2007. Shelton GD, Schule A, Kass PH: Risk factors for acquired myas­ thenia gravis in dogs: 1,154 cases (1991-1995), J Am Med Vet Assoc 211:1428, 1997. Stanley B et al: Esophageal dysfunction in dogs with idiopathic laryngeal paralysis: a controlled cohort study, Vet Surg 39:139, 2010. Walmsley G et al: A Duchenne muscular dystrophy gene hot spot mutation in dystrophin-deficient cavalier King Charles span­ iels is amenable to exon 51 skipping, PLoS One 5(1):e8647, 2010. Warnock JJ et al: Surgical management of cricopharyngeal dys­ phagia in dogs: 14 cases (1989-2001), J Am Vet Med Assoc 223 (10):1462, 2003.

CHAPTER 

122 

Gastroesophageal Reflux PETER HENDRIK KOOK, Zurich, Switzerland

E

sophagitis denotes a localized or diffuse inflammation of the esophageal mucosa. It generally is thought to result from a caustic (e.g., acid, alkali, bile salts) or chemical (e.g., drug-induced) injury that starts at the luminal surface and progresses to the deeper layers of the tissue. In people, gastroesophageal reflux disease (GERD) results from a failure of the normal antireflux barrier to protect against frequent and abnormal amounts of gastroesophageal reflux (GER). Although GER is not a disease, but a normal physiologic process occurring multiple times a day, GERD is regarded as a multifactorial process usually producing symptoms of heartburn and acid regurgitation. The most frequent mechanism for reflux is thought to result from lower esophageal sphincter (LES) incompetence. However, esophageal inflammation also may cause esophageal hypomotility and LES weakness by impairing the excitatory cholinergic pathways to the LES. In cats, these changes have been shown to be reversible with healing of the esophagus (Zhang et al, 2005). GER occurs spontaneously in healthy dogs and is not associated with exercise, positioning of the animal, or sleeping. GER also has been evaluated in anesthetized patients and is affected by positioning of the animal during anesthesia and the type of surgical procedure. It has been reported that intraabdominal procedures have a higher risk for GER, and the duration of preoperative fasting and choice of preanesthetic drugs influence the incidence of GER during anesthesia (Galatos and Raptopoulos, 1995). No information exists on quantification of intraoperative GER and the risk for subsequent esophageal inflammation. Hiatal hernias may predispose to GER in dogs and cats because of the altered functional anatomy of the gastroesophageal pressure barrier (losing the intrinsic support of the crural diaphragm) and impaired esophageal acid clearance. Reflux esophagitis resulting from upper airway obstruction can become a problem in brachycephalic dogs (Lecoindre and Richard, 2004; Poncet et al, 2005), but non–breed-specific upper airway obstruction may cause GER. The supposed pathomechanism is the negative intrathoracic pressure generated by increased inspiratory effort. In veterinary medicine GERD secondary to a primary LES abnormality is poorly understood. Diagnosing GERD based on history and observed symptoms, as it often is done in human medicine, is not applicable. Esophagitis secondary to presumed GER has been reported in cats (Gualtieri and Olivero, 2006; Han et al, 2003); however, the diagnosis was based on a combination of presumably typical historical and clinical signs, as well as

radiographic, endoscopic, or histopathologic findings without actual demonstration of acidic esophageal pH. At present it is not clear if GERD also represents a relevant problem in small animals. More common scenarios for increased esophageal acid exposure in dogs and cats are lodged foreign bodies, frequent vomiting, malpositioned esophageal feeding tubes, potentially aggressive gastric factors such as gastric volume, and duodenal contents associated with delayed gastric emptying. In chronic esophagitis cases, histologic changes comparable with Barrett’s esophagus (replacement of the normal squamous epithelium of the distal esophagus with metaplastic columnar epithelium) rarely can be found.

Historical and Clinical Signs Animals with mild esophagitis may show no clinical signs, whereas animals with severe esophagitis can show reduced appetite, anorexia, odynophagia or dysphagia, ptyalism, coughing, and regurgitation. Clinical signs noted by the author include retching, gagging, repeated swallowing motions, smacking, discomfort at night (or bedtime), and refusal to eat despite apparent interest in food. Although it would appear plausible that severity of clinical signs depends on the extent and depth of esophageal lesions, they do not always correlate and may vary greatly. Hoarseness, stridor or change of phonation, and dyspnea suggest injury to the epiglottis, larynx, and upper airway (Lux et al, 2012). Onset of anesthesiaassociated reflux esophagitis varies from days to weeks after a causative anesthetic event. On physical examination, patients may have evidence of halitosis and laryngeal signs with redness, hyperemia, and edema of the vocal folds and arytenoids. However, the majority of patients have normal physical examinations. Care should be taken to evaluate the respiratory system, because pulmonary manifestations of GERD potentially may include aspiration pneumonia, chronic bronchitis, and interstitial pulmonary fibrosis. Concerning this aspect, idiopathic pulmonary fibrosis is seen nearly exclusively in older West Highland white terriers, a breed that is also notoriously famous for lodged esophageal foreign bodies. Chronic intermittent microaspiration of gastric acid secondary to primary esophageal motility problem could be the causative event in this breed.

Diagnosis Although historical and clinical findings may be suggestive of esophagitis, results of routine laboratory testing are usually normal. Survey thoracic radiographs are 501

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SECTION  VI  Gastrointestinal Diseases

seldom diagnostic for esophagitis, but compatible findings may be mild esophageal dilations or fluid accumulation in the distal esophagus. However, foreign bodies, hiatal hernias, esophageal dilation, ring anomalies, or masses could be detected, and a pathologic lung pattern may reflect aspiration injury to the lungs. Mediastinal or pleural air or liquid accumulation may indicate esophageal perforation. If a perforation is considered likely, an iodinated contrast medium should be used instead of barium. A contrast esophagram is an inexpensive, readily available, and noninvasive test that is most useful in demonstrating stenotic narrowing of the esophagus. No veterinary study has evaluated the ability of barium esophagram to detect esophagitis. However, mucosal irregularities and a prolonged retention of the contrast medium can be seen with moderate to severe inflammation, whereas mild esophagitis most likely will be missed. The benefit of fluoroscopic swallow studies is assessing the esophageal motility during the whole swallow with less chance to miss the moment when the contrast medium passes a narrow point, as could be the case with static images. It is important to perform wet swallows with liquid contrast medium and dry swallows with a bariumfood mixed bolus, because liquids sometimes can pass a partial stricture, whereas a food bolus may be retained. With the exception of detecting strictures, these procedures cannot diagnose GER. Hiatal hernias may be seen during fluoroscopic contrast studies of the LES area by applying pressure on the cranial abdomen. In health the gastroesophageal junction should lie caudal to the hiatus, and no stomach or other viscera should lie cranial to the gastroesophageal junction. However, it can still be difficult to assess the clinical significance of small sliding hiatal hernias. Endoscopic examination is the most sensitive method to diagnose esophagitis, although reliable diagnostic endoscopic criteria and grading schemes for severity of esophagitis have not been established in small animals. No descriptive endoscopic work larger than case reports has been published on canine or feline esophagitis. Early signs of esophagitis are erythema and edema, but these findings are nonspecific and depend on the quality of endoscopic equipment. More reliable signs include increased vascularity because enlarged capillaries develop in response to acid near the mucosal surface. Mucosal striations with visible submucosal vascularity may be seen in the distal third of the esophagus. Another common sign is increased granularity; the mucosal surface appears rough and puckered. Findings compatible with severe esophagitis are areas of exudative pseudomembranes and ulcerative mucosa. In contrast to people, linear mucosal breaks (erosions) with a sharp demarcation line from adjacent normal mucosa uncommonly are seen. Although typical for reflux esophagitis, circular inflammation just above the LES should not be confused with the squamocolumnar junction (demarcation line between the squamous esophageal lining and the columnar gastric lining), which can appear sharply delineated in cats and dogs with reddened gastric mucosa. This is especially the case with esophageal overinsufflation. It could be argued that esophagoscopy without biopsy is insufficient to rule out esophagitis, as are cases with

grossly normal appearing mucosa on endoscopy and necropsy, but histopathologic evidence of esophagitis has been reported (Dodds et al, 1970; Han et al, 2003). This is in accordance with findings in humans, in which endoscopic results in patients with GERD vary from no visible mucosal damage to esophagitis, peptic strictures, or Barrett’s esophagus (a metaplastic change of normal squamous epithelium to columnar epithelium associated  with chronic acid exposure). Because of the composition of the esophageal mucosa with its tough stratified  squamous epithelium, it is difficult to obtain adequate esophageal biopsies; however, adequate endoscopic biopsy specimens from the lower canine esophagus showing the stratified squamous epithelium with basal cell layer, as well as the lamina propria with papillae,  can be obtained by experienced endoscopists (Münster et al, 2012). The endoscopic examination always should include a full gastric inspection with special attention to the cardia and pylorus; this excludes underlying abnormality, such as obstructive lesions or radiolucent foreign bodies, and confirms that the esophagitis is a primary problem. All aforementioned diagnostics may aid in the diagnosis of esophagitis but still fail to detect GER. Approaches other than endoscopy are needed. In humans, catheterfree esophageal pH monitoring has become the gold standard for diagnosing GERD. This technique provides information on distal esophageal acid exposure and also is able to assess symptoms associated with acid reflux episodes. A widely used system in humans is the Bravo system. It includes a small capsule (26 mm × 5.5 mm × 6.5 mm) containing an antimony pH electrode with internal reference, miniaturized electronics with radiofrequency transmitter and battery, a capsule delivery system, as well as an external receiver to monitor intraesophageal pH. The capsule is positioned approximately 3 cm above the LES and attached (i.e., pierced) to the mucosa. Once released from the delivery system, pH data are recorded by a receiver attached to the dog’s harness. Owners are instructed to maintain a logbook to record all events presumed to be related to GER. Our experience with the Bravo Capsule pH test indicates that this technique can be used safely in patients from 5 kg to 50 kg bodyweight, and all dogs tolerate the measurements well. Our preliminary results contradict the previous hypothesis that minute amounts of acid could damage severely the canine esophagus. In healthy dogs with normal upper gastrointestinal endoscopy, the number of refluxes (defined as esophageal pH 5 min) vary considerably over the course of 96 hours. Although single reflux episodes lasting as long as 20 minutes rarely can be recorded, the overall fraction time pH less than 4 remains low and usually ranges between 0 and 3.2% (median 0.3%). These numbers actually are lower than the established norm in humans. First results in dogs with clinical signs commonly attributed to reflux esophagitis are surprising, because clinically relevant reflux episodes could not be demonstrated in the majority of suspected dogs and a temporal relationship between presenting signs observed by owners and reflux episodes lacked overall agreement. Because this is an ongoing study, more dogs must be evaluated before definitive

CHAPTER  122  Gastroesophageal Reflux conclusions can be made. Current disadvantages of the system are the high cost and need of upper endoscopy for accurate placement.

Therapy Treatment ideally should be directed at the underlying causes of the gastroesophageal reflux; it is important to eliminate predisposing factors (e.g., hiatal hernia). Because anesthesia is the most common cause for reflux esophagitis in dogs and cats, it would appear desirable to prevent GER in patients undergoing anesthesia. Pretreatment with high doses of metoclopramide yielded conflicting results, and the administration of ranitidine prior to surgery also did not reduce the incidence of GER (Favarato et al, 2011; Wilson et al, 2006). Similarly, another study failed to demonstrate consistent intraoperative GER prevention with omeprazole given orally 4 hours prior to surgery (Panti et al, 2009). As pointed out above, the primary underlying mechanism for GER in people is believed to be impaired LES function resulting in prolonged esophageal exposure to acid. Therefore treatments for GER have focused on increasing LES pressure or decreasing acid production. Prokinetic drugs increase the pressure of the LES and enhance gastric motility; they therefore influence a  possible underlying motility disturbance of the disease (also see Chapter 125). Metoclopramide, a dopamine antagonist, and cisapride, a serotonin receptor agonist that increases acetylcholine release in the myenteric plexus, are available prokinetic drugs for treating presumed GER. Although experimental pharmacodynamic studies showed a positive strengthening effect of metoclopramide on the canine LES, these effects were of short duration; high doses potentially leading to extrapyramidal signs and sedation are needed (Wilson et al, 2006). Our own studies have failed to document a positive strengthening effect on the LES in healthy dogs. In people, cisapride was the best prokinetic drug before its withdrawal from the market. It is still available in many countries for use in small animals through compounding veterinary pharmacies. Even if the significance of a primary LES incompetence is still uncertain in animals with esophagitis, the use of cisapride seems warranted because esophagitis may lead to a reflex decrease in LES tone. The author uses 0.5 to 0.75 mg/kg q8h PO. Sucralfate, an aluminum salt of a sulfated disaccharide, is considered a mucosal protectant that binds to inflamed tissue to create a protective barrier. It is supposed to block diffusion of gastric acid and pepsin  across the esophageal mucosa and inhibit the erosive action of pepsin and possibly bile. Sucralfate stimulates secretion of growth factors implicated in ulcer healing and of mucus and bicarbonate. The efficacy of administrating sucralfate for the treatment of esophagitis has been questioned, because the rationale for its effectiveness is based on its protective adherence to denuded mucosal surface in an acidic environment. Our ambulatory wireless esophageal pH measurements indicate a weakly alkaline canine esophageal milieu in more  than 90% of the time recorded. In humans with

503

advanced-grade corrosive esophagitis caused by ingestion of chemical agents, intensive high-dose sucralfate therapy has been shown to be beneficial in enhancing mucosal healing and preventing stricture formation. The most clinically effective drugs for treatment of reflux esophagitis in humans are acid suppressive drugs (also see Chapter 123). Proton pump inhibitors (PPI) are the most potent gastric acid suppressants because of their ability to inhibit the proton pump H+, K+-ATPase, which is the final common pathway of gastric acid secretion. In dogs, PPIs (e.g., omeprazole) provide superior gastric acid suppression compared with H2 receptor antagonists (ranitidine or famotidine) and therefore should be considered more effective for the treatment of acid-related disorders (Bersenas et al, 2005; Tolbert et al, 2011). The same is probably true in cats, but objective data are lacking. PPIs ideally are given before feeding the first meal of the day, when most proton pumps become active. Because not all pumps are active at any given time,  a single PPI dose does not inhibit all pumps. For this reason a second dose may be necessary before feeding  12 hours later; the author prefers administration of  1 mg/kg q12h PO. Because the enteric-coated tablets and microspheres should not be broken or crushed for dosing purposes, the use of reformulated omeprazole paste for horses diluted to 40 mg/ml in sesame oil has been evaluated recently and can be considered as an efficacious alternative (Tolbert et al, 2011). However, twice-daily dosing was advised in that study for the reformulated paste because of a reduced duration of effect. Important shortcomings of PPIs include the dependence on food consumption for maximal efficacy, a delayed onset of action compared with H2 receptor antagonists, and soft to liquid feces. Lifestyle changes are part of the initial management of reflux esophagitis in people and include losing weight if overweight, avoiding bedtime snacks, and elevating the head at night. Although this therapy intuitively makes sense, no data are available in small animals. In cases in which a primary LES abnormality clearly has been identified manometrically, surgical fundoplication can correct the physiologic factors contributing  to GER. Nissen fundoplication has been shown to be highly effective in reducing reflux by achieving a constant external pressure on the gastroesophageal junction in canine models. Similarly, in case of a chronic obstructive upper respiratory problem, corrective surgery minimizing or eliminating the obstruction also may resolve inflammatory esophageal lesions. The same applies to hernias. Benign esophageal strictures must be addressed if  they are causing clinical problems. The two nonsurgical  techniques used to widen the narrowed lumen are ballooning and bougienage. Esophageal balloon dilation is performed with a catheter involving an inflatable balloon. The balloon has to be positioned in the stricture and  then expanded either with insufflated fluid or air. Bougienage involves the use of rigid instruments in different diameters (depending on the stricture) pushed longi­ tudinally through the narrow point. Bougienage allows  more force to be applied to the stricture than is possible  with a balloon, which may be important for patients 

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SECTION  VI  Gastrointestinal Diseases

with tough, fibrous strictures or strictures so small  that balloons cannot be inserted through them. Outcomes of esophageal bougienage for the treatment of benign esophageal strictures are similar to those reported for balloon dilation (Bissett et al, 2009). Corticosteroids sometimes are administered to inhibit healing-associated fibroblastic proliferation and contraction and therefore to avoid esophageal stricture formation. Although oral corticosteroids are not considered effective in humans, endoscopically guided submucosal triamcinolone injections at the stricture site prior to ballooning are likely effective for preventing reformation of strictures; however, controlled studies are lacking. The author uses a 23-gauge throughthe-channel flexible injection needle and injects approximately 0.5-cc (10 mg triamcinolone) into each site in a four-quadrant pattern before widening the narrowed lumen. The chest should be radiographed after difficult procedures or if there is evidence of respiratory compromise to check for pneumomediastinum secondary to esophageal tearing. Following a dilation procedure the author allows oral feeding with a watery food consistency after 24 hours.

References and Suggested Reading Bersenas AM et al: Effects of ranitidine, famotidine, pantoprazole, and omeprazole on intragastric pH in dogs, Am J Vet Res 66:425, 2005. Bissett SA et al: Risk factors and outcome of bougienage for treatment of benign esophageal strictures in dogs and cats: 28 cases (1995-2004), J Am Vet Med Assoc 235(7):844, 2009. Dodds WJ et al: Sequential gross, microscopic, and roentgenographic features of acute feline esophagitis, Invest Radiol 5:209, 1970.

Favarato ES et al: Evaluation of metoclopramide and ranitidine on the prevention of gastroesophageal reflux episodes in anesthetized dogs, Res Vet Sci 2011, doi:10.1016/j.rvsc.2011.07.027. Galatos AD, Raptopoulos D: Gastro-oesophageal reflux during anaesthesia in the dog: the effect of age, positioning and type of surgical procedure, Vet Rec 137:513, 1995. Gualtieri M, Olivero D: Reflux esophagitis in three cats associated with metaplastic columnar esophageal epithelium, J Am Anim Hosp Assoc 42:65, 2006. Han E, Broussard J, Baer KE: Feline esophagitis secondary to gastroesophageal reflux disease: clinical signs and radiographic, endoscopic, and histopathological findings, J Am Anim Hosp Assoc 39:161, 2003. Lecoindre P, Richard S: Digestive disorders associated with  the chronic obstructive respiratory syndrome of brachycephalic dogs: 30 cases (1999-2001), Revue Méd Vét 155(3):141, 2004. Lux CN et al: Gastroesophageal reflux and laryngeal dysfunction in a dog, J Am Vet Med Assoc 240(9):1100, 2012. Münster M et al: Assessment of the histological quality of endoscopic biopsies obtained from the canine gastro-esophageal junction, Tierarztl Prax Ausg K Kleintiere Heimtiere 40(5):318, 2012. Panti A et al: The effect of omeprazole on oesophageal pH in dogs during anaesthesia, J Small Anim Pract 50:540, 2009. Poncet CM et al: Prevalence of gastrointestinal tract lesions in 73 brachycephalic dogs with upper respiratory syndrome,  J Small Anim Pract 46:273, 2005. Tolbert K et al: Efficacy of oral famotidine and 2 omeprazole formulations for the control of intragastric pH in dogs, J Vet Intern Med 25:47, 2011. Wilson DV, Evans AT, Mauer WA: Influence of metoclopramide on gastroesophageal reflux in anesthetized dogs, Am J Vet Res 67(1):26, 2006. Zhang X et al: Effect of repeated cycles of acute esophagitis and healing on esophageal peristalsis, tone, and length, Am J Physiol Gastrointest Liver Physiol 288(6):G1339, 2005.

CHAPTER 

123 

Antacid Therapy ALEXA M.E. BERSENAS, Guelph, Ontario, Canada

Pathogenesis of Ulcer Disease Ulcer disease results from an imbalance between gastric acid secretion and the gastric mucosal defense mechanisms. The pathogenesis is multifactorial. The amount of acid in gastric contents is determined by the rate of gastric acid secretion, the neutralization of acid by bicarbonate, the dilution by food and other digestive enzymes, and back diffusion of acid through the gastric mucosa. Gastric acidity plays a role in ulcerogenesis; human studies have established that the healing of acid-related disorders (gastric and duodenal ulcers and erosive esophagitis) is correlated highly with the degree of gastric acid suppression. These studies also have identified that the optimal degree of acid suppression varies with the underlying disease process. However, the degree of gastric acidity is not the only cause of mucosal injury: erosions and ulcers can occur in areas of anacidity. Other factors include increased bile reflux, decreased mucosal perfusion, and decreased delivery of bicarbonate to the protective mucous layer. The key cell in gastric acid secretion is the parietal cell. The parietal cell secretes hydrogen ion via a H+/K+-ATPase pump. Based on gastric stimulation, the proton pump proceeds from an inactive to an active state such that over a period of hours, essentially all the ATPase molecules cycle through an acid-producing state. Secretion of hydrochloric acid is initiated via three systems: endocrine, neurocrine, and paracrine. These systems are mediated by three separate chemical messengers; gastrin, acetylcholine, and histamine, respectively. The goals of antisecretory therapy are to reduce gastric acid secretion, prevent damage to the gastric mucosa, and allow regenerative mucosal mechanisms to prevail (Box 123-1).

Gastric Acid Suppressants H2 Receptor Antagonists Cimetidine, ranitidine, famotidine, and nizatidine are reversible H2-specific receptor antagonists that competitively inhibit binding of histamine, thereby reducing gastric acid secretion. Formulations are available for oral and parenteral administration (IV, IM, and SC). Intravenous continuous rate infusions have been used in human medicine but have not been investigated in veterinary medicine. H2 receptor antagonists (H2RAs) differ in their potency (famotidine > ranitidine = nizatidine > cimetidine); how­ ever, clinically increased potency does not necessarily  correlate to increased efficacy. In developmental studies

using the dog model, H2RAs have been shown to have an effect on canine gastric pH, where they produce an effect on gastric acidity for 6 to 7 hours. Cimetidine, the first H2RA, because of its increased frequency of administration and its interaction with the cytochrome P450 system, has been replaced by later-generation H2RAs. Unfortunately, in the last decade, several veterinary studies have demonstrated underwhelming acid suppression with later-generation H2RAs in dogs. In one veterinary study investigating the effects of different H2RAs on gastric pH in healthy dogs, ranitidine at a clinically recommended dose (2 mg/kg IV q12h) offered no change in gastric pH compared with saline (Bersenas et al, 2005). Results using famotidine at 0.5 mg/kg IV (q12h) were  also underwhelming. Famotidine’s ability to raise substantially intragastric pH in dogs is limited (Tolbert et al, 2011). Clinically, oral famotidine has been shown to be efficacious for reducing the severity but not the prevalence of gastric lesions in racing sled dogs when used as a preventive (Williamson et al, 2007). Attempts at increasing the dose or dosing frequency of famotidine also have failed to show an improved outcome. It is unlikely that famotidine at the commonly used dose of 0.5 mg/kg q12h is very effective, and the once-daily dosing that  has been recommended previously may not be as effective as suggested. Overall, the acid suppression provided by H2RAs at current veterinary doses is low. Some evidence suggests that famotidine should be selected over ranitidine for improved effect (Bersenas et al, 2005). Famotidine appears to help primarily animals that are at lesser risk for gastric lesions or are at risk for less severe gastric lesions. Famotidine remains an excellent drug for routine prophylaxis when cost is a concern or when an injectable drug is preferred. In addition to the H2RAs antisecretory effects, some of these drugs have a prokinetic effect on gastrointestinal motility. Ranitidine and nizatidine have prokinetic properties mediated by inhibition of acetylcholinesterase activity. The H2RAs are metabolized in the liver and excreted unchanged in urine. In renal failure the half-life is increased; therefore a decreased dose or decreased dosing frequency (q24h) is recommended. Otherwise H2RAs have minimal adverse reactions and are considered very safe in humans and small animals.

Proton Pump Inhibitors Omeprazole, pantoprazole, lansoprazole, rabeprazole, esomeprazole, and dexlansoprazole are proton pump inhibitors (PPIs) that block the H+/K+-ATPase enzyme 505

506

SECTION  VI  Gastrointestinal Diseases

BOX 123-1  Dosages for Acid Control in Dogs and Cats H2 Receptor Antagonists Cimetidine: 5-10 mg/kg q6-8h, PO, SC, IM, IV Ranitidine: 1-2 mg/kg q8-12h, PO, SC, IM, IV Famotidine: 0.5-1 mg/kg q12-24h, PO, SC, IM, IV Nizatidine: 2.5-5 mg/kg q24h PO (dog) (dose not well established) Proton Pump Inhibitors Omeprazole: 0.7-1 mg/kg q24h PO; 1 mg/kg q12h for 3-5 days for quicker onset and greater efficacy Pantoprazole: 0.5-1 mg/kg q24h PO, IV (dog and cat); 1 mg/kg bolus IV followed by 0.1 mg/kg/hr for 72 hours CRI (used only in dogs) Cytoprotective Agents Misoprostol: 2-5 μg/kg q8-12h PO (dog); (cat: no dose established) Sucralfate: 0.5-1 g q8-12h PO (dog); 0.25 g q8-12h PO (cat) Antacids Aluminum hydroxide tablets: 10-30 mg/kg q8h PO, alternatively, 12 -1 tablet q6h PO (dog), 14 tablet q6h PO (cat) Aluminum hydroxide or aluminum hydroxide/magnesium hydroxide suspensions: 2-10 ml q2-4h PO (dog) Magnesium hydroxide: 5-10 ml q4-6h PO (dog and cat)

pump on the apical surface of the parietal cell. In contrast to receptor antagonists, PPIs block histamine-2, gastrinand cholinergic-mediated sources of acid production and inhibit gastric acid secretion at the final common pathway of the H+/K+-ATPase proton pump. PPIs provide the most profound acid inhibition of the antisecretory drugs and are indicated for gastric and duodenal ulcers and erosive esophagitis and for the long-term treatment of pathologic hypersecretory conditions. PPIs are substituted benzimidazoles, acid-activated sulfhydryl (SH) agents. All PPIs are available in oral formulation. These are unstable in the acidic environment of the stomach. Enterically administered PPIs are compounded as enteric-coated capsules or tablets and should not be crushed or split. Adjusted doses for smaller patients should be repackaged into new capsules; alternatively, a 2 mg/ml omeprazole suspension using 8.4% sodium bicarbonate as a base (one 20-mg tablet with 10 ml 8.4% NaHCO3) is recommended (Phillips et al, 1996). More recently, a 40 mg/ml omeprazole suspension using an approved equine oral paste formulation (Gastrogard, AstraZeneca) in sesame oil at a ratio of 1:9 has been used (the formulation should be made up daily until further testing is performed) (Tolbert et al, 2011). PPIs are irreversible inhibitors of the ATPase pump that lead to long-term acid suppression (up to 36 hours) despite very short plasma half-lives (0.5 to 2 hours). PPIs routinely are administered once daily and should be administered 1 hour before a meal to coincide with maximal proton pump activity. PPIs take several days to reach steady state because they bind only to the proton

pumps that are actively secreting acid, sparing inactive pumps that are resting in the cytosol. Higher doses of omeprazole provide a more predictable inhibition of gastric acid, and short-term, twice daily dosing is recommended for more efficient acid suppression. Intravenous formulations of PPIs, in North America, are limited to pantoprazole and lansoprazole. Pantoprazole administered once a day has been shown to have similar antisecretory efficacy to injectable famotidine  in healthy dogs (Bersenas et al, 2005). Intravenous PPI use should be reserved for patients unable to take oral medications and have active bleeding ulcers requiring hemostasis (Pang and Graham, 2010) or are at very high risk of developing stress related ulcers (e.g., coagulopathic, mechanically ventilated more than 48 hours) (Cook et al, 1994). Acute gastrointestinal bleeding requires a pH greater than 6 to achieve hemostasis. The most potent acid suppression is achieved by using a constant rate infusion of a PPI after a high–dose bolus (infusions provide a steady state of the drug to inactivate any newly recruited or synthesized proton pumps). Infusional PPIs are endorsed in human medicine at a conventional rate of 80 mg bolus followed by 8 mg/hr for 72 hr (Pang and Graham, 2010). Pantoprazole infusion has been used in dogs when aggressive acid inhibition is required, and  the dose extrapolated from the human dose with no negative effects noted; no veterinary studies have evaluated its efficacy. Long-term use of PPIs has demonstrated an excellent safety profile and commercially available PPIs are equally effective with minimal side effects. Earlier concerns of hypergastrinemia and the development of gastric carcinoids with the long-term use of these drugs have not been substantiated clinically in people or animals. PPIs are metabolized by varying degrees by the cytochrome P450 enzyme system, with omeprazole and esomeprazole more actively reliant on this system. Current recommendations indicate that the use of omeprazole or esomeprazole with clopidogrel should be avoided because of competitive inhibition of clopidogrel metabolism (reducing clopidogrel’s efficacy). Other drug interactions include decreased absorption of coadministered medications dependent on gastric acidity (e.g., ketoconazole, ampicillin esters, iron salts, and digoxin).

Cytoprotective Agents Misoprostol Misoprostol (Cytotec) is a synthetic prostaglandin (PGE1) analog that has cytoprotective effects by enhancing gastric mucosal defense mechanisms (increasing bicarbonate and mucus production and increasing turnover and blood supply of gastric mucosal cells). Misoprostol also has acid inhibitory properties with direct action on the parietal cell causing decreased activity of the proton pump; this effect results in only modest decreases in gastric acid secretion. The main indication for misoprostol use is the prevention of NSAID-induced gastric damage. Misoprostol is not recommended routinely for patients receiving NSAIDs but should be considered for select patients with high 

CHAPTER  123  Antacid Therapy risk of GI ulceration. It is uncertain whether misoprostol improves healing of established ulcers, and it does not have any benefit in treating ulcers not associated with NSAIDs (e.g., corticosteroid administration in dogs with intervertebral disk disease) (Hanson et al, 1997; Neiger et al, 2000). Unfortunately, misoprostol has a very short half-life (30 minutes), which requires frequent dosing (q6-8h); unexpectedly, one canine study found twice-daily dosing to be as effective as q8h administration (Ward et al, 2003). The drug also is associated with gastrointestinal distress, manifested as nausea, vomiting, diarrhea, and abdominal pain that frequently prevents the routine use of this drug. Misoprostol should be avoided in pregnant animals because of stimulation of uterine contractions and risk of abortion.

Sucralfate Sucralfate is an oral antiulcer agent, an anionic sulfated disaccharide that, in the stomach, is broken down into sucrose sulfate and aluminum salt. The negatively charged sulfate binds electrostatically to positively charged protein molecules exposed in damaged mucosa of the GI tract  to form an adhesive paste-like substance that physically protects the ulcer site from pepsin, acid, and bile, and prevents back diffusion of hydrogen ions. In addition, sucralfate stimulates mucus and bicarbonate secretion and stimulates the increase of prostaglandin E2 and epidermal growth factor. Sucralfate is indicated for the treatment of erosions and ulcers in the stomach and upper duodenum and can treat esophageal lesions if gastroesophageal reflux is suspected. Its efficacy as a prophylactic for GI ulceration is not as well known, but no benefit has been attributed to its use with GI hemorrhage in dogs with IVDD administered corticosteroids (Hanson et al, 1997). In stress-related mucosal injury in humans, some studies have found that sucralfate administered prophylactically may be at least as effective as antacids and H2RAs; however, conflicting studies report decreased GI bleeding with the use of acid-lowering therapies (H2RAs). Sucralfate is not absorbed systemically. Within the stomach it may bind to and decrease the absorption of concomitantly administered medications, such as fluoroquinolones, H2RAs, levothyroxine, theophylline, tetracyclines, digoxin, phenytoin, and ketoconazole. Oral drugs should be administered 2 hours prior to sucralfate administration. Sucralfate should not be administered through duodenal or jejunal feeding tubes because its site of action is bypassed. Sucralfate is very safe with very few adverse effects. Patients with advanced renal failure and impaired aluminum excretion who take sucralfate have the potential for aluminum toxicity.

Antacids Antacids work by directly buffering or neutralizing the acidic contents of the stomach. Many over-the-counter antacids are available; these are bases of aluminum, magnesium, calcium, or combinations of these. Some mixtures contain sodium and should be used with caution in patients in whom fluid retention is contraindicated.

507

Familiar antacid product names include Tums (calcium carbonate), Amphojel (aluminum hydroxide), Gaviscon (alginic acid/aluminum/magnesium/sodium bicarbonate), to name only a few. Antacids containing aluminum or magnesium neutralize stomach acid to form water and a neutral salt. In addition to neutralizing stomach acid, aluminum-containing antacids have additional beneficial effects, including decreasing pepsin activity, binding to bile acids in the stomach, and stimulating local prostaglandin (PGE1). Products combining magnesium and aluminum salts take advantage of different buffering capacities of the individual cations and reduce side effects of any cation alone. Antacids are the least therapeutic option for ulcer treatment. Dosages in veterinary medicine are empiric. Antacids are not considered sufficiently effective and, because of a very short duration of action, have laborintensive dosing frequency (q4h) of rather large volumes. Moreover, administration of high doses of antacids may increase the risks of aspiration pneumonia and toxicity related to cation accumulation (particularly in patients with renal dysfunction).

Summary Gastric acid suppression must be evaluated in light of  its necessity for prophylaxis versus ulcer healing. Antacid therapy is extensive and has been recommended in  all conditions in which gastrointestinal ulceration previously has been documented in human and veterinary patients. Potent antisecretory drugs are indicated for patients with overt ulceration. However, as in people, animals with low risk of bleeding may not derive benefit from prophylactic measures to protect the gastric mucosa from acid, and the costs associated with widespread  use of antisecretory drugs may be unnecessary. Further studies in veterinary medicine investigating the benefits of acid-lowering therapies are necessary to evaluate whether their widespread use is warranted or beneficial.

References and Suggested Reading Bell NJV et al: Appropriate acid suppression for the management of gastroesophageal reflux disease, Digestion 51(suppl):59, 1992. Bersenas AME et al: Effects of ranitidine, famotidine, pantoprazole, and omeprazole on intragastric pH in dogs, Am J Vet Res 66:425, 2005. Cook DJ et al: Risk factors for gastrointestinal bleeding in critically ill patients. Canadian Critical Care Trials Group, N Engl J Med 330:377, 1994. Hanson SM et al: Clinical evaluation of cimetidine, sucralfate, and misoprostol for prevention of gastrointestinal tract bleeding in dogs undergoing spinal surgery, Am J Vet Res 58:1320, 1997. Henderson AK, Webster CRL: The use of gastroprotectants in treating gastric ulceration in dogs, Compendium 28:358, 2006. Madanick RD: Proton pump inhibitor side effects and drug interactions: much ado about nothing? Cleve Clin J Med 78:39, 2011. Neiger R et al: Gastric mucosal lesions in dogs with acute intervertebral disc disease: characterization and effects of omeprazole or misoprostol, J Vet Intern Med 14:33, 2000.

508

SECTION  VI  Gastrointestinal Diseases

Pang S, Graham D: Review: a clinical guide to using intravenous proton-pump inhibitors in reflux and peptic ulcers, Therap Adv Gastroenterol 3:11, 2010. Phillips JO et al: A prospective study of simplified omeprazole suspension for the prophylaxis of stress-related mucosal damage, Crit Care Med 24:1793, 1996. Tolbert K et al: Efficacy of oral famotidine and 2 omeprazole formulations for the control of intragastric pH in dogs, J Vet Intern Med 25:47, 2011.

CHAPTER 

Ward DM et al: The effect of dosing interval on the efficacy of misoprostol in the prevention of aspirin-induced gastric injury, J Vet Intern Med 17:282, 2003. Williamson KK et al: Efficacy of famotidine for the prevention of exercise-induced gastritis in racing Alaskan sled dogs, J Vet Intern Med 21:924, 2007.

124 

Gastric Helicobacter spp. and Chronic Vomiting in Dogs MICHAEL S. LEIB, Blacksburg, Virginia

S

piral bacteria were identified in the stomachs of humans and animals in the late 1800s. However, it was not until the early 1980s that Warren and Marshall proposed a relationship between Helicobacter pylori and gastric disease in humans. Soon after, studies demonstrated that spiral bacteria were common in the stomachs of clinically normal dogs and cats, as well as those with signs of gastrointestinal (GI) disease. Experimental infection in dogs and cats resulted in lymphoid follicular gastritis; however, clinical signs were absent or very mild. Currently a direct causal relationship between spiral bacteria and chronic gastritis and vomiting or with gastric neoplasia has not been established firmly in dogs or cats. However, based on clinical experience and several clinical studies evaluating dogs and cats treated for Helicobacter spp. and identifying improvement or resolution of clinical signs, the author believes that gastric Helicobacter spp. can cause or contribute to the clinical signs in some dogs and cats with chronic gastritis and vomiting (Happonen et al, 2000; Jergens et al, 2009; Leib et al, 2007). In addition, a potential relationship between gastric lymphoblastic lymphoma and Helicobacter heilmannii in cats has been proposed (Bridgeford et al, 2008). The author routinely determines whether gastric Helicobacter spp. are present in all dogs and cats with chronic

vomiting that undergo upper GI endoscopy in his clinic. In most instances, dogs and cats with gastric Helicobacter spp. and gastritis, with and without inflammatory bowel disease (IBD), are treated initially for Helicobacter spp. If clinical signs continue, dietary or antiinflammatory therapies for gastritis and IBD are instituted. Although the potential pathogenic role of gastric Helicobacter spp. in dogs and cats is being investigated, a thorough diagnostic evaluation to search for other potential causes of chronic vomiting always should be performed before considering Helicobacter spp. to be the primary etiologic agent. The purpose of this chapter is to describe the commonly used methods of identifying gastric spiral bacteria in dogs and cats and to review the evidence behind current treatment recommendations. Recommendations for humans with H. pylori have been modified by the results of hundreds of clinical studies. Treatment recommendations in dogs and cats no doubt also will change as further studies are performed.

Pathogenesis Helicobacter spp. are gram-negative, microaerophilic, motile, curved-to-spiral bacteria with multiple terminal flagella. They contain large quantities of the enzyme

CHAPTER  124  Gastric Helicobacter spp. and Chronic Vomiting in Dogs urease, which results in the production of ammonia and bicarbonate when in contact with urea that is present in gastric juice. This reaction alters the pH immediately surrounding the bacteria and helps them colonize the acidic environment of the stomach. More than 35 Helicobacter spp. have been identified in humans and animals. At least seven species have been identified in the stomachs of dogs and cats. In addition to the gastric species, others also have been identified in the intestine and liver. H. pylori is the most common gastric species in humans. H. pylori has been shown to be a major cause of gastritis and peptic ulcers and to increase the risk of gastric cancer. Infection rates can approach 100% in developing countries and 25% to  60% in developed countries. Infection usually is acquired in childhood and most often persists for life; natural immunity does not clear the infection. Most infected humans remain asymptomatic, but peptic ulcers may occur in approximately 16% of those infected, whereas gastric cancer may develop in 1% to 2% of infected humans. Symptomatic disease usually takes decades to develop in humans. Development of clinical signs is related to bacterial virulence, environmental factors, and host genetics, especially relating to the cytokine response to infection. Eradication of H. pylori usually results in healing of gastric and duodenal ulcers and remission of low-grade gastric mucosa–associated lymphoid tissue (MALT) lymphoma. Although H. pylori has been identified in a research colony of cats, infections in pet dogs and cats with other species of Helicobacter is more common. Gastric Helicobacter spp. usually found in dogs and cats are larger than H. pylori (1.5 to 3 µm). Initially these large spiral bacteria (4 to 10 µm) were called Gastrospirillum hominis but were later reclassified as Helicobacter heilmannii. Other large gastric spiral bacteria such as Helicobacter felis, Helicobacter bizzozeronii, and Helicobacter salomonis are found and are indistinguishable from H. heilmannii using routine light microscopy. Multiple species also can be present within an individual animal. Gastric or duodenal ulceration associated with Helicobacter spp. is rare in dogs and cats, demonstrating a major pathophysiologic difference between H. pylori and the gastric spiral bacteria commonly found in dogs and cats. In addition to the role of Helicobacter spp. in the pathogenesis of gastritis and chronic vomiting in dogs and cats is the potential for zoonotic transmission. Most evidence indicates zoonotic transmission to be very low, but the potential is real. H. heilmannii is a rare cause of gastritis in humans, accounting for approximately 0.1% of cases. An epidemiologic survey of humans with H. heilmannii gastritis showed that contact with dogs and cats was a significant risk factor (Meining et al, 1998). In addition, there was an association between H. heilmannii gastritis and gastric lymphoma, although this relationship could be coincidental (Stolte et al, 1997). Some studies have identified cat ownership as a risk factor for H. pylori infection in humans, whereas others have found contact with dogs or cats not to be a risk factor for H. pylori infection. Although the potential for zoonotic transmission appears slight, until this issue is resolved conclusively, it seems prudent to identify the presence of gastric Helicobacter spp. in dogs

509

and cats during the diagnostic evaluation of chronic vomiting.

Diagnostic Tests Invasive methods of diagnosis of gastric Helicobacter infection in humans include bacterial culture, routine microscopic or ultrastructural examination, polymerase chain reaction, or rapid urease testing of gastric mucosal biopsy specimens, usually obtained via endoscopy. Noninvasive methods of diagnosis include urea breath testing, fecal antigen determination, and serology. Although many of these noninvasive tests have been investigated in dogs and cats, they are not routinely available. Presently the clinical diagnosis of gastric Helicobacter spp. in dogs and cats requires endoscopic examination or exploratory celiotomy for retrieval of gastric biopsy samples. Recently, gastric washing with saline has identified spiral bacteria in a small group of cats. In the author’s clinic, spiral bacteria are identified on gastric biopsy, from gastric brush cytology specimens, or indirectly by a positive rapid urease test using a gastric mucosal sample. Results from a rapid urease test and gastric brush cytology are available much sooner than results from histopathology. For reasons discussed in the following paragraphs, gastric brush cytology and histologic evaluation of biopsy samples are considered to be the most practical diagnostic tests available to the practicing veterinarian.

Brush Cytology Gastric brush cytology is the least expensive and most practical diagnostic method with the quickest turnaround time. After completion of an endoscopic examination and collection of biopsy samples from the duodenum  and stomach, a brush cytology specimen is collected. A guarded cytology brush is passed through the biopsy channel of the endoscope into the gastric body along the greater curvature. The cytology brush is extended from the sheath and gently rubbed along the mucosa from the antrum toward the fundus, along the greater curvature. Hemorrhagic areas associated with previous biopsy sites should be avoided. The brush is retracted into the protective sheath and withdrawn from the endoscope. The brush is extended from the sheath, gently rubbed across several glass microscope slides, which are air dried, and stained with a rapid Wright stain (Dip Quick stain). The slide is examined under 100× oil immersion. Areas with numerous epithelial cells and large amounts of mucus are examined initially for Helicobacter spp. If present, the spiral bacteria are seen easily. They are usually at least as long as the diameter of a red blood cell, and their classic spiral shape is obvious (Figure 124-1). The number of spiral bacteria can be highly variable, from one every several fields to massive numbers in most fields. At least 10 oil immersion fields are examined on two slides before the specimen is considered negative. Unlike diagnostic tests that involve using a single or several small biopsy samples, brush cytology gathers surface mucus and epithelial cells from a much larger area, increasing the chances for identification of bacteria. Brush cytology  was found to be more sensitive than urease testing or

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SECTION  VI  Gastrointestinal Diseases

histopathologic examination of gastric tissues in identifying Helicobacter spp. organisms in dogs and cats (Happonen et al, 1996).

Rapid Urease Test The rapid urease test detects the presence of bacterial urease, produced by the Helicobacter spp., in a gastric biopsy sample. A commercially available test, the CLOtest, is used in the author’s clinic (Figure 124-2). Individual tests cost less than $10. The test consists of an agar gel with urea and a pH indicator, phenol red, within a small plastic well. The tests should be kept refrigerated before

use. A routine microbiologic urea slant tube also can be used for this same purpose. An endoscopic biopsy sample obtained from the angularis incisura of the stomach  is pushed into the gel. The test is maintained at room temperature and examined frequently for a 24-hour period. If bacterial urease is present, urea is hydrolyzed to ammonia, which changes the pH of the gel. The color of the gel turns from yellow to magenta. The rate at which the gel changes color is proportional to the number of Helicobacter spp. present in the sample. When large numbers of bacteria are present in the biopsy sample, the rapid urease test quickly changes color, often within 15 to 30 minutes. If the color of the gel has not changed within 24 hours, the test is interpreted as negative. Occasionally, false-positive tests occur, perhaps because of contamination of other urease-producing pharyngeal or intestinal bacteria. False-negative tests may occur because of the patchy distribution of bacteria within the stomach or the use of drugs that decrease acid secretion (increase in pH alters the activity of urease). Because of false positives and negatives, the cost of the tests, the turnaround time for results (especially if negative), and the ease and reliability of brush cytology, the author finds the rapid urease test to be a less valuable diagnostic method.

Histopathologic Identification

10 µm

Figure 124-1  Gastric brush cytology specimens stained with Dip Quick stain. Cellular debris is permission from Pract Vet 27:221,

Large numbers of spiral bacteria are visible. scattered throughout the photograph. (With Leib MS, Duncan RB: Compend Contin Educ 2005.)

Histopathologic identification of Helicobacter spp. within gastric biopsy samples, using hematoxylin and eosin (H&E) or special stains, has a specificity of 100% and a sensitivity of greater than 90% in studies in humans. Because of the patchy distribution of organisms within the stomach, examination of samples from multiple gastric locations increases sensitivity. In the author’s clinic, samples from the pylorus, angularis incisura, gastric body along the greater curvature, and cardia are examined routinely. Spiral bacteria can be seen within the mucus covering the surface epithelium, the gastric pits, glandular lumen, and the parietal cells (Figure 124-3). In

10m

Figure 124-2  CLOtest. The top well is negative. The bottom

well has changed color and is positive. (With permission from Leib MS, Duncan RB: Compend Contin Educ Pract Vet 27:221, 2005.)

Figure 124-3  Photomicrograph of gastric mucosal samples

stained with H&E showing spiral bacteria along the mucosal surface (arrows). (With permission from Leib MS, Duncan RB: Compend Contin Educ Pract Vet 27:221, 2005.)

CHAPTER  124  Gastric Helicobacter spp. and Chronic Vomiting in Dogs

511

TABLE 124-1  Treatment Protocols for Gastric Helicobacter Species in Dogs Protocol

Drugs

Dosage mg/kg

Frequency/day

Duration (days)

Happonen, 2000

Amoxicillin Metronidazole Bismuth subcitrate

20 10 6

q12h q12h q12h

10-14 10-14 14-28

Leib, 2007

Amoxicillin Metronidazole Bismuth subsalicylate

q12h q12h q12h

14 14 14

Famotidine

15 10 25 kg-524 mg 0.5

q12h

14

Jergens, 2009

Amoxicillin Metronidazole Bismuth subsalicylate suspension Clarithromycin

22 11-15 0.22 ml/kg 7.5

q12h q12h q6-8h q12h

21 21 21 14

Cornetta, 1998; Simpson, 1999

Amoxicillin

20

q12h

14

Metronidazole Famotidine

20 0.5

q12h q12h

14 14

Amoxicillin Clarithromycin Lansoprazole

50 25 1

q12h q12h q12h

7 7 7

Anacleto, 2011

cats, bacteria have been identified submucosally within gastric lymphoid follicles. Spiral bacteria associated with the mucosal surface or within gastric pits are relatively easy to detect with routine H&E staining of tissues. However, if the distribution of bacteria favors gastric glands and glandular epithelial cells, bacteria are detected much more readily with a modified Steiner’s silver stain. Because of similarities in morphologic characteristics it is not possible to identify specific species using routine histologic staining techniques. Histopathologic evaluation of biopsy samples also allows assessment of inflammation in the stomach and duodenum or identification of neoplasia that may be the cause of the animal’s clinical signs.

Treatment Many studies evaluating therapy have been performed in humans with H. pylori. The most effective treatment regimens contain two or three antimicrobials combined with a proton pump antagonist, given for 1 to 2 weeks. Multiple antibiotics are used because treatment with a single antibiotic has resulted in eradication rates less than  20%. Studies in humans not only have demonstrated effective regimens but also have evaluated protocols  associated with the highest treatment compliance: those with the fewest side effects, the least number of tablets/ day, and the shortest duration of therapy. Treatment  protocols with eradication rates determined 4 weeks  after completion of therapy that are higher than 80% to 90% are considered clinically effective. Reappearance rates after eradication of approximately 1% have been 

demonstrated, thought mostly to be the result of recrudescence. Successful treatment of bacteria within the gastric lumen is difficult. Antibiotics must penetrate the thick mucus layer within the gastric lumen and be active at an acid pH. The volume of gastric contents is changing constantly as a meal is ingested and because of acid secretion and gastric emptying. In addition, metronidazole and clarithromycin, and rarely amoxicillin, resistance has been detected in strains of H. pylori. Table 124-1 lists treatment protocols described in the veterinary literature and used in the author’s hospital.  In one study the author (Leib et al, 2007) treated 24 pet  dogs with gastric Helicobacter spp. and chronic vomiting with either amoxicillin, metronidazole, and bismuth subsalicylate (triple therapy) or triple therapy and famotidine (quadruple therapy). The median duration of vomiting before therapy was 19 weeks, and the median frequency of vomiting was 3.5 episodes per week. The presence  of gastric Helicobacter spp. was determined by histologic assessment of gastric biopsy specimens obtained before therapy, 4 weeks, and 6 months after completion of therapy. Eradication rates were 70% and 78.5% 4 weeks after therapy for the triple and quadruple therapy, respectively. Eradication rates decreased to 44.4% and 41.7% 6 months after therapy for the triple and quadruple therapy groups, respectively. Eight dogs that were negative at 4 weeks were positive at 6 months because of either reinfection or recrudescence of infection. Both treatments reduced the vomiting frequency compared with the historical vomiting frequency. The median reduction in the frequency of vomiting episodes during

512

SECTION  VI  Gastrointestinal Diseases

the first 4-week period after therapy was 91.8% for tripletherapy dogs and 72% for quadruple-therapy dogs. After completion of therapy, the median reduction in the frequency of vomiting episodes for the entire 6-month period was approximately 86% for both groups. Almost 78% of dogs that were Helicobacter spp. negative at 6 months had at least a 90% reduction in vomiting frequency. In addition, dogs negative at 6 months had a significant improvement in the severity of their histologic gastritis scores. These data suggest that gastric Helicobacter spp. caused or contributed to clinical signs in some of the dogs in this study, and successful treatment dramatically decreased the incidence and severity of clinical signs. Because it often is presumed that treatment compliance may decrease as the number of drugs administered increases, omitting acid suppressors in treatment protocols might improve client compliance and treatment success in some cases. Acid suppression may not be necessary in dogs and cats with gastric Helicobacter spp. because peptic ulceration is very uncommon when compared with its incidence in humans. However, proton pump antagonists such as omeprazole have proven to have other potential benefits in humans with H. pylori, including bacteriostatic effects in vitro, facilitation of bacterial clearance from the stomach when combined with antibiotics, and inhibition of bacterial urease. Further study of the potential role of acid suppression in dogs and cats with gastric Helicobacter spp. is warranted. The high infection rates 6 months after therapy in the Leib study (2007) were thought to be caused by initial treatment failure (25%), reinfection from the environment, or recrudescence of infection. High rates of treatment failure and potential recrudescence indicate that more effective treatment regimens should be developed to reach higher than 80% to 90% eradication rates. In  the author’s study it was not possible to differentiate between reinfection and recrudescence. It is possible  that both treatments were effective initially, and reinfection from the environment occurred. Because of canine  social habits and the relatively unsanitary nature of the environment in which they live, reinfection after successful eradication therapy seems more likely to occur in  dogs than in humans. If further research confirms that  reinfection commonly occurs, treatment strategies should include minimizing environmental contamination and exposure (Anacleto et al, 2011), treatment of asymptomatic animals within the household, and possibly periodic retreatment if clinical signs recur. Only two other published studies are known to evaluate the effects of triple antimicrobial therapy on gastric Helicobacter spp. in pet dogs with upper GI signs (Happonen et al, 2000; Jergens et al, 2009). In the first study, seven of nine dogs that received amoxicillin, metronidazole, and bismuth subcitrate (see Table 124-1) became negative for Helicobacter spp. Clinical signs improved in all treated dogs, including two that remained positive. However, complete resolution of clinical signs required additional therapies. Four of these dogs were reevaluated a mean of 2.5 years after therapy, and all were found to be positive for gastric Helicobacter spp. However, these four dogs remained normal or only occasionally had mild clinical signs. In the second study (Jergens et al, 2009),

three dogs and two cats with chronic vomiting were treated with amoxicillin, metronidazole, and bismuth subsalicylate for 3 weeks (see Table 124-1) and fed an elimination diet. All five became Helicobacter spp. negative and vomiting also resolved after treatment. The results of these studies also provide evidence that gastric Helicobacter spp. contributed to the clinical signs in these dogs. Because of the need to identify more effective treatment protocols, the author recently investigated the effectiveness of a dual antibiotic protocol using clarithromycin and amoxicillin for 2 weeks. The combination of clarithromycin and amoxicillin with a proton pump antagonist has been very effective in eradicating H. pylori in humans with peptic ulceration. Because famotidine did not improve results in previous study and because of the additional cost of such therapy and the potential for decreased client compliance, a proton pump antagonist was not used. Only preliminary results are available for the 14 dogs treated. The median duration of vomiting was 47 weeks, and the median frequency of vomiting was 2.5 episodes per week. Approximately 71% (10 of 14) of dogs were Helicobacter spp. negative 4 weeks after therapy and only 50% (5 of 10) after 6 months. The median reduction in the vomiting frequency was 79.4%, although there was considerable variation. However, only 40% of dogs negative 6 months after treatment had at least a 90% reduction in vomiting frequency. Experimental studies in dogs cannot be compared directly to studies in pets with clinical signs but can provide assessment of bacterial eradication rates. Two studies evaluated the 2-week treatment of asymptomatic beagles naturally infected with gastric Helicobacter spp. with famotidine, amoxicillin, and metronidazole (see Table 124-1) (Cornetta et al, 1998; Simpson et al, 1999). In both reports all dogs were positive for gastric Helicobacter spp. 29 days after completion of therapy. These studies included bismuth as a third antimicrobial agent. Besides its beneficial effects in healing peptic ulcers in humans, bismuth compounds have antimicrobial effects and can suppress but not eliminate H. pylori from humans. Bismuth compounds have been shown to decrease the adherence of H. pylori from the gastric epithelium, distort bacterial structure by causing vacuolization, and be present within the cell wall and on the external surface of the bacteria. A recent study (Anacleto et al, 2011) treated 10 naturally infected dogs with amoxicillin, clarithromycin, and lansoprazole BID for 7 days. Dogs housed individually remained Helicobacter spp. negative after 60 days, but 80% of those housed with infected dogs became reinfected. However, only five dogs in this study were housed individually. Crowded housing conditions were associated commonly with reinfection, which may have contributed to disappointing eradication rates 6 months after treatment in these experimental studies. In summary, although the role of gastric Helicobacter spp. as a cause of chronic vomiting in dogs and cats remains speculative, enough clinical and experimental evidence suggests that gastric spiral bacteria cause or contribute to chronic vomiting and gastritis in many dogs and cats. In the author’s studies between 40% and 78%

CHAPTER  125  Gastric and Intestinal Motility Disorders of dogs with chronic vomiting, chronic gastritis, and Helicobacter spp. dramatically improve after successful treatment. It seems prudent to determine if gastric spiral bacteria are present in dogs and cats with chronic vomiting. This can be accomplished easily with brush gastric cytology specimens or routine histologic assessment of gastric biopsy samples. If other etiologies of chronic vomiting are not identified, a treatment protocol for gastric Helicobacter spp. is indicated. If clinical signs do not improve after treatment, dietary trials or antiinflammatory drugs should be considered. Based on all the studies performed and the author’s clinical experience, the author’s current treatment recommendation is amoxicillin and clarithromycin given q12h PO and omeprazole given q24h PO for 3 weeks. However, this combination has not been tested in a large number of dogs or cats with chronic vomiting. Additional studies will further define the potential pathogenic role of gastric Helicobacter spp. in dogs, and more effective treatment recommendations no doubt will emerge.

References and Suggested Reading Anacleto TP et al: Studies of distribution and recurrence of Helicobacter spp gastric mucosa of dogs after triple therapy, Acta Cirugica Brasileira 26:82, 2011. Bridgeford EC et al: Gastric Helicobacter species as a cause of feline gastric lymphoma: a viable hypothesis, Vet Immunol Immunopathol 123:106, 2008.

CHAPTER 

513

Cornetta AM et al: Use of [13 C] urea breath test for detection of gastric infection with Helicobacter spp in dogs, Am J Vet Res 59:1364, 1998. Flatland B: Helicobacter infection in humans and animals, Compend Contin Educ Pract Vet 24:688, 2002. Geyer C et al: Occurrence of spiral-shaped bacteria in gastric biopsies of dogs and cats, Vet Rec 133:18, 1993. Happonen I et al: Comparison of diagnostic methods for detecting gastric Helicobacter-like organisms in dogs and cats, J Comp Pathol 115:117, 1996. Happonen I, Linden J, Westermarck E: Effect of triple therapy on eradication of canine gastric Helicobacters and gastric disease, J Small Anim Pract 41:1, 2000. Jergens AE et al: Fluorescence in situ hybridization confirms clearance of visible Helicobacter spp. associated with gastritis in dogs and cats, J Vet Intern Med 23:16, 2009. Leib MS, Duncan RB: Diagnosing gastric Helicobacter infections in dogs and cat, Compend Contin Educ Pract Vet 27:221, 2005. Leib MS, Duncan RB, Ward DL: Triple antimicrobial therapy and acid suppression in dogs with chronic vomiting and gastric Helicobacter spp, J Vet Intern Med 21:1185, 2007. Meining A, Kroher G, Stolte M: Animal reservoirs in the transmission of Helicobacter heilmannii, Scand J Gastroenterol 33:795, 1998. Neiger R, Simpson K: Helicobacter infection in dogs and cats: facts and fiction, J Vet Intern Med 14:125, 2000. Simpson K et al: Gastric function in dogs with naturally acquired gastric Helicobacter spp. infection, J Vet Intern Med 13:507, 1999. Stolte M et al: A comparison of Helicobacter pylori and H. heilmannii gastritis: a matched control study involving 404 patients, Scand J Gastroenterol 32:28, 1997.

125 

Gastric and Intestinal   Motility Disorders FRÉDÉRIC P. GASCHEN, Baton Rouge, Louisiana

T

he prevalence of canine and feline nonobstructive gastrointestinal (GI) motility disorders cannot be documented precisely. They may go unnoticed by the animal’s owner because of subtle clinical signs that  are difficult to recognize until the problem is severe. However, these disorders likely are of significant clinical importance. They may result from primary segmental or diffuse inflammatory or neoplastic infiltration of the GI wall. GI motility also may be influenced by a variety of diseases affecting other organs, such as abdominal inflammation (e.g., pancreatitis, postoperative ileus) or diseases such as endocrinopathies, electrolyte abnormalities (e.g.,

hypokalemia, hypocalcemia), and uremic syndrome. Moreover, diseases affecting the autonomous nervous system (e.g., dysautonomia) often significantly affect GI motility. Most available information on canine and feline GI motility has been obtained from studies using dogs and cats as animal models; only a few studies focus on spontaneous canine and feline GI motility disorders. In dogs and cats, motility disorders resulting from obstruction of gastric outflow, of the small intestine or colon by foreign bodies, or by space-occupying lesions  are a common occurrence. Their diagnosis generally is

514

SECTION  VI  Gastrointestinal Diseases

BOX 125-1  Clinical Signs Associated with Delayed Gastric Emptying in Dogs and Cats Vomiting May occur long after food intake, when the stomach should be empty (>8-10 hr postprandial) Occasionally projectile vomiting (no prodromal signs, such as nausea with salivation) Abdominal distention, bloated abdomen Cranial abdominal discomfort, colic Increased belching Nausea with associated signs Dysorexia/anorexia Weight loss Pica and/or polydipsia

straightforward, and their treatment is surgical. Therefore they will not be further discussed in this chapter.

Disorders of Gastric Emptying Physiology After ingestion of solid food, the gastric antrum acts as a pump from which peristaltic waves originate, while the gastric body acts as a high compliance reservoir. The mechanical action of the antral pump is divided into three phases: (1) propulsion, (2) emptying of fine particles and mixing, and (3) retropulsion of particles larger than 1  mm for continued grinding. In healthy animals, the rate of gastric emptying is modulated by the composition of the diet (e.g., moisture and fat, protein and carbohydrate content) and is under the influence of neural and endocrine factors. Complete emptying of  the stomach is followed by synchronized housekeeping  contractions (migratory motor complexes [MMC] phase III).

Clinical Signs Signs associated with disorders of gastric motility in dogs and cats are listed in Box 125-1. However, the signs may be difficult to recognize before the problem becomes severe.

Etiology Primary Disorders of Gastric Motility Primary functional disorders appear to be rare in small animals. Slower gastric emptying occurs in dogs following circumcostal gastropexy performed after gastric dilationvolvulus (GDV). Gastric motility is impaired in the fasting and postprandial phases in these dogs (Hall et al, 1992). However, it has not been established whether this abnormal motility is involved in the etiology of GDV or simply a consequence of surgical treatment. The exact role of gastric dysmotility in canine GDV has not been elucidated to date. Dysautonomia is discussed in further detail later;  it also may influence gastric emptying. The diagnosis of duodenogastric reflux (DGR) in dogs has been the subject

of controversy because this reflux may occur as a physiologic event. Moreover, most instances of vomiting are accompanied by some degree of DGR. However, a syndrome characterized by bilious vomiting, often before the morning meal, has been observed in apparently healthy dogs and attributed to DGR. Initial treatment consists of a late evening meal and may require addition of drugs lowering gastric acidity (H2-receptor antagonist, protonpump inhibitor) and/or prokinetics. Secondary Disorders of Gastric Motility Inflammation of the GI tract or other abdominal organs, abdominal surgery, or metabolic disorders may cause secondary gastric motility abnormalities. Gastric or Intestinal Inflammation.  GI inflammation is a common cause of gastric motility changes. Therefore it is hardly surprising that GI parasites, gastric ulcers, parvovirosis, adverse food reactions, dysbiosis, and inflammatory bowel disease (IBD) often are accompanied by abnormal gastrointestinal motility. Acute canine pancreatitis also is associated commonly with decreased gastric and intestinal motility. This can complicate treatment significantly and probably is caused by extension of the inflammatory process to stomach and duodenum, which are in close proximity of the pancreas. In a similar manner peritonitis also affects gastric motility, and postoperative ileus is a frequent occurrence (see later). Diseases Affecting Multiple Organ Systems.  Systemic disorders also may affect GI motility. Hypoadrenocorticism often is accompanied by decreased gastric motility. Furthermore, abnormal small intestinal and colonic motility have been shown in dogs with ablation of 66% of renal mass and chronic renal disease, whereas gastric emptying seemed normal. However, it is not known if a larger reduction of functional renal mass, as is observed in clinical cases (>75%), may have negative effects on gastric motility. Finally, delayed gastric emptying may be induced by various medications; opioid analgesics and anticholinergics may interfere with GI neurotransmitters and cause impaired smooth muscle function. Vincristine, a frequently used chemotherapy agent, recently has been shown to decrease gastric antral motility transiently (Tsukamoto et al, 2011).

Diagnostic Approach A detailed history and physical exam may help identify subtle changes suggestive of GI dysmotility. However, the initial approach of the dog or cat with suspected GI motility disorder consists of first ruling out obstructive GI disease with abdominal radiographs. Presence of food in the stomach after prolonged fasting (i.e., more than 10 to 12 hours) suggests delayed gastric emptying. In addition, an abdominal ultrasound exam may reveal severely decreased gastric and duodenal motility. Once GI obstruction has been ruled out, CBC, chemistry panel, and urinalysis are necessary to look for underlying disorders that may secondarily influence motility. Evaluation of Gastrointestinal Motility The various methods available to investigate gastric emptying have been reviewed in detail (Wyse et al, 2003).

CHAPTER  125  Gastric and Intestinal Motility Disorders

250

10

40

225

9

38

205

36

8

185

6

125

5

30

105

4

85

28 26

65

3

45

2

22

1

20

0 43:12 46:30

18

25 5 8 0:00

4:48

9:36

14:24

19:12

24:00

28:48

33:36

38:24

Temperature C

32

145

pH

Pressure mm Hg

34

7

165

515

24

Figure 125-1  Wireless motility capsule recording in a young healthy male mixbreed dog. The

top line reflects the temperature (in degrees Celsius), the line below represents the pH, while the bottom line shows the pressure profile (in mm Hg). Time is shown on the X axis (in hours [h] and minutes [min]). The massive rise in pH at 6 h 42 min indicates exit of the capsule from the stomach. The slight decline in pH at 9 h 20 min indicates entry into the large bowel. Gastric emptying time was 6 h 38 min, small bowel transit time was 2 h 38 min, and large bowel transit time was 36 h 57 min.

They aim at evaluating the gastric emptying or intestinal transit time of solid food and include radionuclide scintigraphy, radiographic contrast studies (barium meals  and barium impregnated polyethylene spheres, or BIPS), and abdominal ultrasound. Gastric emptying also can be  measured using indirect techniques relying on duodenal absorption of compounds that subsequently can be detected in the breath (e.g., 13C-octanoid acid) or in the blood (e.g., acetaminophen). Recently, a wireless motility capsule (SmartPill) has been validated for use in dogs (Boillat et al, 2010) (Figure 125-1). These noninvasive methods may be very useful, but all have potential pitfalls. Some require special equipment that can be found only at referral centers. Potential exposure of the veterinary staff to radiation may represent a problem. Some techniques can be performed only after the animals have been manually or chemically restrained, a potential source of interference with gastric motility. Radionuclide scintigraphy is recognized as the current gold standard in dogs and cats. Radiographic studies are accessible in clinical veterinary practice. Liquid barium has been used widely to assess GI transit times. The dose of barium suspension is 6 to 12 ml/kg in dogs and 12 to 16 ml/kg in cats and should be administered when the stomach is empty. Barium sulfate should be present in the duodenum by 15 minutes in the dog and by 5 minutes in the cat. The stomach should be free of barium after 1 to 4 hours in the dog and after 20 minutes in the cat. However, assessment of gastric emptying of liquids is an insensitive technique, with the exception of mechanical obstructions resulting from foreign bodies or other space-occupying

lesions obstructing the gastric or intestinal lumen. Mixing barium with food may allow better evaluation of the  solid phase of gastric emptying. Unfortunately, barium can dissociate easily from the test meal and cause the  study to be unreliable. Barium-impregnated polyethylene spheres (BIPS) have been used for evaluation of GI transit times in dogs and cats. They come in two sizes (1.5- and 5-mm diameter) and can be used easily in practice. However, correlation between gastric emptying of BIPS and the gold standard has been disappointing in dogs and in cats, and the use of these spheres has been limited.

Treatment Therapy of functional, nonobstructive disorders of gastric motility is based on two main axes: dietary modification and judicious use of prokinetic drugs. Proper diagnosis and treatment of any underlying disease that might affect gastric motility is an essential premise. Dietary modifications designed to facilitate gastric emptying are based on important facts from digestive physiology. For example, gastric emptying of liquid food is faster than that of solid foods. Diets with high caloric density tend to remain longer in the stomach. Gastric emptying of fat is slower than that of proteins, which is slower than that of carbohydrates. Consequently, feeding liquid or semi-liquid diet of low caloric density, low in fat and protein, should maximize gastric emptying. Increased feeding frequency and small meal size also are useful. In addition, prokinetic drugs may be beneficial in nonobstructive disorders of gastric emptying. Their properties are discussed at the end of this chapter.

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SECTION  VI  Gastrointestinal Diseases

Small and Large Intestinal Motility Physiology Three physiologic motility patterns are described in the small intestine: peristaltic waves (aboral movement of chyme over long intestinal segments), stationary contractions (leading to intestinal segmentation), and clusters  of contraction (mixing and aboral movement of chyme over short segments). Diarrhea usually is associated with the occurrence of pathologic giant aboral contractions. The colon also exhibits several contraction types. The individual phasic contractions and the migrating and nonmigrating motor complexes produce extensive mixing and kneading of fecal material and slow net aboral propulsion. The giant motor complexes (GMC) occur at 10-hour intervals and produce mass movements of feces, ending in defecation. Primary Disorders of Small or Large Bowel Motility Primary disorders of small or large bowel motility include dysautonomia, intestinal pseudo-obstruction, chronic constipation, and megacolon. Dysautonomia is a rare idiopathic disease affecting the autonomic nervous system that occurs in specific regions such as the midwestern United States, Great Britain, and parts of continental Europe. Feline dysautonomia has been reported from many countries without breed, gender, or age predisposition, and its prevalence has decreased over the last 20 years. Canine dysautonomia affects most frequently young, midsize to large dogs that roam freely in rural areas in the midwestern United States. Toxic, infectious, or immune-mediated causes have been suspected, but  the etiology remains unknown. Histopathology reveals  widespread degeneration of autonomic neurons and ganglions. Dysautonomia is a systemic disease with dire consequences. GI signs represent only a part of the clinical picture. In dogs, they include vomiting, diarrhea, constipation, tenesmus, and regurgitation (Harkin et al, 2002). In cats, regurgitation and constipation are described as the most frequent GI signs (Sharp et al, 1984). Mortality is 70% in cats and 90% in dogs. Several reports of chronic intestinal pseudo-obstruction have been published. The disorder is defined by the  presence of segmental or diffuse chronic intestinal dilatation and dysmotility in the absence of mechanical obstruction. Most animals were diagnosed initially with GI obstruction based on abdominal imaging findings; however, surgery revealed dilated intestinal loops with no obstruction. All dogs were euthanized, but one cat was treated with cisapride and prednisolone and survived. Histopathology revealed fibrosing leiomyositis affecting the small intestinal tunica muscularis. No breed or age predilections were reported. Nonobstructive chronic constipation may occur in older dogs and cats; however, it appears to be most prevalent in the feline species. Feline idiopathic megacolon is associated with colonic smooth muscle dysfunction that may be primary or secondary. A detailed discussion of the disease can be found elsewhere (Washabau and Holt, 1999). Prokinetics are an important part of treatment. The existence of a syndrome comparable to IBS in dogs

has been a subject of controversy. The term chronic idiopathic large bowel diarrhea has been suggested for dogs without histologic evidence of mucosal inflammation. Some of these dogs appear to respond to dietary fiber supplementation, whereas others do not and require behavior-modifying drugs (Lecoindre and Gaschen, 2011). Secondary Disorders of Small or Large Bowel Motility Intestinal motility can be affected secondarily by a  wide variety of disease processes. Intestinal inflammation (enteritis, colitis) may result in shortened transit times. In an experimental model, dogs with acute colitis had a decrease in nonpropulsive motility and an increase in GMCs, resulting in frequent defecation and tenesmus. Decreased nonpropulsive motility may be explained by disturbances of the circular colonic smooth muscle cells associated with inflammation. Abdominal inflammation also may delay intestinal motility (e.g., pancreatitis, peritonitis, postsurgical ileus). Medications also may influence intestinal motility negatively. Mu-receptor agonists increase antral contractions but decrease antral propulsion. Similarly they increase intestinal tone and segmentation but decrease intestinal propulsion. Furthermore, they strengthen the activity  of the ileocolic and anal sphincters. The mu-receptor agonist loperamide or diphenoxylate combined with  the anticholinergic atropine is used in the treatment of  acute episodes of diarrhea. They may lead to dysmotility if administered for more than a few days. Postoperative ileus (POI) has been documented to occur in humans, dogs, and cats. Four major pathways have been identified: 1. Neurogenic: stimulation of inhibitory neural pathways associated with surgical stress 2. Inflammatory: stimulation of macrophages and neutrophils upon bowel manipulation, and release of proinflammatory mediators that reduce GI motility 3. Hormonal: release of corticotrophin-releasing factor and stimulation of proinflammatory cytokines in the bowel 4. Pharmacologic: in particular by the use of exogenous opioids as analgesics and their general inhibitory effect of GI motility In dogs, POI caused reduced duration of MMC phase III activity and motility index. These changes were reversed after administration of metoclopramide at 0.4 mg/kg IV q6h (Graves et al, 1989). Constant-rate infusion (CRI) of lidocaine (0.025 to 0.05 mg/kg/min IV after loading bolus of 0.5 to 1 mg/kg IV, use low end of doses for cats) during the surgical intervention is thought to decrease the severity of POI because of the drug’s antinociceptive, antihyperalgesic, and antiinflammatory properties. However, the current consensus is that lidocaine CRI does not have any direct effect on GI motility.

Prokinetic Drugs Prokinetic drugs and their mode of action have been reviewed in detail elsewhere (Washabau, 2003) and  are summarized in this paragraph and in Table 125-1.

CHAPTER  125  Gastric and Intestinal Motility Disorders

517

TABLE 125-1  Mode of Action and Posology of Commonly Used Prokinetics in Small Animals Name

Mode of Action

Site of Action

Other Effects

Dose*

Metoclopramide

Serotoninergic (5-HT4 receptors)

Pyloric antrum Duodenum (?)

Antiemetic (D2 receptor antagonist)

0.2-0.5 mg/kg q8h PO, SC CRI: 1-2 mg/kg/24 hr

Cisapride

Serotoninergic (principally 5-HT4 receptors)

Lower esophagus (C) LES Pyloric antrum Small intestine Colon

0.1-0.5 mg/kg PO q8-12h

Mosapride (Pronamid, DS Pharma)

Serotoninergic (5-HT4 receptor-specific)

Pyloric antrum

0.5-2 mg/kg PO q12-24h (D) Available only in Japan

Prucalopride (Resolor, Movetis)

Serotoninergic (5-HT4receptor-specific)

Pyloric antrum Small intestine (?) Colon

0.02-0.6 mg/kg PO q12-24h Available only in Europe

Erythromycin

Motilin analog

Pyloric antrum Small intestine Colon

Antibiotic (at 10-20× higher dose)

0.5-1.0 mg/kg PO q8h

Ranitidine

Acetyl-cholinesterase inhibitor (stimulation of M3 receptors)

Pyloric antrum (small intestine, colon)

H2-antagonist (decreases gastric acid production)

1-2 mg/kg q12h PO or slowly IV (after dilution)

Nizatidine

Same as ranitidine

Same as raniditine

Same as ranitidine

2.5-5 mg/kg q24h PO

*For dogs and cats, unless otherwise specified. D, Dog; GMC, giant migrating contraction (colon); LES, lower esophageal sphincter.

Serotonergic drugs (cisapride, metoclopramide, mosapride, and prucalopride) act on 5-hydroxytryptamine (5-HT) receptors of different types. Metoclopramide (MCP) often is used as an antiemetic for its inhibitory effects on  dopamine receptors in the chemoreceptor trigger zone (CRTZ) of the medulla oblongata. MCP acts on 5-HT3 receptors (antagonist) and 5-HT4 (agonist). These effects stimulate contraction of smooth muscle cells of the stomach and intestine. Cisapride (CSP), another serotonergic drug, binds to 5-HT4 receptors and stimulates smooth muscle contractions. CSP was withdrawn from the pharmaceutic market because of its cross-reactivity with serotoninergic receptors in the myocardium and the risk of lethal cardiac arrhythmias in people. It currently is available as a generic substance from compounding pharmacies; however, generic cisapride may not be consistently available in all countries. Mosapride (Pronamid) is a highly selective 5-HT4 agonist that has been approved recently for use in dogs in Japan. Its activity has been documented in several studies and appears limited to the pyloric antrum in dogs. However, it may be of benefit in constipated cats. Prucalopride (Resolor) is another highly selective 5-HT4 agonist recently approved for use in people in Europe. It has been shown to stimulate gastric contractions in dogs and colonic motility in cats and dogs. Motilin agonists include erythromycin (EMC), a macrolide antibiotic with gastrokinetic properties at low doses. EMC triggers MMC phase III, a motility pattern responsible for cleaning the stomach during the interdigestive phase. The administration of EMC stimulates gastric emptying without any attention to particle size. This early release of gastric contents can

lead to “dumping” of insufficiently processed food in the small intestine. Furthermore, in cats EMC increases the lower esophageal sphincter pressure. Beside their role in decreasing gastric acid production, ranitidine and nizatidine are acetylcholinesterase inhibitors that increase the concentration of acetylcholine in the synaptic cleft between postganglionic myenteric neurons and smooth muscle cells of the stomach and intestine. They stimulate the activity of GI smooth muscle. All other H2 receptor antagonists lack this prokinetic effect. Domperidone (Motilium) is available in several countries outside the United States. It is a potent antiemetic (D2 receptor inhibitor). Its prokinetic effects are mediated by antagonism of α2- and β-adrenoreceptors, but their potency is questioned in dogs and cats. Other compounds recently have been shown to have prokinetic effects in dogs, but their clinical use has not been established yet. Yohimbine (Yobine) is an α2adrenergic receptor antagonist used in reversal of xylazine sedation in dogs. Intravenous doses of 0.5 to 3  mg/kg IV have been shown to induce GMC in dogs (Nagao et al, 2007). This property may be interesting in the treatment of postoperative ileus (see earlier). However, the package insert mentions that doses of 0.55  mg/kg may occasionally induce “brief seizures” and muscle tremors; therefore caution is recommended. It is not known if other α2-adrenergic receptor antagonists such as atipamezole exert similar direct prokinetic activities. Acotiamide, a novel specific acetylcholinesterase inhibitor, recently has been shown to increase gastric, small intestinal, and colonic motility in dogs after oral administration. Capsaicin is the major pungent ingredient of hot

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SECTION  VI  Gastrointestinal Diseases

peppers. It has been shown to stimulate the release of peptides, including the prokinetic molecule calcitonin gene-related peptide (CGRP). In dogs, intragastric capsaicin induced contractions in the antrum, small intestine, and colon within 15 minutes. Once in the small bowel, the compound had inhibitory effects on GI motility. Finally, intracolonic application of 5 to 10  mg capsaicin stimulated colonic motility and defecation. Research in new prokinetic agents is ongoing. Dogs likely will be used as an animal model for new substances to be developed in the future.

References and Suggested Reading Boillat CS et al: Variability associated with repeated measurements of gastrointestinal tract motility in dogs obtained by use of a wireless motility capsule system and scintigraphy, Am J Vet Res 71:903, 2010. Graves GM, Becht JL, Rawlings CA: Metoclopramide reversal of decreased gastrointestinal myoelectric and contractile activity in a model of canine postoperative ileus, Vet Surg 18:27, 1989. Hall JA et al: Gastric emptying of nondigestible radiopaque markers after circumcostal gastropexy in clinically normal

CHAPTER 

dogs and dogs with gastric dilatation-volvulus, Am J Vet Res 53:1961, 1992. Harkin KR, Andrews GA, Nietfeld JC: Dysautonomia in dogs: 65 cases (1993-2000), J Am Vet Med Assoc 220:633, 2002. Lecoindre P, Gaschen FP: Chronic idiopathic large bowel diarrhea in the dog, Vet Clin North Am Small Anim Pract 41:447, 2011. Nagao M et al: Role of alpha-2 adrenoceptors in regulation of giant migrating contractions and defecation in conscious dogs, Dig Dis Sci 52:2204, 2007. Sharp NJH, Nash AS, Griffiths IR: Feline dysautonomia (the KeyGaskell syndrome): a clinical and pathological study of forty cases, J Small Anim Pract 25:599, 1984. Tsukamoto A et al: Ultrasonographic evaluation of vincristineinduced gastric hypomotility and the prokinetic effect of mosapride in dogs, J Vet Intern Med 25:1461, 2011. Washabau RJ: Gastrointestinal motility disorders and gastrointestinal prokinetic therapy, Vet Clin North Am Small Anim Pract 33:1007, 2003. Washabau RJ, Holt D: Pathogenesis, diagnosis, and therapy of feline idiopathic megacolon, Vet Clin North Am Small Anim Pract 29:589, 1999. Wyse CA et al: A review of methods for assessment of the rate of gastric emptying in the dog and cat: 1898-2002, J Vet Intern Med 17:609, 2003.

126 

Current Veterinary Therapy: Antibiotic Responsive Enteropathy ALBERT E. JERGENS, Ames, Iowa

A

ntibiotic-responsive enteropathy (ARE) denotes a clinical syndrome characterized by acute or chronic diarrhea in animals that responds to antibiotic treatment (Hall, 2011). Well-recognized gastrointestinal (GI) disorders broadly responsive to antibiotics may be found in Box 126-1. Previously, this clinical disorder was termed idiopathic small intestinal bacterial overgrowth (SIBO), which implied that an absolute increase in bacterial numbers of the small intestine was responsible for disease pathogenesis. The term ARE is more appropriate than SIBO, given the unreliable nature of culturedependent assays in quantifying intestinal bacterial numbers and the misunderstanding of what constitutes normal versus abnormal microbial densities and composition mediating GI disease.

Host-Microbiota Interactions in Healthy Animals The GI tract in dogs and cats is colonized with a vast microbiota that is estimated to range between 1012 to 1014 organisms from 10 to 12 different bacterial phyla (Suchodolski, 2011). These bacteria play a crucial role  in immune system development and help to maintain  gut health through regulatory signals delivered to the epithelium that mediate mucosal homeostasis. Major functions of the intestinal microbiota affecting GI health include metabolic activities that cultivate energy and nutrients (e.g., short-chain fatty acids [SCFA], folate, and vitamin K), the trophic effects on intestinal epithelia  and immune structure/function (i.e., bacterial-induced

CHAPTER  126  Current Veterinary Therapy: Antibiotic Responsive Enteropathy

BOX 126-1 

Dietary influences Mucosal barrier

Gastrointestinal Disorders Responsive to Antibiotics • Infection with enteropathogenic bacteria • Small intestinal bacterial growth (SIBO) • Idiopathic SIBO? • Secondary causes of SIBO • Inflammatory bowel disease (IBD) associated with dysbiosis • IBD responsive to metronidazole • Tylosin-responsive diarrhea • Granulomatous colitis in boxer dogs

519

Normal motility

Gastric secretions Pancreatic enzymes

Bacterial interactions

Figure 126-1  Host mechanisms contributing to microbial

host gene expression and regulation of T-cell repertoires), and protection against invasion by pathogenic microbes via the production of antimicrobial substances, such as bacteriocins. Fecal bacterial culture useful for identifying a specific enteric pathogen (e.g., Campylobacter jejuni) has given way to culture-independent molecular techniques for in-depth analysis of complex bacterial communities. Contemporary studies using molecular microbiology have determined that the majority (>70%) of the GI microbiota is uncultivable, and composition and total bacterial numbers in different GI segments and luminal contents differ considerably as compared with the mucosa. It now is realized that the composition of gut flora in healthy dogs and cats is distinctly different. Healthy cats were shown to have a large number of total and anaerobic bacteria in the small intestines, which appear to be stable before and after antibiotic (metronidazole) administration (Johnston et al, 2000). A separate investigation similarly found high (104 to 108 CFU/ml) numbers of obligate anaerobes in the duodenum of cats but showed no differences in bacterial composition between healthy cats and cats with signs of GI disease (Johnston et al, 2001). Traditional bacterial culture techniques have shown that the canine duodenal microflora typically harbors a bacterial count of greater than 105 CFU/ml of duodenal juice; however, significantly higher counts have been observed in some breeds and in dogs with no signs of intestinal disease. Moreover, marked variation in the enteric microbiota may occur among individual healthy dogs and among the intestinal compartments within individual dogs.

Pathogenic Mechanisms Several different pathogenic mechanisms may contribute to the development of ARE. Aberrant host-microbial interactions have been associated with enteropathogenic bacterial infection, quantitative increases in total microbial numbers (SIBO), imbalances in enteric microbial composition (i.e., dysbiosis), and/or secondary to defects in mucosal barrier integrity (Hall, 2011). Colonization of the GI tract by pathogenic bacteria (i.e., infectious diarrhea) may induce gastroenteritis by direct mucosal invasion (e.g., invasive Salmonella spp.) or the secretion

homeostasis. A variety of factors may affect the numbers and diversity of the gastrointestinal microbiota, including environmental factors (diet), host factors (gastric acid secretion, pancreatic digestive proteases, normal intestinal peristalsis, functional innate immunity, secretory immunoglobulins), and bacterial factors (immune modulation, competition for substrate and binding sites, interaction [“crosstalk”] with enterocytes, production of antibacterial substances).

of enterotoxins, which are directly injurious to intestinal epithelia (e.g., Clostridium difficile) or which stimulate the secretion of fluid and electrolytes (Clostridium perfringens), causing secretory diarrhea. Still other bacteria may produce diarrhea in dogs and cats through bacterial attachment to the intestinal epithelial surfaces (i.e., enteroadherent streptococci). Adherent and invasive Escherichia coli (AIEC) now are associated with the development of granulomatous colitis in susceptible boxer dogs (Simpson et al, 2006). Canine SIBO traditionally is defined on the basis of increased numbers of total bacteria in duodenal juice, but controversy exists as to what bacterial quantity constitutes normal. Under physiologic conditions, the bacterial population of the small intestine is controlled by several host mechanisms (Figure 126-1). Although the numeric limits of bacteria found within asymptomatic dogs may vary by breed and within individuals of the same breed, there is general consensus that SIBO may occur secondary to exocrine pancreatic insufficiency, impaired clearance of bacteria (e.g., intestinal obstruction, motility disorder), and morphologic injury to the mucosa (e.g., infiltrative mucosal disease). Increased numbers of intestinal bacteria (i.e., SIBO) may cause malabsorption and diarrhea through (1) competition for nutrients (the bacterial binding of cobalamin, which impairs its intestinal absorption); (2) bacterial metabolism of nutrients into secretory products (e.g., hydroxylated fatty acids, deconjugated bile salts) that promote colonic secretions; and (3) biochemical injury to the intestinal brush border, which decreases enzyme activity causing maldigestion (Hall, 2011). Antibiotic-responsive diarrhea also may develop secondary to disrupted barrier function, aberrant mucosal immunity, or qualitative changes in the intestinal microbiota (i.e., dysbiosis). Studies show that some dogs (i.e., German shepherd dogs [GSD]) with ARE have selective IgA deficiency caused by a defect in IgA secretion at the small

520

SECTION  VI  Gastrointestinal Diseases

intestinal surface. Affected GSD have normal or increased numbers of mucosal IgA-producing plasma cells and  CD4+ T cells, suggesting underlying immune dysfunction, possibly resulting from loss of tolerance to commensal microbial antigens. Other studies indicate that host genetics, the mucosal immune system, and environmental factors (i.e., diet and enteric microbial imbalances) may play a role in mediating chronic intestinal inflammation in dogs. Studies in GSD have identified mutations in select innate immune genes (i.e., TLR2, TLR5, NOD2) regulating normal host responses to the enteric microbiota (Kathrani et al, 2010). It is possible that these genetic defects in innate immune sensing may cause aberrant host responses to be directed against commensal bacteria as if they were pathogens. Molecular studies have shown imbalances in microbial abundance and composition (i.e., enriched mucosal association with members of Entero­bacteriaceae and Clostridiaceae) in diseased intestines of dogs with chronic enteropathy, including inflammatory bowel disease (IBD) (Suchodolski et al, 2010). Increased numbers of mucosal-associated Enterobacteriaceae also have been associated with clinical signs, up-regulated cytokine expression, and histopathologic lesions in cats with IBD (Janeczko et al, 2008).

Specific Gastrointestinal Disorders Responsive to Antibiotics Enteropathogenic Bacterial Infection A variety of bacterial enteropathogens (e.g., Clostridium difficile, Clostridium perfringens, Salmonella spp., Campylobacter jejuni, and Escherichia coli causing granulomatous colitis in boxers) may cause enteritis or enterocolitis in dogs and cats. Diagnosis of bacterial enteritis is particularly troublesome for clinicians because of the high prevalence of most of these bacteria in healthy animals and the technical difficulties related to successful isolation and identification of pathogenic species. Several of these bacteria (e.g., C. jejuni, Salmonella spp.) have important zoonotic implications. Clinical Findings Animals with bacterial-associated diarrhea may present with clinical signs of small or large intestinal disease or both. Clinical signs are not pathognomonic for a specific bacterial species and they may vary considerably (i.e., from mild, self-limiting diarrhea to fatal hemorrhagic diarrhea) with the same infection in different animals. Large-bowel diarrhea is observed most frequently with active infection. Physical findings often are normal with the exception of rectal examination, which confirms diarrhea, mucoid feces, and fresh blood. Diagnosis Diagnostic strategies for bacterial enterocolitis vary but may include fecal culture, fecal cytology, detection of fecal toxins, ELISA for detection of bacterial antigens, and/or molecular testing (i.e., fecal RT-PCR). Cytologic examination of fecal smears is easy and may be useful  to detect bacteria with specific morphology (i.e., curved rod appearance of Campylobacter spp.), C. perfringens

TABLE 126-1  Treatment Options for Antibiotic-Responsive Enteropathy GI Disorder

Antibiotic

Dosage

Campylobacteriosis

Erythromycin

(D) 10-15 mg/kg PO q8h (C) 10 mg/kg PO q8h 10 mg/kg PO q8h

Tylosin C. perfringens infection

Metronidazole Amoxicillinclavulanic acid

(D) 10 mg/kg PO q12h (C) 62.5 mg PO q12h 12.5-22 mg/kg PO q12h

SIBO/idiopathic ARE

Oxytetracycline Metronidazole Tylosin

10-20 mg/kg PO q8h 10 mg/kg PO q12h 10 mg/kg PO q8h

Idiopathic IBD

Metronidazole Tylosin

10 mg/kg PO q8h 10 mg/kg PO q8h

Tylosin-responsive diarrhea in dogs

Tylosin

25 mg/kg PO q24h

Granulomatous colitis in boxer dogs

Enrofloxacin

5-10 mg/kg PO q24h for 6 weeks

ARE, Antibiotic-responsive enteropathy; D, dogs; C, cats; GI, gastrointestinal; IBD, inflammatory bowel disease; PO, by mouth; SIBO, small intestinal bacterial overgrowth.

endospores, or increased fecal leukocytes suggestive  of active infection. A summary of the most useful diagnostic tests for enteropathogenic bacteria include the following: • C. jejuni: fecal culture • C. difficile: toxin testing by ELISA and organism detection (i.e., culture, antigen ELISA, or RT-PCR) • C. perfringens: enterotoxin ELISA • Salmonella: fecal culture Diagnostic panels in which feces are screened for multiple organisms may be most cost effective and detect coinfections (Weese, 2011). Treatment Treatment recommendations for enteropathogens are largely empiric. For clostridial infections, metronidazole is a convenient and useful antibiotic choice (Table 126-1). Campylobacteriosis in animals with clinical signs may be treated with erythromycin or fluoroquinolone antibiotics. Antibiotic use in salmonellosis is controversial and is indicated only in animals with severe GI disease. The efficacy of probiotics or prebiotics as adjunctive treatments for infectious diarrhea remains unclear.

Small Intestinal Bacterial Overgrowth The original culture-dependent techniques for determination of small intestinal bacterial overgrowth (SIBO) (i.e., ≥105 total CFU/ml or ≥104 anaerobic CFU/ml) revealed results of questionable validity. Now it is realized that

CHAPTER  126  Current Veterinary Therapy: Antibiotic Responsive Enteropathy much higher numbers of enteric bacteria are present in clinically healthy dogs and cats. It is reasonable to assume that GI disorders that diminish host defenses via decreased intestinal motility, decreased gastric acid secretion, or exocrine pancreatic function (e.g., exocrine pancreatic insufficiency [EPI]) may favor bacterial proliferation and the development of secondary SIBO. SIBO is a wellrecognized complication of EPI in dogs unresponsive to enzyme supplementation alone. Clinical Findings Clinical signs in dogs with SIBO include small intestinal diarrhea characterized as watery, fetid, and of large volume, which may be accompanied by alterations in appetite and weight loss. Clinical signs involving extrapancreatic disorders besides EPI reflect the primary organ of involvement. Diagnosis A definitive diagnosis of SIBO is difficult because quantification of bacterial numbers is flawed and indirect tests for microbial growth/metabolism are unreliable (German et al, 2003). Serum cobalamin is the most useful assay because it may detect distal small intestinal (i.e., ileum) disease and the need to treat for this vitamin deficiency. A presumptive diagnosis of SIBO may be made by ruling out other causes for chronic small bowel diarrhea and by showing resolution of clinical signs following antibiotic administration. Treatment The primary treatment for secondary SIBO is correction of the underlying disorder causing enteric microbial imbalances. Bacterial alterations should be assumed polymicrobial and treated with a broad-spectrum antibiotic such as oxytetracycline, metronidazole, or tylosin, which have good efficacy against anaerobic bacteria. The optimal duration of therapy is unknown, but 4 to 6 weeks of antibiotic treatment generally is recommended.

Inflammatory Bowel Disease Associated with Dysbiosis Idiopathic IBD likely results from complex interplay between the mucosal immune system and environmental factors (including the enteric microbiota) in a genetically susceptible host. Direct interaction of the intestinal microbiota with components of the innate immune system is believed to evoke pathologic host responses and intestinal inflammation in humans and animals. Alterations in microbial abundance and composition characterized by reductions in microbial diversity and increased mucosa-associated Enterobacteriaceae have been associated with IBD in dogs and cats (Suchodolski et al, 2010; Janeczko et al, 2008). It is unknown whether these noninvasive microbial perturbations are a cause or consequence of chronic immune-mediated intestinal inflammation. Clinical Findings Clinical signs in affected animals include chronic vomiting, diarrhea, inappetence, or weight loss, and the clinical

521

course may be progressive or intermittent with periodic flares. Diagnosis A diagnosis of IBD is one of exclusion and includes careful integration of patient history, physical examination findings, diagnostic testing to detect GI versus non-GI diseases, and intestinal biopsy for histopathology. Molecular studies for microbial abundance (i.e., 454 pyrosequencing of the 16S rRNA bacterial gene) and mucosal asso­ciation (i.e., fluorescence in situ hybridization [FISH] performed on endoscopic biopsy specimens) have demonstrated microbial imbalances in association with histopathologic inflammation in the intestines of dogs and cats with IBD. Treatment Treatment for IBD is aimed at reducing mucosal inflammation and correcting microbial imbalances contributing to disease pathogenesis. In general, an approach using sequential treatment with diet, select antibiotics, and/or glucocorticoids has proven successful in most case studies. Metronidazole (MTZ) may be used along with steroids or immunosuppressive drugs in animals having moderateto-severe clinical disease.

Tylosin-Responsive Diarrhea in Dogs The term tylosin-responsive diarrhea (TRD) refers to a specific diarrheal syndrome in dogs that responds to tylosin therapy within a few days (Westermarck et al, 2005). In TRD, the stool remains normal as long as  treatment continues, but diarrhea may reappear several weeks after discontinuing the antibiotic. Most affected dogs are young to middle-aged and are medium-sized to giant breeds. The etiology of the diarrhea remains unknown. Clinical Findings Dogs with TRD usually have large bowel diarrhea characterized by increased frequency of defecation, mucus,  and fresh blood in the feces. Physical findings are unremarkable. Diagnosis A diagnosis of TRD is made on rapid resolution of GI signs following the administration of tylosin. Treatment Tylosin administered at 25 mg/kg once daily for 7 days has proven effective in one study (Kilpinen et al, 2011). Intermittent drug therapy may be required in some dogs having recurring GI signs. Long-term diarrhea may be controlled using daily doses of 25 mg/kg.

Granulomatous Colitis AIEC is involved in the pathogenesis of granulomatous colitis in susceptible boxer dogs as well as some other breeds. Identification and appropriate antibiotic therapy are effective in resolution of the disease in most cases (see Chapter 134).

522

SECTION  VI  Gastrointestinal Diseases

References and Suggested Reading German AJ et al: Comparison of direct and indirect tests for small intestinal bacterial overgrowth and antibiotic-responsive diarrhea in dogs, J Vet Intern Med 17:33, 2003. Hall E: Antibiotic-responsive diarrhea in small animals, Vet Clin North Am Small Anim Pract 41:273, 2011. Janeczko S et al: The relationship of mucosal bacteria to duodenal histopathology, cytokine mRNA, and clinical disease activity in cats with inflammatory bowel disease, Vet Microbiol 128:178, 2008. Johnston KL et al: Effects of oral administration of metronidazole on small intestinal bacteria and nutrients of cats, Am J Vet Res 61:1106, 2000. Johnston KL et al: Comparison of the bacterial flora of the duodenum in healthy cats and cats with signs of gastrointestinal tract disease, J Am Vet Med Assoc 218:48, 2001. Kathrani A et al: Polymorphisms in the TLR4 and TLR5 gene are significantly associated with inflammatory bowel disease in German shepherd dogs, PLoS ONE 5:e15740, 2010.

CHAPTER 

Kilpinen S et al: Effect of tylosin on dogs with suspected tylosinresponsive diarrhea: a placebo-controlled, randomized, doubleblinded, prospective clinical trial, Acta Vet Scand 53:26, 2011. Simpson K et al: Adherent and invasive Escherichia coli is associated with granulomatous colitis in boxer dogs, Infect Immun 74:4778, 2006. Suchodolski JS et al: Molecular analysis of the bacterial microbiota in duodenal biopsies from dogs with idiopathic inflammatory bowel disease, Vet Microbiol 142:394, 2010. Suchodolski JS: Companion animals symposium: microbes and gastrointestinal health of dogs and cats, J Anim Sci 89:1520, 2011. Weese JS: Bacterial enteritis in dogs and cats: diagnosis, therapy, and zoonotic potential, Vet Clin North Am Small Anim Pract 41:287, 2011. Westermarck E et al: Tylosin-responsive chronic diarrhea in dogs, J Vet Intern Med 19:177, 2005.

127 

Cobalamin Deficiency in Cats KENNETH W. SIMPSON, Ithaca, New York PAUL A. WORHUNSKY, Ithaca, New York

G

astrointestinal disease may decrease the availability of a number of micronutrients, such as vitamins and minerals, with important consequences for the pathogenesis, diagnosis, and treatment of gastrointestinal disease. Measuring the serum concentration of cobalamin (CBL) aids in the detection of gastrointestinal disease, guides therapeutic intervention, and informs prognosis in cats.

Cobalamin Absorption Metabolism of CBL in cats is very different from that in people. CBL homeostasis is a complex, multistep process that involves participation of the stomach, pancreas, intestines, and liver (Figure 127-1). After ingestion, CBL is released from food in the stomach. It then is bound to a nonspecific CBL-binding protein of salivary and gastric origin called haptocorrin. Intrinsic factor (IF), a CBL-binding protein that promotes CBL absorption in the ileum, is produced by the pancreas, not the stomach, in cats. In contrast, humans produce only gastric IF, and deficiency usually is associated with atrophic gastritis and the resultant lack of gastric IF production. The affinity of CBL for haptocorrin is high at acid pH, so most CBL is bound to haptocorrin in the

stomach. Upon entering the duodenum, haptocorrin is degraded by pancreatic proteases, and CBL is transferred from haptocorrin to IF, a process facilitated by the high affinity of IF for CBL at neutral pH. Cobalamin-IF complexes traverse the intestine until they bind to specific receptors (previously called intrinsic factor cobalamin receptor [IFCR] but recently dubbed cubilin) located in the microvillus pits of the apical brush-border membrane of ileal enterocytes. CBL then is transcytosed to the portal bloodstream bound to a protein called transcobalamin 2 (TC II), which mediates CBL absorption by target cells. A portion of CBL taken up by hepatocytes is thought to be reexcreted rapidly in bile bound to haptocorrin. CBL of hepatobiliary origin, in common with dietary-derived CBL, is thought to undergo transfer to IF and receptormediated absorption, thus establishing enterohepatic recirculation of the vitamin. This situation of rapid turnover means that cats with CBL malabsorption can deplete totally their body CBL stores within 1 to 2 months. The half-life of exogenous parenteral CBL was 13 days in healthy cats as compared with 5 days in cats with GI disease. This is completely different from people, in whom CBL depletion may take several years, possibly because of the presence of long-term storage enabled by the CBL-binding protein TCI, which is absent in cats.

CHAPTER  127  Cobalamin Deficiency in Cats

523

by boiling the sample. The Immulite assay also has been shown to correlate with the RIA. Hemolyzed blood samples also affect test performance.

Cbl Cbl-R

Liver Cbl-R Pancreas IF Cbl-TCII R Cbl-IF

Figure 127-1  The pathway of cobalamin absorption involving

the gastrointestinal tract, pancreas, and liver. Cbl, Cobalamin; Cbl-R, cobalamin bound to haptocorrin; Cbl-IF, cobalamin bound to intrinsic factor; Cbl-TCII, cobalamin bound to transcobalamin 2; IF, intrinsic factor.

TABLE 127-1  Factors Influencing Serum Concentrations of Cobalamin in Cats Increase

Decrease

High dietary content

Dietary deficiency

Parenteral supplementation

Inflammatory bowel disease

*Cholestatic liver disease

Alimentary lymphoma (multicentric lymphoma†) Exocrine pancreatic insufficiency Pancreatitis* Cholangitis* Hyperthyroidism* Intestinal bacterial utilization† Receptor abnormality†

*Recognized disease association, pathomechanism unclear. †Theoretic cause not adequately documented in cats.

Serum concentrations of CBL are labile and reflect  the balance between dietary intake, bacterial use and  production, intestinal absorption, and body losses.  Factors influencing serum CBL in cats are summarized in Table 127-1.

Measurement of Serum Cobalamin CBL can be measured using a bioassay, radioimmunoassay (RIA), or an Immulite assay. The bioassay was the original method used and has been shown to correlate with RIA. In the RIA method an assay must be used  that denatures endogenous CBL-binding proteins, usually

Interpretation of Serum Cobalamin Concentrations Normal reference ranges for CBL in cats may differ greatly between laboratories. This can have a substantial impact on diagnosing the presence of subnormal CBL and determining the prevalence of subnormal CBL in cats (see below). The interpretation of circulating CBL concentrations with regard to small intestinal disease is valid only if exocrine pancreatic insufficiency, dietary CBL supplementation, or parenteral administration has been excluded. Furthermore, dietary vitamin content of the diet warrants attention. Finding a low CBL concentration is useful in supporting the presence of an intestinal disorder. When low CBL is detected and exocrine pancreatic insufficiency (EPI), intestinal obstruction, or a stagnant loop has been excluded, localization of the problem to the ileum can  be inferred. Simultaneous evaluation of CBL and folate  do not distinguish reliably the type of intestinal disease  in cats. Concomitant increases in folate and CBL are  most consistent with high dietary intake, supplementation, and hemolysis. The authors have observed high  CBL concentrations in some cats with cholestatic liver disease in the absence of parenteral supplementation. Finally, normal serum concentrations of CBL neither exclude nor support a diagnosis of intestinal disease.

Diseases Associated with Subnormal Serum Cobalamin Gastrointestinal Disease Subnormal serum CBL concentrations have been reported most frequently in middle-aged cats presented for investigation of suspected gastrointestinal disease. Predominant clinical findings associated with low serum CBL concentration are weight loss, diarrhea, vomiting, anorexia, lethargy, and thickened intestines. Low serum CBL was linked to body condition score and abnormalities in hematologic and serum biochemical variables such as increased mean corpuscular volume (MCV) and reduced serum phosphorous in some studies (Reed, Gunn-Moore, and Simpson, 2007; Simpson et al, 2001). The types of gastrointestinal disease associated with subnormal serum CBL concentrations include inflammatory bowel disease (IBD), intestinal lymphoma, cholangiohepatitis or cholangitis, pancreatitis, and exocrine pancreatic insufficiency. This diverse spectrum of diseases is thought to reflect the involvement of pancreas, intestine, and liver in feline CBL homeostasis as depicted in Figure 127-1. The prevalence of low serum CBL reported in cats  with signs of gastrointestinal disease ranges from 0.1% to 78%. This large variation is potentially a consequence of the assay used, the reference intervals for normal values,  the patient population, and the geographic location. In single-disease studies, prevalence of low CBL concentration is particularly high in cats with EPI (10/10 evaluated)

524

SECTION  VI  Gastrointestinal Diseases

and 78% of 32 cats with GI lymphoma. In the first  study to examine CBL deficiency in cats, 49 out of 80  cats (61%) had a serum CBL concentration below the reference range (900 to 2800 pg/ml; mean ± SD = 1775 ± 535 pg/ml SD; n = 33) using a RIA that correlated with the bioassay (Simpson et al, 2001). Conversely, in a recent British study only 11 out of 39 cats (28.2%) had a CBL concentration below the reference range (290 pg/ml) using an Immulite assay (Maunder et al, 2012). To examine the source of this variability, the authors reanalyzed the original data set from U.S. cats using the 290 pg/ ml cutoff. This yielded a prevalence of 27%. Given the correlation between the RIA and Immulite assays, this suggests that differences in reference ranges between different studies using validated CBL assays have a major impact on the identification of cats with subnormal CBL concentrations. The cause of this variation in reference intervals (e.g., age of cats, presence or absence of occult GI disease, and geographic location [northern vs. southern United States, or Australia vs. United Kingdom]) remains to be determined.

Nongastrointestinal Disease Low serum CBL recently has been described in cats with hyperthyroidism. Whether hyperthyroidism alone or with concurrent GI disease is responsible for low levels remains to be determined. In people and dogs multicentric lymphoma has been associated with low CBL. This may reflect use of CBL by rapidly dividing cells. Whether this occurs in cats has not been determined. Relationship Between Low Serum Cobalamin and Cobalamin Deficiency CBL is an essential cofactor for the activity of methylmalonyl-CoA mutase and methionine synthase. In people, reduced activity of these two enzymes causes the  biochemical signatures of CBL deficiency, methylmalonicacidemia/methylmalonicaciduria (MMA) and homocysteinemia/homocysteinuria. Cats with undetectable or subnormal serum CBL concentrations have increased serum concentrations of MMA but not homocysteine. In one study, 68% of cats with a CBL less than 290 pg/ml had elevated MMA concentrations but normal homocysteine. Cats with elevated MMA also had substantial disturbances in amino acid metabolism, compared with healthy cats, with significantly increased serum concentrations of methionine (133.8 versus 101.1 µmol/L) and significantly decreased serum concentrations of cystathionine (449.6 versus 573.2 nmol/L) and cysteine (142.3 versus 163.9 µmol/L). Furthermore, treatment of CBLdeficient cats having high MMA concentrations with parenteral CBL resulted in a reduction in MMA concentrations and weight gain. Cats with the largest decrease in MMA concentration gained the most weight. These studies illustrate that measurement of serum CBL is a useful marker of GI disease and that treatment of cats with CBL deficiency diagnosed on the basis of elevated MMA is of therapeutic benefit. Because MMA is not measured routinely in most clinical laboratories, it would be of practical value to know the serum CBL concentration at which CBL deficiency develops (i.e., the

point at which cats would benefit from treatment with parenteral CBL). Initial studies conducted in cats with subnormal CBL concentrations (defined as 95% for carbohydrates and fat in the diet) and contain more than 20% to 25% protein (on

a dry matter [DM] basis, not necessarily novel, but may be considered if IBD is a component), less than 10% to 15% fat (this number may have be to significantly lower in severely affected dogs), and less than 5% insoluble dietary fiber. Soluble fibers (e.g., fructooligosaccharides, inulin, guar gum) may be beneficial to the GI tract in typical amounts and should not be excluded, but insoluble fibers, such as cellulose or other poorly digestible fibers intended for weight loss or fecal bulking purposes, should not be a major component of the diet because they reduce nutrient digestibility. Commercially available veterinary prescription products vary widely in amount of protein and fat in the diet; this is especially true in novel or hydrolyzed diets that are not formulated specifically for severe intestinal disease. Currently, Royal Canin’s Gastrointestinal Low Fat diet, which contains 7% fat DM and chicken as the protein source, is the diet lowest in fat and most highly digestible that is available commercially. See Table 132-1 for a comparison of the protein and fat levels of selected diets used in dogs with PLE. In many dogs with PLE, a commercially available, highly digestible diet often works well for dietary control of the disease. However, in the most severely affected dogs, nontraditional therapy using homemade diets or adding nutritional modules (elemental diets developed for human enteral nutrition) may be needed. Human elemental diets are not complete and balanced for dogs, so they can be used only short term or in addition to other diets. However, these can be very effective during the initial stages of therapy, because they require minimal digestive function for the nutrients to be absorbed. Once the dog’s albumin is stabilized (not necessarily normal), a gradual transition back to a commercial diet or a combination of commercial food and special diet can be made for long-term control. Although many elemental diets are on the market, only a few are low in fat and moderate to high in protein. (Note: There are many high-protein modules, but most are also high-fat recovery diets and therefore are not acceptable for dogs with PLE.) The one most commonly used product in the author’s practice is Vivonex TEN (15% protein, 3% fat) (www.Nestle-nutrition.com), but other products in that same line also may be considered: Vivonex Plus (18% protein, 6% fat), Vivonex RTF (20% protein, 10% fat), or Tolerex (8% protein, 2% fat). All of these elemental diets have 100% free amino acids as the protein source, all are lactose and gluten free, and all have added glutamine and arginine for gut health. However, they are not complete and balanced diets for dogs, so they must be used short term (a few weeks) if they are fed alone (uncommon in the author’s practice), or they must be fed as a supplement with a balanced diet to prevent development of vitamin and mineral imbalances. None of these diets contain an adequate amount of protein, amino acids (e.g., taurine, arginine), and fatty acids (arachidonic acid) to meet the nutritional needs of cats and should NOT be used in cats. An alternative approach is to feed a homemade diet containing highly digestible but very low-fat protein sources, such as low-fat turkey breast, cooked egg whites, and nonfat cottage cheese. There are many potential options for this approach. Seeking the advice and counsel of a nutrition specialist is important to help with recipe

CHAPTER  132  Protein-Losing Enteropathies

543

TABLE 132-1  Comparisons of Selected Highly Digestible, Hypoallergenic, and Hydrolyzed Diets Used in the Management of Protein-Losing Enteropathies in Dogs % Protein Dry*

% Protein Can*

% Fat Dry*

Royal Canin Digestive Low Fat

20.5

16.7

5.0

3.4

Chicken, pork

Hill’s Prescription Diets i/d

26.5

27.8

14.1

14.3

Chicken, egg

Hill’s Prescription Diets i/d low fat

25.9

25.1

7.4

8.5

Purina Veterinary Diets EN

23

—

10.5

—

Chicken

P&G Iams Low Residue

24.6

33

10.7

18.9

Chicken

Royal Canin Hypoallergenic HP

19

—

17

—

Soy protein isolate

Hill’s Prescription Diet z/d

19

19.5

13.9

13.9

Chicken

Purina Veterinary Diets HA

18

—

—

Soy protein isolate

Royal Canin Hypoallergenic PD

19

17.7

10.5

16.7

Duck

Royal Canin Hypoallergenic PV

19.5

16.7

10

11.7

Venison

Royal Canin Hypoallergenic PR

19.5

18.4

10.5

13.3

Rabbit

Hill’s Prescription Diet d/d duck

18

17.4

16.7

16.6

Duck

Hill’s Prescription Diet d/d salmon

18.4

18.9

15.5

14.8

Salmon

Purina Veterinary Diets DRM

24

—

12

—

Salmon/trout

8.0

% Fat Can*

Protein Source

Chicken/turkey, pork

*Dry matter basis.

planning and evaluation of any homemade diets, especially if the diet is needed long term or as a primary source of nutrition for the dog. Another approach is to use recipes published for these specific purposes that have been generally approved by nutrition specialists. One such book containing a number of user-friendly and easyto-prepare recipes for dogs with GI disease is HomePrepared Dog and Cat Diets, second edition, by P. Schenck (Wiley Blackwell, 2010). Finally, in addition to the above considerations, many dogs are hypocobalaminemic and require cyanocobalamin injections to replenish and maintain their vitamin B12 levels using well-established doses for lifelong supplementation. Other vitamins, particularly the fat-soluble vitamins D, E, and K, may become deficient in dogs with severe PLE. Measuring serum retinol, ionized calcium, and calcitriol levels before starting vitamin A or calcitriol therapy is recommended, because oversupplementation can be very harmful. Supplementation of vitamin E is unlikely to be harmful; 300 IU vitamin E can be injected IM and is sufficient for 2 to 3 months. Vitamin K is required for proper functioning of clotting factors 2, 7, 9, and 10 of the clotting cascade and can be assessed by measurement of the prothrombin time (PT). If the PT is prolonged in dogs with severe PLE, injections of vitamin K1 (Mephyton, 1 mg/kg/day SC once every 3 to 5 days) are sufficient to prevent bleeding until the GI disease is stabilized.

Oncotic Support Improvement of the dog’s nutritional status and use of high-protein, low-fat diets help tremendously to increase serum protein levels and provide oncotic support to

reverse the leakage of fluid out of vessels. However, in many severely affected dogs, the hypoproteinemia has been so severe and chronic that stabilization of the dog is essential before diagnostic evaluation or further treatment. In those dogs, colloid therapy using hydroxyethyl starches (Hetastarch or the new veterinary product Vetstarch) at a dose of 5 to 20  ml/kg/day IV infusion can be effective in pulling edema fluid back into the vascular space and holding it there for short periods of time  (Chan, 2008). This can be especially helpful before endoscopic procedures in reducing the gut mucosal edema that often can complicate the anesthetic and biopsy process and help improve the digestive process by reducing the barrier to uptake of nutrients from the GI lumen. Alternatives to synthetic colloids, such as administration of plasma as a source of albumin and a colloid to increase colloid oncotic pressure, have been advocated in the past. However, the volume of plasma required to have any impact on the serum albumin level at all is substantial. In an example, a dog weighing 20  kg and having a serum albumin of less than 1.0  g/dl received more than 10 units (100  ml/unit, 1000  ml plasma) of canine plasma over a 36-hour period, more than 2.5 times the recommended amount of plasma. The albumin reached only 1.0  g/dl and then dropped immediately after the plasma was discontinued. Further, recent studies have shown that plasma administration in dogs with severe panhypoproteinemia does not substantially improve oncotic pressure compared with synthetic colloids (Chan, 2008). However, although improving oncotic pressure is important in the short term, ultimately it requires stabilization of the GI tract to reduce ongoing losses and increase protein uptake to reverse the disease effects and stabilize the dog. This involves

544

SECTION  VI  Gastrointestinal Diseases

finding the appropriate diet and using antiinflammatory drug therapy.

Reducing Intestinal Inflammation Whether or not PLE in a particular dog is associated with IBD (see Chapter 131), which it often is, the leakage of lymph and protein into villous spaces surrounding the lacteals causes inflammation and granuloma formation. Lipogranulomas may cause further lymphatic obstruction and thus increased lymph leakage through the gut wall. Aggressive antiinflammatory therapy is the only known treatment for the inflammation associated with lymphatic leakage and granuloma formation, and immunosuppressive doses of prednisone (2 to 4 mg/kg q48h PO) have been the standard approach. Unfortunately, highdose steroid therapy has a number of potential adverse effects that are detrimental, and in the case of hypoproteinemic patients with poor oncotic support, addition of a drug that causes significant polydipsia and its resultant increases in free water can result in dramatic worsening (or lack of improvement) in edema or ascites. As a result, use of other immunosuppressive or antiinflammatory drug therapies has been considered more often. To date, no controlled studies in dogs with PLE compare the therapeutic effectiveness of azathioprine to cyclosporine or mycophenolate; however, each of these drugs has been used with varying degrees of success in dogs with PLE. The drug currently recommended most commonly as the next drug of choice, based on its effectiveness in a small number of dogs with PLE and IBD and its relative lack of severe side effects, is cyclosporine at a dose of 5 mg/kg q12h PO (Allenspach et al, 2006). Azathioprine also is used for its multimodal immunosuppressive effects but must be started together with prednisone, because a period of 2 to 3 weeks on the drug is needed to achieve steady state therapeutic levels. The most commonly recommended dose is 1 mg/kg q24h PO for 5 days then q48h PO thereafter. The most common side effects associated with the use of azathioprine are development of a hepatopathy, bone marrow suppression, or pancreatitis. The most common adverse effect of cyclosporine therapy is development of a secondary infection (often times fungal). Because many dogs require long-term therapy to control their disease, this can be a significant factor. As in humans with PLE, dogs may develop dysbiosis (disruption of the enteric microbiota) as either a trigger for the disease or as a result of the disease. However, it is unusual for antibiotic therapy alone to be effective in the management of PLE without appropriate dietary and antiinflammatory therapies already in place. Further, dysbiosis frequently can be resolved with improvement in gut function, reduction of protein leakage, and feeding highly digestible diets that minimize maldigestion. The most commonly used antibiotics in dogs with chronic enteropathies are metronidazole (10 to 15 mg/kg q12h PO) or tylosin (10 to 20 mg/kg q12h PO), and these remain appropriate choices. Other antibiotics should be used judiciously and only when cultures, antigen, or PCR testing indicates pathogen overgrowth requiring intervention. Finally, to date, no studies have been published

using probiotic therapy as an adjunct to the overall management of dogs with PLE, but the use of probiotics would seem reasonable and prudent (see Chapter 128).

Preventing Complications of Protein-Losing Enteropathies The most important complication of dogs with PLE is their tendency to be hypercoagulable (because of antithrombin deficiency and other factors) and prone to development of thromboembolic disease. Because there is no effective clot removal therapy in dogs, the best approach is to use preventive therapy when indicated  to lessen the risk of clot formation. In hospitalized dogs  with severe antithrombin deficiency, administration of fresh frozen plasma and heparin may provide temporary replacement of the anticlotting proteins to prevent development of massive thrombosis. However, for long-term therapy, this is completely impractical. Thus, in all dogs with PLE and especially those with thrombocytosis (such as many Yorkshire terriers) and decreased levels of antithrombin, anticoagulant therapy with aspirin (10 mg/kg q24h PO) or clopidogrel (2 to 4 mg/kg q24h PO) is indicated. The dose for aspirin indicated above is higher than previously reported but results from new studies that reveal a higher dose is required to achieve consistent antiplatelet effects. Gastroprotection is indicated because this dose may cause GI ulceration (Goodwin et al, 2011). Because dogs with PLE often have disease recurrence or fluctuations in their level of control, all dogs with PLE should have frequent reassessment (every 3 to 6 months) of their protein values, coagulation status, fat-soluble vitamin and cobalamin levels, and overall health because this is the best way to make appropriate adjustments in therapy.

References and Suggested Reading Allenspach K et al: Pharmacokinetics and clinical efficacy of cyclosporine treatment of dogs with steroid-refractory inflammatory bowel disease, J Vet Intern Med 20:239, 2006. Berghoff N et al: Gastroenteropathy in Norwegian Lundehunds, Compend Contin Educ Vet 29:456, 2007. Casamian-Sorrosal D et al: Comparison of histopathologic findings in biopsies from the duodenum and ileum of dogs with enteropathy, J Vet Intern Med 24: 80, 2010. Chan DL: Colloids: current recommendations, Vet Clin North Am Small Anim Pract 38:587, 2008. Dossin O, Lavoue R: Protein losing enteropathies in dogs, Vet Clin North Am Small Anim Pract 41:399, 2011. Gaschen L et al: Comparison of ultrasonographic findings with clinical activity index (CIBDAI) and diagnosis in dogs with chronic enteropathies, Vet Radiol Ultrasound 48:51, 2007. Goodwin LV et al: Hypercoagulability in dogs with protein losing enteropathy, J Vet Intern Med 25:273, 2011. Littman MP et al: Familial protein losing enteropathy and protein losing nephropathy in Soft Coated Wheaten Terriers: 222 cases, (1983-1997), J Vet Intern Med 14:68, 2000. Shales CJ et al: Complications following full thickness small intestinal biopsy in 66 dogs: a retrospective study, J Small Anim Pract 46:317, 2005. Willard MD et al: Intestinal crypt lesions associated with protein losing enteropathy in a dog, J Vet Intern Med 14:298, 2000.

CHAPTER 

133 

Feline Gastrointestinal Lymphoma KEITH P. RICHTER, San Diego, California

Epidemiology

Gross Pathologic Findings

Lymphoma is the most frequently diagnosed feline cancer and the most common gastrointestinal (GI) neoplasm in cats (Rissetto et al, 2011). Lymphoma occurs in several anatomic locations; the GI tract is the most common site, accounting for 32% to 72% of total cases. Discrepancies in the reported incidence of the various forms of lymphoma may be the result of the differences in classification schemes used, a change in incidence over time, differences in feline leukemia virus (FeLV) subtypes in various geographic areas, and a decreased incidence of non-GI forms since the introduction of an FeLV vaccine. An increase in the proportion of lymphoma of the GI tract over time is apparent by comparing incidences in the same institutions over different time periods. For example, in the New England area the percentage of lymphomas in cats that occurred in the GI tract increased from 8% in 1979 to 18% in 1983 and to 32% in 1996 (Francis et al, 1979; Cotter, 1983; Moore et al, 1996). Likewise, in the New York City area the percentage increased from 27% in 1989 to 72% in 1995 (Mooney et al, 1989; Mauldin et al, 1995). This increased incidence in the GI form over time could be due to a decreased incidence of FeLV infection, and therefore fewer cats died at a young age secondary to FeLV-induced diseases. Thus more cats are living longer, and they may then develop the GI form. Another explanation is that cats may be undergoing more complete evaluations more recently than in the past. The association between FeLV and lymphoma in cats is well established. The incidence of FeLV antigenemia in cats with GI lymphoma ranges from 0 to 38%. However, such estimation of FeLV infection rate is influenced significantly by the method of testing. Underestimation of FeLV incidence with immunohistochemistry (IHC) versus polymerase chain reaction (PCR) has been suggested. In one study PCR testing detected FeLV viral nucleic acid sequences in up to 63% of cats with GI lymphoma, whereas only 38% of cats were positive by IHC (Jackson et al, 1993). Generally cats with leukemia or mediastinal lymphoma tend to be young and FeLV positive, whereas those with GI lymphoma typically are older and FeLV antigen negative. An association between lymphoma and feline immunodeficiency virus (FIV) also has been proposed, especially when coinfected with FeLV, although most cats with GI lymphoma in the author’s experience are negative for FIV exposure.

The gross appearance of feline GI lymphoma varies with the specific anatomic location. Many segments of the GI tract, including the liver, may be involved. There can be a focal mass or diffuse infiltration. In some cases, especially with low-grade lymphocytic lymphoma, the gross appearance may be normal. When a focal alimentary tract mass is present, there is usually transmural thickening with or without mucosal ulceration. Mural thickening is often eccentric, resulting in preservation of the lumen, although a functional obstruction may develop. This contrasts with intestinal carcinoma, which often results in a mechanical obstruction from decreased luminal diameter, often appearing as a “napkin ring.” With diffuse infiltration the intestinal wall may be visibly and/or palpably thickened. Mesenteric lymphadenopathy is often obvious grossly or on ultrasonographic examination. Intussusception can develop secondary to intestinal lymphoma; the jejunum is the most common location. Hepatic involvement can have a variable appearance. In some cases the liver appears to be grossly normal, whereas in others there may be an enhanced lobular pattern, a mottled appearance, or a gross nodular appearance. In summary, the appearance of lymphoma is extremely variable in all regions of the GI tract. In light of how commonly this neoplasm develops in cats, lymphoma should be considered as a differential diagnosis for GI illness with normal or grossly abnormal organ appearance.

Histopathology and Immunohistochemistry There are different grades of GI lymphoma, commonly referred to as low grade (lymphocytic or small cell), high grade (lymphoblastic, immunoblastic, or large cell), and intermediate grade. Less common descriptions such as large granular lymphocytic lymphoma also exist (which behave in a manner similar to high-grade lymphoma). Many published reports are either of undetermined grade or predominantly high-grade lymphomas, although lowgrade lymphocytic lymphomas have been described more recently in large case series (Fondacaro et al, 1999; Kiselow et al, 2008; Moore et al, 2012; Stein et al, 2010). In the study by Fondacaro et al (1999) 50 of 67 cats (75%) diagnosed with GI lymphomas had low-grade lymphocytic lymphoma. Criteria used to classify lymphoma as lymphocytic have been described (Fondacaro et al, 1999; Moore et al, 2012). In marked contrast to palpable masses 545

546

SECTION  VI  Gastrointestinal Diseases

of lymphoblastic lymphoma, masses formed by lymphocytic lymphoma are not distinct microscopically, because the mucosa beyond the apparent mass also is involved. The use of a standard grading scheme for GI lymphoma may lead to a greater recognition of low-grade lymphocytic lymphoma. However, criteria have been difficult to establish because of the difficulty in interpreting small endoscopic biopsies, differences in pathologists’ opinions, a lack of characterization using IHC, and only recent availability of polymerase chain reaction (PCR) clonality studies (see Chapter 65). Consequently further studies are needed to define specific criteria for differentiating lymphocytic lymphoma, lymphocytic inflammation, and T-cell infiltrative disease and to correlate such classifications with clinical outcome. In addition, the role of endoscopic biopsies versus full-thickness biopsies must be better defined. The results of one study suggested that surgical biopsies are superior to endoscopic biopsies for the detection of GI lymphoma (Evans et al, 2006). However, many cats in that study did not have their duodenum entered endoscopically (many were blind biopsies), few biopsies were obtained, the quality of the biopsies were not described, histologic grading was not reported, and clonality studies were not performed. Many pathologists are comfortable making the diagnosis on endoscopic biopsy analysis, whereas others believe that full-thickness biopsies are necessary. The author relies heavily on the analyses of endoscopic biopsies in his practice. Although it is customary to consider a continuum from inflammatory bowel disease to lymphoma, there are little supporting data. Recently IHC has been used to better characterize feline lymphoma. In some studies GI lymphomas were more likely to be of B cell rather than T-cell phenotype, whereas other studies describe a predominantly T-cell phenotype. Notably, most cats with low-grade GI lymphoma have a T-cell phenotype. In a limited number of studies immunophenotype did not appear to correlate with response to chemotherapy treatment or survival, although more recently one study reported a better outcome in cats having the T-cell phenotype (Moore et al, 2012). Thus further study is necessary to determine the clinical value of immunophenotyping. More recently, detection of lymphoid neoplasia has been accomplished by detecting antigen receptor gene rearrangements. This method is especially useful to determine if the lymphocyte population is monoclonal or oligoclonal (thus suggestive of lymphoma) versus polyclonal (which is more suggestive of inflammation). It is especially helpful to detect the presence of low-grade lymphoma when present concurrently with inflammatory disease. This technique employs PCR to amplify the hypervariable regions of immunoglobulin or T-cell receptor genes. In the absence of neoplasia, this region differs from cell to cell. Amplifying this region can help determine if the products are monoclonal (or oligoclonal) or polyclonal based on their appearance on polyacrylamide gel electrophoresis. This method has been named PARR (PCR for antigen receptor rearrangements) or TCRG (T-cell receptor gamma gene rearrangements). This appears to  be a more sensitive and objective method for detection of lymphoma (especially the low-grade form or in less

severe lesions) compared with conventional histopathology (Moore et al, 2005; Moore et al, 2012). In one study, detection of TCRG rearrangements had a 91% sensitivity in detecting mucosal T-cell lymphoma regardless of the severity of the lesion (Moore et al, 2012).

Clinical Findings Signalment In some studies, males appear to be predisposed to GI lymphoma. Although a breed predilection is not apparent, most cats are domestic shorthair. The median age ranges from 9 to 13 years in different studies, with an age range spanning from 1 to 18 years (although most cats are older than 6 years).

Clinical Signs and Physical Examination Findings Regardless of the histologic grade, clinical signs include weight loss, anorexia, vomiting, diarrhea, lethargy, and polydipsia/polyuria. Importantly, many cats have minimal or no vomiting and/or diarrhea, with anorexia, weight loss, or both as the only historical findings. Therefore, when confronted with these signs in a geriatric cat with an otherwise unrewarding initial evaluation, clinicians should consider GI lymphoma as a differential diagnosis. Physical findings may include poor body condition, thickened intestinal loops, and/or a palpable abdominal mass. The presence of an abdominal mass is more suggestive of high-grade lymphoma. Notably many cats may have a normal abdominal palpation.

Ancillary Test Findings Laboratory findings generally are noncontributory, with mild anemia and/or hypoalbuminemia most commonly seen. Up to 78% of cats with low-grade GI lymphoma have hypocobalaminemia, so measurement of serum cobalamin concentrations should be included in the database of cats with suspected lymphoma (Kiselow et  al, 2008). Abnormalities on plain abdominal and thoracic radiographs are also uncommon and usually nonspecific. An abdominal ultrasound examination may be helpful  in many cases and is considered more sensitive than radiography. Lesions can be nodular (focal or multifocal) or diffuse. Although the most common ultrasonographic abnormality observed is thickening of the gastric or intestinal wall, other important findings include loss of normal intestinal wall layering, localized mass effects associated with the intestine, decreased intestinal wall echogenicity, regional hypomotility, regional lymphadenopathy, and rarely ascites. The finding of a thickened and prominent muscularis layer of the intestine is also a feature suggestive of lymphoma and less commonly seen with inflammation. Because ultrasonography provides information about the specific site of involvement of the lesion as well as other abdominal organs, it assists in staging the regional extent of disease and in screening for concurrent disorders. It also allows for precise guidance of fine-needle aspiration or biopsy for cytologic or

CHAPTER  133  Feline Gastrointestinal Lymphoma histopathologic sampling, and it can be used to assess response to therapy noninvasively and objectively. A limitation of ultrasonography is the difficulty in assessing the exact anatomic location and extent of certain lesions, possibly because of the inability of ultrasound waves to penetrate gas-filled structures, such as the bowel, and lack of distinct fixed anatomic landmarks. Furthermore, ultrasonography results depend on the operator, operator’s level of experience, and ultrasound system. Findings also may be normal, especially in cases of low-grade lymphoma. Endoscopy can be an effective tool for diagnosing GI mucosal lymphoma when involved areas are within reach of an endoscope. It is critical that the small intestine be examined with endoscopy because there is significant evidence for a predisposition for the small intestine for lymphoma compared with the stomach or large intestine (Fondacaro et al, 1999; Moore et al, 2012; Rissetto et al, 2011). The results of one retrospective study suggested that simultaneous sampling of the upper small intestine and the ileum (rather than just upper GI endoscopy alone) may increase the detection rate for low-grade lymphoma (Scott et al, 2011). Another study showed a higher incidence of mucosal T-cell lymphoma in the jejunum compared with the duodenum or ileum (Moore et al, 2012). Most gross endoscopic findings are nonspecific, with considerable overlap with inflammatory bowel disease and other GI diseases. In many cases the endoscopic appearance can be grossly normal.

Treatment Reports of treatment strategies for feline GI lymphoma are fairly limited, and only a few of these reports give detailed results in cats specifically with GI lymphoma. In addition, the outcome for different forms of GI lymphoma remains ill-defined because many reports do not describe histologic grade or the results of complete anatomic staging; they report various anatomic locations collectively, and different combinations of chemotherapeutic agents were used. A summary of reported treatments and outcomes  in cats with GI lymphoma is provided in Table 133-1.  Few studies have evaluated outcome by histologic  grade; however, those evaluating high-grade lymphomas only generally report poor outcomes (Fondacaro et al, 1999; Mahony et al, 1995; Moore et al, 2012). In general, response rates for high-grade GI lymphoma are in the  25% to 50% range, with reported median survival times (MSTs) of 2 to 9 months. The poor outcomes reported in some older studies for which grades were not specified likely were for high-grade lymphomas. For cats with highgrade GI lymphoma, combining doxorubicin with other agents in a multiagent protocol such as cyclophosphamide/vincristine (Oncovin)/prednisolone (CHOP) and L-­ asparaginase is associated with longer remission and survival times when compared with single-agent doxo­ rubicin or COP alone. A few large case series describe outcomes in cats with just the low-grade form of the disease, demonstrating a much better outcome compared with the high-grade form (Fondacaro et al, 1999; Kiselow et al, 2008; Moore

547

et al, 2012; Stein et al, 2010). In these studies, cats were treated with a relatively low-grade chemotherapy protocol of prednisone and chlorambucil (Leukeran). Depending on the study, prednisone generally was given at doses ranging from 5 to 10 mg per day. Chlorambucil was administered at a high pulse dose of 15 mg/m2 of body surface area PO q24h for 4 days, repeated every 3 weeks (Fondacaro et al, 1999), at a low every-other-day dose of 2 mg/cat (Kiselow et al, 2008), or at a lower pulse dose of 20 mg/m2 of body surface area PO once every 2 weeks. For all these regimens, the results were similar. Remission rates for the low-grade form vary from 69% to 96%, with median remission duration varying from 23 to 30 months for those cats that achieve a complete remission. However, it is unknown whether these cats would do better with a more aggressive multiagent protocol. Adverse reactions to chlorambucil are uncommon but can include self-limiting vomiting, diarrhea, anorexia, lethargy, and neutropenia. It may be difficult to distinguish some of these chemotherapy-related side effects from active or progressive lymphoma. Cats rarely require hospitalization or discontinuation of therapy. Neurologic side effects (including myoclonus and seizures) also have been described in cats receiving chlorambucil, but these are rare. The author currently recommends 10 mg prednisolone (because of more reliable pharmacokinetics in cats compared with prednisone) q24h PO and 2 mg chlorambucil q48h PO (which is much simpler for clients to understand than pulse dose therapy). For smaller cats or those that do not tolerate chlorambucil well, the author decreases the frequency of administration to every 3 days. For cats in which administration of oral medication is difficult, the high pulse dose regimen of chlorambucil (or even cyclophosphamide; see below) can be used to decrease the frequency of oral medications. In addition, the author has used injections of methylprednisolone acetate (Depo Medrol) at a dose of 10 to 20 mg IM every 10 to 11 days in place of oral prednisolone for those cats that do not accept oral medication readily. Parenteral cobalamin supplementation should be administered to cats with hypocobalaminemia. Rescue therapy with cyclophosphamide also has been described for cats with low-grade GI lymphoma (Fondacaro et al, 1999; Stein et al, 2010). It can be given at a dose of 200 to 250 m2 of body surface area PO once every 3 weeks or dividing this dose on days 1 and 3 every other week. Second remissions are common and can result in prolonged survival. The role of surgery in the treatment of GI lymphoma has been evaluated. Studies have shown either no effect or a negative effect of surgical intervention on diseasefree interval and survival. However, this effect is most likely not caused by the surgical intervention itself but is more likely because cats requiring surgery (i.e., those with GI obstruction) have shorter survival periods because of the severity of their disease. The main indications for surgery are partial or complete intestinal obstruction, intestinal perforation, or obtaining biopsy specimens for definitive diagnosis. Some patients with solitary masses that are surgically resected and subsequently receive chemotherapy can have long survival times.

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SECTION  VI  Gastrointestinal Diseases

TABLE 133-1  Reported Outcomes Following Treatment for Cats with Gastrointestinal Lymphoma

Authors

Number of Cats (Number of GI Lymphoma Cases)

Cotter, 1983

7 (7)

Protocol

Percent with Complete Response

Median Survival Time (or DiseaseFree Interval)

Comments

COP

86

26 weeks ST

Grade not reported

COP + M

NR

12 weeks ST

Grade not reported

Jeglum, Whereat, and Young, 1987

14 (14)

Mooney et al, 1989

103 (28)

COP + M + LA

62

30 weeks ST if CR

Outcome in GI LSA not reported separately; grade not reported

Mauldin et al, 1995

132 (95)

COP + M + DOX + LA

67

30 weeks ST

Outcome in GI LSA not reported separately but location did not affect outcome; grade not reported

Zwahlen et al, 1998

21 (21)

COP + M + DOX + LA

38

40 weeks ST (41.5 weeks if CR)

Grade not reported

Malik et al, 2001

60 (14)

COP + M + DOX + LA

80

17 weeks ST (27 weeks if CR)

Outcome in GI LSA not reported separately; grade not reported

Kristal et al, 2001

19 (7)

DOX

26

12 weeks ST (64 weeks if CR)

Outcome in GI LSA not reported separately; grade not reported

Mahony et al, 1995

28 (28)

COP

32

7 weeks ST (30 weeks DFI if CR)

25 high grade; 3 low grade

Fondacaro et al, 1999

11 (11)

COP or COP + DOX + LA

18

11 weeks ST

All high grade

Fondacaro et al, 1999

29 (29)

Chlorambucil, prednisone

69

74 weeks/17 months ST (99 weeks/23 months if CR)

All low grade

Kiselow et al, 2008

41

Chlorambucil, prednisone

56 (+ 39% PR)

101 weeks/23 months ST (DFI = 128 weeks/30 months if CR)

All low grade

Stein et al, 2010

28 (29)

Chlorambucil, prednisone/ prednisolone

96

112 weeks/26 months DFI

All low grade

COP, Cyclophosphamide/vincristine/prednisone; CR, complete response; DFI, disease-free interval; DOX, doxorubicin; GI, gastrointestinal; LA, L-asparaginase; LSA, lymphosarcoma; M, methotrexate; NR, not reported; PR, partial response; ST, survival time.

Some patients with transmural focal disease may be  at risk for perforation when treated with cytotoxic chemotherapy that induces a rapid response, although this is rare in the author’s experience. Surgery may result in dehiscence at intestinal anastomosis sites and may require a delay in initiation of chemotherapy to allow proper wound healing. After resection of a focal GI or mesenteric mass, chemotherapy is still warranted because most cases have diffuse or multifocal microscopic involvement, and lymphoma should be considered a systemic disease in most cases.

Prognostic Factors Few prognostic factors have been defined for cats with GI lymphoma. Histologic grade is a strong indicator of

outcome. Compared with cats with high-grade lymphoma treated with a multiagent chemotherapy regimen, cats with low-grade lymphoma treated with oral prednisolone and chlorambucil have a significantly better remission rate and survival time. Therefore low- and high-grade GI lymphomas in many ways represent different disease entities and must be considered separately. In a majority of studies the most significant prognostic indicator for a positive outcome is initial response to chemotherapy. In general cats that survive the initial induction period and achieve remission also have a better long-term outcome. Although this may seem intuitively obvious, it may give clinicians and owners encouragement to continue chemotherapy treatment in cats that attain a CR. Otherwise there is no consistent association with any patient or tumor characteristic that is predictive

CHAPTER  133  Feline Gastrointestinal Lymphoma of outcome (including sex, immunophenotype, clinical stage, age, and body weight). In most recent studies, FeLV virus antigenemia was not a negative prognostic factor. Some studies also showed little benefit of an exhaustive “staging evaluation” because very few factors have enough impact on prognosis to make their determination helpful. Investigators have looked at molecular markers as prognostic factors. However, argyrophilic nucleolar organizer region (AgNOR) frequency and proliferating cell nuclear antigen labeling index (PCNA-LI) showed no correlation with response to chemotherapy or survival (Rassnick et al, 1999; Vail et al, 1998). Similarly the immunophenotype of tumor cells also does not seem to correlate with outcome in cats, although more recently one study reported a better outcome in cats having the T-cell phenotype (Moore et al, 2012). This is in contrast to dogs, in which a T-cell phenotype has long been recognized as a negative prognostic factor for response to therapy and survival. Concentration of serum α1-acid glycoprotein, an acute-phase protein, has been evaluated in cats with lymphoma, and was not shown to be useful in predicting response to treatment or survival. Limitations of many studies published include incomplete staging, inconsistent grading, multiple unsampled GI locations, lack of prospective randomization to different chemotherapy protocols, lack of control (untreated) patients, and lack of confirmation of remission through follow-up biopsies. Prospective, controlled, and randomized cohort studies with large numbers of cats aimed  at investigating the response of each grade of GI lymphoma to uniform chemotherapeutic regimens seem  warranted. Furthermore, additional studies to correlate clinical outcome with immunophenotype and molecular markers are needed.

References and Suggested Reading Cotter SM: Treatment of lymphoma and leukemia with cyclophosphamide, vincristine, and prednisone. II. Treatment of cats, J Am Anim Hosp Assoc 19:166, 1983. Evans SE et al: Comparison of endoscopic and full-thickness biopsy specimens for diagnosis of inflammatory bowel disease and alimentary tract lymphoma in cats, J Am Vet Med Assoc 229:1447, 2006. Fondacaro JV et al: Feline gastrointestinal lymphoma: 67 cases (1988-1996), Eur J Comp Gastroenterol 4:5, 1999. Francis DP et al: Comparison of virus-positive and virus-negative cases of feline leukemia and lymphoma, Cancer Res 39:3866, 1979.

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Jackson ML et al: Feline leukemia virus detection by immunohistochemistry and polymerase chain reaction in formalinfixed, paraffin-embedded tumor tissue from cats with lymphosarcoma, Can J Vet Res 57:169, 1993. Jeglum KA, Whereat A, Young K: Chemotherapy of lymphoma in 75 cats, J Am Vet Med Assoc 190:174, 1987. Kiselow MA et al: Outcome of cats with low-grade lymphocytic lymphoma: 41 cases (1995-2005), J Am Vet Med Assoc 232:405, 2008. Kristal O et al: Simple agent chemotherapy with doxorubicin for feline lymphoma: a retrospective study of 19 cases (19941997), J Vet Intern Med 15:125, 2001. Mahony OM et al: Alimentary lymphoma in cats: 28 cases (19881993), J Am Vet Med Assoc 207:1593, 1995. Malik R et al: Therapy for Australian cats with lymphosarcoma, Aust Vet J 79:808, 2001. Mauldin GE et al: Chemotherapy in 132 cats with lymphoma: 1988-1994, Proceedings of the 15th Annual Conference of the Veterinary Cancer Society, Tucson, Ariz, 1995, p 35. Mooney SC et al: Treatment and prognostic factors in lymphoma in cats: 103 cases (1977-1981), J Am Vet Med Assoc 194:696, 1989. Moore AS et al: A comparison of doxorubicin and COP for maintenance of remission in cats with lymphoma, J Vet Intern Med 10(6):372, 1996. Moore PF et al: Characterization of feline T cell receptor gamma (TCRG) variable region genes for the molecular detection of feline intestinal T cell lymphoma, Vet Immunol Immunopathol 106:167, 2005. Moore PF et al: Feline gastrointestinal lymphoma: mucosal architecture, immunophenotype, and molecular clonality, Vet Pathol 49(4):658, 2012. Rassnick KM et al: Prognostic value of argyrophilic nucleolar organizer region (AgNOR) staining in feline intestinal lymphoma, J Vet Intern Med 13:187, 1999. Rissetto K et al: Recent trends in feline intestinal neoplasia: an epidemiologic study of 1,129 cases in the Veterinary Medical Database from 1964 to 2004, J Am Anim Hosp Assoc 47:28, 2011. Scott KD et al: Utility of endoscopic biopsies of the duodenum and ileum for diagnosis of inflammatory bowel disease and small cell lymphoma in cats, J Vet Intern Med 25:1253, 2011. Stein TJ et al: Treatment of feline gastrointestinal small-cell lymphoma with chlorambucil and glucocorticoids, J Am Anim Hosp Assoc 46:413, 2010. Vail DM et al: Feline lymphoma (145 cases): proliferation indices, cluster of differentiation 3 immunoreactivity, and their association with prognosis in 90 cats, J Vet Intern Med 12:349, 1998. Zwahlen CH et al: Results of chemotherapy for cats with alimentary malignant lymphoma: 21 cases (1993-1997), J Am Vet Med Assoc 213:1144, 1998.

CHAPTER 

134 

Canine Colitis KENNETH W. SIMPSON, Ithaca, New York ALISON C. MANCHESTER, Ithaca, New York

T

he term colitis frequently is used to describe the clinical syndrome characterized by bloody mucoid diarrhea and tenesmus, or dyschezia, presumed to be caused by inflammation of the colonic mucosa. The modifiers acute and chronic are used to describe the chronicity of clinical signs. However, a definitive diagnosis  of colitis requires histopathologic examination of the colonic mucosa. Thus a clinical diagnosis of “acute colitis” rarely is confirmed by colonic biopsy because most patients do not require endoscopy and respond to conventional therapy. Conversely, a clinical diagnosis of “chronic colitis” always should be confirmed by histopathology, because the success of treatment is related closely to the histopathologic appearance. This chapter reviews the diagnosis and treatment of canine colitis with an emphasis on the management of lymphoplasmacytic and granulomatous colitis.

imaging are normal, enabling the problem to be localized to the large bowel. The next step in the investigation of large bowel diarrhea is colonoscopic examination of the rectum, colon, and cecum and, if indicated, the terminal ileum (e.g., concurrent signs of small bowel diarrhea or low serum cobalamin). Principal differential diagnoses  at this stage include inflammatory bowel disease, polyps, and neoplasia. At least 8 to 10 endoscopic biopsies of normal and abnormal mucosa should be acquired for histopathologic evaluation because lesions can be patchy. Where granulomatous colitis is suspected (see granulomatous colitis later), biopsies should be obtained for bacterial culture. Rigid proctoscopy is an alternative to flexible endoscopy for investigating and biopsying the distal colon and rectum.

Diagnostic Approach

A definitive diagnosis of colitis is based on histopathologic evaluation of colonic biopsies. Colitis falls under the umbrella term inflammatory bowel disease (IBD), which usually is defined by increased cellularity of the lamina propria. The extent of colonic inflammation varies from focal to diffuse involvement. The type and degree of cellular accumulation is also variable and is categorized subjectively as normal, mild, moderate, or severe. Increased numbers of lymphocytes and plasma cells, so-called “lymphoplasmacytic enteritis,” is the most frequently reported form of colitis. Colonic infiltration with macrophages or neutrophils is less common and raises the possibility of an infectious process, and culture, special staining, and fluorescence in situ hybridization (FISH) are indicated. The presence of moderate-to-large numbers of eosinophils in intestinal biopsy samples, often accompanied by circulating eosinophilia, suggests possible parasitic infestation or dietary intolerance. The emphasis on cellularity has meant that abnormalities in mucosal morphology have been somewhat overlooked. Crypt hyperplasia often is interpreted as a regenerative response to an inflammatory stimulus. Erosions, ulcers, and fibrosis are interpreted to infer colitis of increased severity. A major problem of histopathologic evaluation is the subjectivity and variability of reporting. The recent finding that the WSAVA standardization of pathology scheme, like previous standardized photographic schemes, has poor agreement among pathologists, questions further the ability of standardized grading in its current form to translate to improved diagnosis and

The diagnostic approach to dogs presenting with signs of colitis is directed at detecting or ruling out extracolonic causes of tenesmus, dyschezia, or fresh blood in the feces, such as prostatomegaly, perineal hernia, constipation, pelvic canal abnormalities, anal sac and perianal problems, and the various causes of large bowel diarrhea (Table 134-1). In dogs with acute signs of large bowel diarrhea, the diagnostic plan typically consists of fecal examination for parasites (Giardia spp., whipworms), fecal culture (Campylobacter and Salmonella spp., with or without Clostridium spp.), and possibly fecal ELISA for Clostridium toxins. Acute colitis frequently responds to symptomatic therapy with anthelminthics (e.g., fenbendazole) or diet. If the dog is systemically unwell, or large bowel diarrhea is severe or chronic, a biochemical profile, urinalysis, and complete blood count should be submitted to screen for systemic disease. Rectal cytology can be informative in detecting fungi (Histoplasma spp.) and ingested bacteria within neutrophils. Survey radiographs of the abdomen often yield little information about primary colonic disease but can be performed to screen for masses or foreign bodies and to evaluate the relationship of  the colon to other viscera and the pelvic canal. Ultrasonography is useful for ruling out extracolonic causes  of large bowel diarrhea, detecting ileocecocolic lesions, and assessing mural infiltration of masses and regional lymph nodes. In many animals with large bowel diarrhea the physical exam, fecal exam, laboratory testing, and 550

Histopathologic Features of Colitis

CHAPTER  134  Canine Colitis

TABLE 134-1  Causes of Large Bowel Diarrhea Etiologic Category

Cause

Infectious/ parasitic

Salmonella, Campylobacter, Clostridium spp., invasive E. coli, Trichuris vulpis, Giardia, Histoplasma, Prototheca spp.

Dietary

Indiscretion, intolerance, allergy

Metabolic

Pancreatitis, uremia, hypoadrenocorticism, hypothyroidism

Inflammatory

Lymphoplasmacytic, granulomatous, neutrophilic, eosinophilic

Neoplasia

Adenocarcinoma, lymphosarcoma, polyps

Anatomic

Stricture, ileocolic or cecocolic intussusception, cecal eversion, foreign bodies

Functional

Motility disorders, idiopathic, “irritable bowel syndrome” Secondary to small intestinal disease

management of patients with IBD. A further limitation  of the WSAVA scheme in respect to colitis is that it does not consider goblet cells, which correlate with the presence of granulomatous colitis and severity of lymphoplasmacytic colitis and show dramatic increases after treatment. Clearly, the emphasis on histopathologic evaluation has to shift from the subjective reporting of  cellularity toward identifying and reporting features  that correlate with presence of disease and its outcome. Although histopathologic changes can be helpful, they frequently represent a common endpoint of many different diseases.

Management of Chronic Colitis Lymphocytic Plasmacytic Colitis The predominant form of chronic colitis in dogs is  characterized by mucosal infiltration with lymphocytes  and plasma cells and frequently is referred to as lymphocytic plasmacytic colitis. The cause of lymphocytic plasmacytic colitis has not been determined, but it is suspected that intestinal inflammation in dogs, like people, is a consequence of uncontrolled intestinal inflammation  in response to a combination of elusive environmental, enteric microbial, and immunoregulatory factors in genetically susceptible individuals. Analysis of mucosal immunopathology has shown canine lymphocytic plasmacytic colitis is associated with an increase in CD3+ T cells, IgA and IgG, plasma cells, and up-regulation of proinflammatory cytokines interleukin-2 (IL-2) and tumor necrosis factor-α (TNF-α). There is currently no information on genetic susceptibility of dogs to lymphocytic plasmacytic colitis. In a recent study the authors sought to examine the relationship of mucosal bacteria to lymphocytic plasmacytic colitis in 23 dogs (unpublished observations). The authors observed

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BOX 134-1  Medical Management of Colitis Dietary Options Highly digestible Restricted antigen/novel protein Hydrolyzed protein Fiber Supplementation Psyllium: 1T small, 2T medium, 3T large breed with each meal Anthelminthics Fenbendazole: 50 mg/kg q24h PO for 3 days, repeat in 21 days Antimicrobials Metronidazole: 10-15 mg/kg q24h PO for 5 days Tylosin: 10-15 mg/kg q8h PO for 14-28 days, maintenance 5 mg/kg q24h PO Enrofloxacin: use in biopsy proven GC, 7.5 mg/kg q24h PO for at least 6 weeks Antiinflammatory Sulfasalazine: 20-30 mg/kg q8-12h PO Mesalamine: 10-20 mg/kg q12h PO Immunosuppressive Prednisolone: 2 mg/kg q24h PO, maintain remission for 10-14 days then taper over 6-8 weeks Azathioprine: 2 mg/kg q24h PO for 7 days, then 2 mg/kg q48h PO Cyclosporine: 5 mg/kg q24h PO 10 wks Motility Modifiers and Spasmolytics Diphenoxylate or loperamide: 0.1-0.2 mg/kg q8h PO Dicyclomine HCl (Bentyl): 0.2 mg/kg q6-8h PO if severe straining

numerous spiral bacteria inhabiting the mucus and glands of the healthy and inflamed colon that were consistent with enterohepatic Helicobacter spp. Findings included no evidence of Brachyspira spp., a decrease in the total number of mucosal bacteria, and a reduction in the proportion of Clostridium spp. relative to total bacteria and Enterobacteriaceae. These findings parallel the “dysbiosis” that is described in small intestinal IBD in dogs and establish that the density and composition of the colonic mucosal flora is related to the presence and severity of lymphocytic plasmacytic colitis in dogs (see Chapter 131). The authors observed a correlation between goblet cells, mucosal bacteria, and the histologic severity of colitis. The loss of mucus and goblet cells may be related to the dysbiosis associated with colitis. However, it is not clear if the microbial shifts are a cause or a consequence of inflammation, and their role in the etiopathogenesis of colitis has not been established. Treatment Studies in dogs with lymphocytic plasmacytic colitis provide reasonable evidence that various subsets of dogs respond to treatment with diet, antibiotics, or immunosuppressive therapy (Box 134-1). At present, because there

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is no reliable means for predicting which dogs will respond to which treatment, standard treatment consists of a series of therapeutic trials. Most dogs with lymphocytic plasmacytic colitis usually have been trial treated with fenbendazole or metronidazole before the definitive diagnosis is obtained. Dogs that have not received these drugs typically are treated with them before embarking on sequential therapeutic trials with diet, antibiotics, and immunosuppressive agents. Diet.  Several clinical studies indicate that dogs with lymphocytic plasmacytic colitis and idiopathic colitis with minimal histologic change can respond to dietary modification. In a study of 13 dogs with lymphocytic plasmacytic colitis, clinical signs resolved in all 13 dogs (with a 2- to 28-month follow-up) after they were fed a cottage cheese and rice diet. In 11 dogs, two commercial diets (antigen restricted and low residue) not previously fed to these dogs were substituted successfully for the initial test diet, without causing recurrence of signs. Only 2 of these 11 dogs subsequently tolerated a switch to diets that had been fed at the time of onset of signs of colitis (Nelson, Stookey, and Kazacos, 1988). In a subsequent study, 11 dogs with idiopathic chronic colitis were treated for 4 months with a commercial antigen–restricted diet. Within 1 month, four key signs associated with colitis (straining, fecal blood, fecal mucus, and fecal consistency) were improved significantly and remained so for the subsequent 3 months. Sulfasalazine also was used in the initial stages of management to control presenting signs. However, within 1 month 60% of the dogs required either no sulfasalazine (or less than when originally presented); within 2 months 90% were stabilized with no drug therapy (Simpson, Maskell, and Markwell, 1994). In a third study, 27 dogs with idiopathic colitis had soluble fiber (psyllium) added to a highly digestible intestinal diet, with a good to excellent response observed in most dogs. In some dogs, the fiber dosage was reduced or eliminated, or a grocery store brand of dog food was substituted, without causing the diarrhea to return (Leib, 2000). Taken as a whole, these studies indicate that a large proportion of dogs with lymphocytic plasmacytic colitis and idiopathic colitis with minimal histologic change respond to diets that are easily assimilable, antigen restricted, or hydrolyzed, with or without the addition of psyllium. Treatment responses typically occur within 2 weeks. Additional Therapy.  In patients that fail dietary modification and psyllium, the author adds an antibiotic, usually tylosin or metronidazole (if not previously treated) for 2 weeks. Dogs that respond to tylosin but relapse after cessation of treatment can be maintained on it chronically at a reduced dose (5 mg/kg q24h PO). In patients in which diet and antimicrobials fail, a treatment trial with sulfasalazine or aminosalicylic acid can be considered. However, these drugs are associated with keratoconjunctivitis sicca, and tear production should be measured before and during their use. The next line of treatment is corticosteroid therapy, typically prednisolone 1 to 2 mg/kg q12h PO for 10 to  14 days and then tapered over 6 to 8 weeks. In dogs 

that exhibit severe side effects of steroids, require longterm steroid therapy, or are refractory to steroids, the author typically introduces azathioprine. If azathioprine is unsuccessful, cyclosporine (5 mg/kg q24h PO for 10 weeks) may be used. The majority of dogs with lymphocytic plasmacytic colitis have favorable clinical responses to combinations of diet, antimicrobials, and prednisolone. When treatment failure occurs, it is important to reevaluate the patient carefully to determine if the diagnosis is accurate. Weight loss, frequent vomiting, hypoalbuminemia, hypocobalaminemia, and lymphadenopathy are inconsistent with lymphoplasmacytic colitis. Therefore another review of the histopathology is warranted to ensure  the diagnosis is lymphocytic plasmacytic colitis and  that infectious agents have been ruled out before escalating to more aggressive immunosuppressive therapy.  This should include comprehensive fecal analysis, rectal cytology, and special stains of intestinal biopsies.

Granulomatous Colitis Granulomatous colitis (also called histiocytic colitis) is much less common than lymphocytic plasmacytic colitis and is characterized by mucosal infiltration of macrophages with variable concurrent infiltrates of neutrophils, lymphocytes, and plasma cells. Granulomatous colitis raises the probability of an underlying infectious etiology, such as E. coli (e.g., boxer dogs and French bulldogs); Streptococcus, Campylobacter, Yersinia, and Mycobacteria spp.; or fungal (e.g., Histoplasma spp.) or algal (e.g., Prototheca spp.) infections. Culture of mucosal biopsies, intestinal lymph nodes, and other abdominal organs and imaging of chest and abdomen should be undertaken in cases of granulomatous or neutrophilic colitis to detect infectious organisms and systemic involvement. Special stains such as Gomori methenamine silver (GMS), periodic acid-Schiff (PAS), Gram, and modified Steiner are traditional cytochemical methods used to search for infectious agents in fixed tissues. Fluorescence in situ hybridization (FISH) with a probe directed against eubacterial 16S rRNA is a more contemporary and sensitive method of detecting bacteria within formalin fixed tissues (www.vet.cornell.edu/labs/simpson). It is imperative not to immunosuppress patients with granulomatous or neutrophilic infiltrates until infectious agents have been excluded. The prognosis for idiopathic granulomatous or neutrophilic enteropathies is guarded to poor if an underlying cause is not identified. Granulomatous Colitis of Boxer Dogs Granulomatous colitis of boxer dogs (GCB), also known as histiocytic ulcerative colitis (HUC), was described first by Van Kruiningen in a kennel of boxer dogs in 1965. The clinical hallmarks of the disease are severe large bowel diarrhea often accompanied by profound weight loss, anemia, and hypoalbuminemia. Granulomatous colitis of boxer dogs, although rare, occurs worldwide with reported cases originating from Australia, Japan, North America, and Europe. The pathognomonic lesion of GCB for the pathologist is mucosal infiltration with large numbers of macrophages staining positively with

CHAPTER  134  Canine Colitis PAS and usually is accompanied by mucosal ulceration and loss of goblet cells. The poor response of GCB to empiric therapy and immunosuppression led to a reappraisal of antibiotic therapy. Multiple independent studies have documented dramatic clinical responses to enrofloxacin and an association between GCB and intramucosal E. coli. In the first study to link definitively invasive E. coli to GCB, colonic biopsies from affected boxer dogs (n = 13) and controls (n = 38) were examined by FISH with a eubacterial 16S rDNA probe (Simpson et al, 2006). Culture, 16S ribosomal DNA sequencing, and histochemistry were used to guide subsequent FISH. Intramucosal gram-negative coccobacilli were present in 100% of GCB but not in controls, and invasive bacteria hybridized with FISH probes to E. coli. Independent support for these findings was provided by the immunolocalization of E. coli to macrophages within the colons of 10 out of 10 GCB. E. coli strains isolated from affected boxer dogs are novel in phylogeny and have an adherent and invasive pathotype (AIEC) similar to strains isolated from people with Crohn’s disease. Subsequent studies have examined further the relationship of intramucosal E. coli to clinical and histologic outcome in boxer dogs with GC. In one study, clinical response to enrofloxacin was noted in seven out of seven dogs within 2 weeks (mean dose of 7 mg/kg/day for a mean duration of 9 1 2 weeks) and was sustained in six dogs (mean disease-free interval = 45 months). Post-enrofloxacin FISH was negative for E. coli in four out of five dogs. E. coli resistant to enrofloxacin were present in the FISH-positive dog that relapsed clinically. Antibiotic resistance is an increasing problem, and enrofloxacin-resistant E. coli were isolated from 6 out of 14 GCB in a recent study. Of the enrofloxacin-resistant cases, four out of six also were resistant to macrophage-penetrating antimicrobials such as chloramphenicol, rifampicin, and trimethoprim sulfamethoxazole. Enrofloxacin treatment before definitive diagnosis was associated with antimicrobial resistance and poor clinical outcome (Craven et al, 2010). Taken as a whole, these findings indicate that invasive E. coli play a critical role in the initiation and/or progression of GCB. Unfortunately, antimicrobial resistance is becoming common among GCB-associated E. coli and affects clinical response. To optimize outcome in GCB the authors recommend that antimicrobial therapy should be guided by mucosal culture and antimicrobial susceptibility testing rather than by empiric wisdom. Granulomatous Colitis of Non-Boxer Dogs Isolated cases of granulomatous colitis with clinical and histologic similarity to boxer dogs (i.e., PAS-positive macrophages) have been described in the mastiff, Alaskan malamute, Doberman pinscher, English bulldog, and French bulldog. A recent study of six French bulldogs (age 5 to 12 months; 5 male, 1 female) has demonstrated that GC in French bulldogs is phenotypically, histologically, and microbiologically analogous to GC in boxer dogs. FISH of colonic mucosa revealed multifocal accumulations of intramucosal E. coli in colonic biopsies of six out of six dogs. Treatment with enrofloxacin (5 out of 6 dogs) or marbofloxacin (1 out of 6 dogs) at 4.4 to 10 mg/kg

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(median 10 mg/kg) q24h PO 6 to 10 weeks was associated with rapid clinical remission. All dogs remained free of clinical signs over a 3- to 30-month follow-up period (Manchester et al, 2012). Boxers, bulldogs, and mastiffs cluster in the group of mastiff-type dogs, along with bull terriers, rottweilers, and bullmastiffs based on genetic similarity using microsatellite markers, suggesting a potential shared genetic predisposition to this form of colitis. However, at this time it is not clear if GC in breeds other than boxers and French bulldogs is associated with invasive bacteria in general or E. coli. In dogs with confirmed or suspected GC or neutrophilic colitis, the authors recommend FISH analysis and culture of colonic biopsies to help evaluate the presence and type of adherent or invasive bacteria and their susceptibility to antimicrobial agents. Absence of bacteria would prompt a search for other infectious agents. Because treatment successes are predicated on the judicious selection of appropriate antimicrobial drugs, the authors caution against empiric use of macrophagepenetrating antimicrobial drugs in dogs with suspected but not proven E. coli–associated granulomatous colitis.

References and Suggested Reading Craven M et al: Antimicrobial resistance impacts clinical outcome of granulomatous colitis in boxer dogs, Vet Intern Med 24:819, 2010. Davies DR et al: Successful management of histiocytic ulcerative colitis with enrofloxacin in two boxer dogs, Aust Vet J 82:58, 2004. Day MJ et al: Histopathological standards for the diagnosis of gastrointestinal inflammation in endoscopic biopsy samples from the dog and cat: a report from the World Small Animal Veterinary Association Gastrointestinal Standardization Group, J Comp Pathol 138(suppl1):S1, 2008. Hostutler RA et al: Antibiotic-responsive histiocytic ulcerative colitis in 9 dogs, J Vet Intern Med 18:499, 2004. Jergens AE et al: Colonic lymphocyte and plasma cell populations in dogs with lymphocytic-plasmacytic colitis, Am J Vet Res 60:515, 1999. Kleinschmidt S et al: Characterization of mast cell numbers and subtypes in biopsies from the gastrointestinal tract of dogs with lymphocytic-plasmacytic or eosinophilic gastroenterocolitis, Vet Immunol Immunopathol 120:80, 2007. Leib MS: Treatment of chronic idiopathic large-bowel diarrhea in dogs with a highly digestible diet and soluble fiber: a retrospective review of 37 cases, J Vet Intern Med 14:27, 2000. Manchester AC et al: Association between granulomatous colitis in French Bulldogs and invasive Escherichia coli and response to fluoroquinolone antimicrobials, J Vet Intern Med 27(1):56, 2012. Mansfield CS et al: Remission of histiocytic ulcerative colitis in Boxer dogs correlates with eradication of invasive intramucosal Escherichia coli, J Vet Intern Med 23:964, 2009. Nelson RW, Stookey LJ, Kazacos E: Nutritional management of idiopathic chronic colitis in the dog, J Vet Intern Med 2:133, 1988. Ridyard AE et al: Apical junction complex protein expression in the canine colon: differential expression of claudin-2 in the colonic mucosa in dogs with idiopathic colitis, J Histochem Cytochem 55:1049, 2007. Ridyard AE et al: Evaluation of Th1, Th2 and immunosuppressive cytokine mRNA expression within the colonic mucosa of dogs with idiopathic lymphocytic-plasmacytic colitis, Vet Immunol Immunopathol 86:205, 2002.

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Roth L et al: A grading system for lymphocytic plasmacytic colitis in dogs, J Vet Diagn Invest 2:257, 1990. Simpson JW, Maskell IE, Markwell PJ: Use of a restricted antigen diet in the management of idiopathic canine colitis, J Small Anim Pract 35:233, 1994. Simpson KW et al: Adherent and invasive Escherichia coli is associated with granulomatous colitis in boxer dogs, Infect Immun 74:4778, 2006. Simpson KW, Jergens AE: Pitfalls and progress in the diagnosis and management of canine inflammatory bowel disease, Vet Clin North Am Small Anim Pract 41:381, 2011. Suchodolski JS et al: Molecular analysis of the bacterial microbiota in duodenal biopsies from dogs with idiopathic inflammatory bowel disease, Vet Microbiol 142:394, 2010.

CHAPTER 

van der Gaag I: The histological appearance of large intestinal biopsies in dogs with clinical signs of large bowel disease, Can J Vet Res 52:75, 1988. Westermarck E et al: Tylosin-responsive chronic diarrhea in dogs, J Vet Intern Med 19:177, 2005. Willard MD et al: Effect of tissue processing on assessment of endoscopic intestinal biopsies in dogs and cats, J Vet Intern Med 24(1):84, 2010. Willard MD et al: Interobserver variation among histopathologic evaluations of intestinal tissues from dogs and cats, J Am Vet Med Assoc 220:1177, 2002.

135 

Laboratory Testing for the Exocrine Pancreas ROMY M. HEILMANN, College Station, Texas JÖRG M. STEINER, College Station, Texas

D

iseases of the exocrine pancreas are important and occur frequently in dogs and cats. Recent studies that established a far higher prevalence of exocrine pancreatic disease in both species than was  estimated about 30 years ago suggest that exocrine pancreatic disease in general, and more specifically pancreatitis, have long been underdiagnosed in both species. Because of the relative inaccessibility of the pancreas, the diagnosis of exocrine pancreatic disease can pose a challenge and requires a combination of patient history, thorough clinical examination, evaluation of biochemical markers that are highly sensitive and specific for  exocrine pancreatic disease, and the use of diagnostic imaging techniques.

Laboratory Tests for Pancreatitis Pancreatitis is a common and important disease in dogs and cats; antemortem diagnosis of pancreatitis can be challenging. Depending on the severity, patients may or may not exhibit classical clinical signs, nonspecific signs, or signs of severe systemic complications. Particularly cats often show only mild clinical signs that can be masked by other disease processes commonly associated with feline chronic pancreatitis (i.e., cholangitis and or inflammatory bowel disease). Thus the diagnosis of pancreatitis

can be elusive, and probably a significant number of especially mild or subclinical cases remain undiagnosed. Clinical pathology findings (e.g., leukocytosis or  leukopenia, hyper- or hypoglycemia, hypocalcemia and hypophosphatemia, increased liver enzyme activities, hypercholesterolemia) are seen commonly but are nonspecific and do not help to arrive at a diagnosis of pancreatitis. However, routine blood work is essential to rule out major differential diagnoses and to assess the patient with pancreatitis for systemic complications. Abdominal radiography is not useful for diagnosing patients with pancreatitis but, like routine laboratory data, abdominal radiographs are important in ruling out other differential diagnoses. Abdominal ultrasonography can be useful for diagnosing pancreatitis, but stringent diagnostic criteria are crucial (see Chapter 137). For many years, serum amylase activity alone or in combination with serum lipase activity was used as an indicator for acute pancreatic acinar cell damage and biomarker for pancreatitis. Today more sensitive and  specific laboratory tests for diagnosing pancreatitis, most importantly pancreatic lipase immunoreactivity (Spec cPL, Spec fPL), are available. Other tests that have been evaluated for the diagnosis of pancreatitis include systemic and urinary concentrations of trypsinogen-activation peptide (TAP), a by-product

CHAPTER  135  Laboratory Testing for the Exocrine Pancreas of the activation of trypsinogen that is undetectable in the circulation unless trypsinogen is activated prematurely within the pancreas because of pancreatitis. However, TAP is not clinically useful for the diagnosis  of pancreatitis in dogs and cats. The concentration of serum trypsin-alpha1-proteinase inhibitor (α1PI) complex, derived from prematurely activated trypsin leaking from the inflamed pancreas and scavenged by α1PI, and serum α2-macroglobulin as a scavenger for prematurely activated trypsin are also not useful for the diagnosis of pancreatitis. Serum C-reactive protein (CRP), an acutephase protein, has been measured in dogs with acute pancreatitis. Because CRP is not specific for the pancreas and may increase with any inflammatory disease, infection, or trauma, CRP is not useful to diagnose pancreatitis but may be useful as a marker of disease severity.

Serum Amylase and Lipase Activities Amylase and lipase are digestive enzymes produced by pancreatic acinar cells. Damage to these cells as occurs with pancreatic necrosis and inflammation during pancreatitis leads to increased amounts of both enzymes in the systemic circulation. Because many different lipases and amylases originate from a wide range of tissues, their activities that are measured by catalytic assays are not pancreas specific. An increased serum amylase activity can be found in patients with conditions other than  pancreatitis; conversely, a normal serum amylase activity does not rule out pancreatitis. Similarly, the sensitivity and specificity of serum lipase activity for canine pancreatitis are low. To be suggestive of pancreatitis in dogs, serum amylase or lipase activities must be increased at least threefold to fivefold above the upper limit of the reference range, but both are of low diagnostic value. In cats, serum amylase and lipase activities have a very low sensitivity for pancreatitis and thus are of no diagnostic value in this species.

Serum Trypsin-like Immunoreactivity Assays for serum trypsin-like immunoreactivity (TLI) measure cationic trypsinogen, trypsin (if present), and some trypsin molecules complexed with proteinase inhibitors. Serum TLI reflects the amount of functional pancreatic tissue present and is highly sensitive and specific for the diagnosis of exocrine pancreatic insufficiency (see later) but lacks sensitivity in the diagnosis of pancreatitis in dogs and cats. Increased serum TLI concentrations can be measured in dogs and cats with pancreatitis, presumably because of leakage of trypsinogen and prematurely activated trypsin from the inflamed pancreas. However, the half-life of TLI in serum is thought to be very short, and a significant degree of inflammation is required for serum TLI concentrations to be increased. In dogs, the sensitivity and specificity of serum cTLI concentration for pancreatitis have been reported as less than 40% and 65% to 100%, respectively. In cats, serum fTLI concentration appears to be more useful clinically, but the increase of serum fTLI above the diagnostic cutoff value used for pancreatitis was of much shorter duration than that of serum fPLI in

555

mild experimentally induced feline pancreatitis. The sensitivity and specificity of serum fTLI concentration for the diagnosis of pancreatitis in cats range between 33% and 86% and 56% and 90%, respectively. TLI also may be increased in patients with renal failure, and thus a serum chemistry profile and urinalysis should be performed to rule out renal disease if the serum TLI concentration is increased. With the availability of newer, more sensitive and specific diagnostic tests (Spec cPL and  Spec fPL), serum TLI concentration should no longer be employed for the diagnosis of pancreatitis in either species.

Serum Pancreatic Lipase Immunoreactivity In contrast to serum lipase activity, immunoassays for pancreatic lipase immunoreactivity (PLI) measure lipase that originates exclusively from the exocrine pancreas. Increased amounts of pancreatic lipase escape into the systemic circulation during pancreatic inflammation  and necrosis and can be measured using species-specific immunoassays. Sensitivities of 82% to 94% have been reported for the diagnosis of clinically significant pancreatitis by serum cPLI concentration. In a study that evaluated the sensitivity of various serum markers in dogs with less severe pancreatitis, measurement of serum cPLI concentration showed the highest sensitivity of any diagnostic test evaluated with 64% (Steiner et al, 2008). However, a single measurement of cPLI in serum cannot predict the histopathologic severity of pancreatitis. In cats, sensitivities  of serum fPLI for diagnosing patients with pancreatitis  range from 54 (subclinical or mild disease) to 100% (moderate to severe pancreatitis). Unlike serum fTLI, serum fPLI was increased persistently in cats with experimentally induced pancreatitis, presumably because of a delayed renal elimination of the larger negatively charged protein measured. Measurement of serum PLI is a practical test that requires a serum sample after withholding food for 8 to 12 hours. Commercially available tests that measure PLI in dogs (Spec cPL) and cats (Spec fPL) are reported to perform similarly to the originally developed assays. Concentrations of at least 400 µg/L (Spec cPL) in dogs and at least 5.4 µg/L (Spec fPL) in cats are consistent with a diagnosis of pancreatitis. Equivocal test results (Spec cPL: 201 to 399 µg/L; Spec fPL: 3.6 to 5.3 µg/L) require further evaluation of the patient or repeated testing. Recently, patient side tests (SNAP cPL and SNAP fPL) for use in  the clinic have been introduced. In these tests, a color intensity of the sample spot that is lighter than the reference spot indicates that pancreatitis is very unlikely and other differential diagnoses should be considered. In  contrast, a sample spot that is equal to or darker than  the reference spot indicates an abnormal cPL or fPL concentration, suggesting pancreatitis. As a positive SNAP  cPL/SNAP fPL indicates a Spec cPL/Spec fPL in the equivocal or diagnostic range for pancreatitis, Spec cPL/Spec  fPL should be measured to verify the diagnosis of pancreatitis and to obtain a baseline concentration that then can be used to monitor the progression of disease in  the patient.

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Studies in dogs and cats with induced chronic renal failure (CRF) suggest that serum cPLI and fPLI can be used as diagnostic tests in patients with CRF because serum PLI is either not affected or only minimally affected. Also serum cPLI was not affected by long-term administration of prednisone (Steiner et al, 2009). Serum PLI is specific for the exocrine pancreas and is the most sensitive serum test that currently is available for the diagnosis of pancreatitis in dogs and cats. However, as for other diseases,  the integration of all clinically available data, especially abdominal ultrasonography and serum PLI, are expected to yield the best diagnostic accuracy.

time and other causes of malassimilation. A test that is more applicable in the clinical setting and that measures primarily the activity of pancreatic trypsin and chymotrypsin in feces is the determination of fecal proteolytic activity (FPA) by either qualitative gelatin digestion methods or semiquantitative azocasein hydrolysis or radial enzyme diffusion into agar containing a casein substrate. However, false-negative and false-positive test results occur frequently, and more sensitive and specific tests for the diagnosis of EPI in dogs and cats are available. Thus FPA can no longer be recommended for the diagnosis of EPI in both species.

Laboratory Tests for Exocrine Pancreatic Insufficiency

Fecal Pancreatic Elastase-1

Exocrine pancreatic insufficiency (EPI) is a deficiency of enzyme and fluid secretion from the exocrine pancreas. As a result of deficiency of digestive enzymes in the  small intestine (SI), the syndrome is characterized by clinical signs of maldigestion. Because of the large secretory reserve capacity of the exocrine pancreas and a high degree of metabolic pathway redundancy for the digestion of some nutrients, clinical signs of maldigestion may not occur until the vast majority of the functional pancreatic mass has been lost. Although EPI may be suspected based on clinical signs, medical history, and patient signalment, the clinical signs are usually nonspecific and EPI must be differentiated from other causes of maldigestion and malabsorption. Routine blood work (i.e., complete blood count [CBC] and chemistry profile) is often within normal limits or shows nonspecific changes that may be due to concurrent disease. Serum cobalamin concentration is decreased severely in most dogs (Batchelor et al, 2007) and cats (Thompson et al, 2009) with EPI (in >80% of cases in both species). In fact, EPI is an important reason for cobalamin deficiency in both species, because the exocrine pancreas is an important source of intrinsic factor in dogs and  cats. Decreased serum cobalamin and increased serum folate concentrations also may reflect secondary SI dysbiosis; a decrease in both may indicate concurrent chronic small intestinal disease (e.g., inflammatory bowel disease). Serum glucose concentration is usually normal but may be increased in patients with concurrent diabetes mellitus (most commonly seen in patients in which EPI is due to chronic pancreatitis destroying endocrine and exocrine portions of the pancreas). Diagnostic imaging studies (i.e., abdominal radiography and ultrasonography) are not sensitive or specific and thus not useful for diagnosing EPI. In clinical practice, exocrine pancreatic function testing is the method of choice to confirm or rule out EPI before proceeding with further evaluation of the patient. Laboratory techniques used in the past to diagnose EPI include the microscopic examination of feces for the presence of undigested food, the assessment of oral fat absorption by measuring plasma turbidity, the starch tolerance test, and the in vivo assessment of pancreatic enzyme activity in the intestinal juice after oral administration of the synthetic chymotrypsin substrate bentiromide. These tests are of limited usefulness because of practical constraints and are affected by the gastrointestinal transit

Elastase-1 is a digestive protease exclusively synthesized and secreted by the pancreas in the form of an inactive zymogen, proelastase. After its release and transport into the duodenum via the pancreatic ductal system, pancreatic proelastase-1 is activated in the intestinal lumen, where it resists proteolytic degradation and withstands the intestinal passage virtually undegraded. Thus the  concentration of pancreatic elastase-1 (pE1) in feces theoretically should reflect the functional capacity of the  exocrine pancreas. Fecal pE1 can be measured in dogs by a species-specific enzyme-linked immunosorbent assay (ELISA) and has been reported to be sensitive and specific (95% and 92%, respectively) for clinical EPI when associated with typical clinical signs and using a cutoff value for EPI of 10 µg/g or less in a single fecal sample (Spillmann et al, 2000). Despite its lack of cross-reactivity with pE1 from other species (that may be contained in pancreatic enzyme supplements) and its potential to distinguish exocrine pancreatic disease from primary intestinal disorders (with potentially high luminal amounts of neutrophil elastase), a remarkable day-to-day variation and significant overlap between healthy dogs and dogs with EPI exist. A high false-positive rate renders the test unreliable and poses a risk for unnecessary treatment costs. Although fecal pE1 may aid in ruling out EPI, a positive result always should be confirmed by a more sensitive test (i.e., measurement of serum TLI). A situation in which fecal pE1 measurement could be useful is EPI resulting from occlusion or obstruction of the pancreatic duct, in which serum cTLI will likely be normal (which has not been reported and is probably extremely rare).

Serum Trypsin-like Immunoreactivity Assays for TLI concentration in serum measure cationic trypsin (if present) and its zymogen form (trypsinogen) in the circulation, presumably of leakage of trace amounts into the pancreatic venous or lymphatic vessels and to some degree also trypsin complexed by scavenging proteins. Because the analyte measured as serum TLI originates only from the pancreas and reflects the amount of functional pancreatic tissue present, serum TLI is highly sensitive and specific for the diagnosis of EPI in dogs and cats. Normal ranges used at the authors’ laboratory are 5.7 to 45.2 µg/L, with a cutoff value for diagnosing EPI of at least 2.5 µg/L for dogs, and 12.0 to 82.0 µg/L, with

CHAPTER  135  Laboratory Testing for the Exocrine Pancreas a cutoff for EPI of at least 8.0 µg/L for cats. An abnormally low serum TLI (dogs: ≤2.5 µg/L; cats: ≤8.0 µg/L) associated with clinical signs is considered diagnostic for EPI. An equivocal serum cTLI concentration (i.e., between 2.5 and 5.7 µg/L) can be seen in patients with chronic SI disease but also in dogs in the process of developing  EPI. Equivocal cTLI results may be found in dogs with autoimmune atrophic pancreatitis (see Chapter 136) tested early in the disease course and may precede the onset of clinical EPI. Conversely, a normal serum cTLI, especially when low normal, does not preclude the evolution of mild to moderate pancreatic dysfunction. In patients with EPI secondary to chronic intermittent or recurrent acute pancreatitis a normal serum cTLI could be due to an acute exacerbation of inflammation in the residual glandular tissue of the pancreas. If serum cTLI measures between 2.5 and 5.7 µg/L, retesting the patient in approximately 4 weeks is recommended to rule out subclinical EPI. Also, although TLI reflects the functional pancreatic mass, repeated testing is not predictive for the disease, and the need for dietary enzyme replacement therapy cannot be inferred from the TLI concentration alone but has to be based on the clinical evaluation of the patient. Concurrent renal disease or a decreased rate of glomerular filtration may result in a slightly higher serum TLI concentration than reflected by the amount of functional pancreatic acinar tissue and thus in a falsely normal serum TLI. A normal serum TLI also is assumed to occur in patients with a pancreatic duct obstruction, congenital deficiency of intestinal enteropeptidase, or a selective pancreatic enzyme deficiency not involving trypsin. Measurement of serum TLI requires a single serum sample after withholding food for 8 to 12 hours. Postprandially, serum TLI may increase slightly and transiently. Serum TLI is the most sensitive and specific pancreatic function test currently available and remains the gold standard for diagnosing EPI in dogs and cats. Determination of the underlying disease process may require morphologic evaluation of the pancreas by pancreatic biopsy, but histologic pancreatic atrophy does not reflect the remaining functional pancreatic reserve.

Serum Pancreatic Lipase Immunoreactivity The analyte measured as pancreatic lipase immunoreactivity (PLI) in serum is of exclusively pancreatic origin. Low concentrations of serum cPLI can be detected in dogs with EPI, but the overlap between healthy dogs and dogs with EPI renders the TLI assay superior for the diagnosis of EPI. Also, the PLI assays commercially available today (Spec cPL, Spec fPL) have been optimized for diagnosing patients with pancreatitis and are not useful for the diagnosis of EPI.

557

Exocrine Pancreatic Neoplasia Lymphoma and pancreatic adenocarcinoma (AC) are the most common neoplasias of the exocrine pancreas in dogs and cats but are rare in both species. Clinical signs usually are nonspecific but can be severe. A local inflammatory response to avascular tumor necrosis may cause clinical signs of pancreatitis. Clinical pathology findings are unremarkable or nonspecific. Serum lipase activity may be extremely high in dogs with pancreatic AC, but serum amylase and lipase activities are reported not  commonly in patients with pancreatic adenocarcinoma. Serum TLI or PLI concentrations have not been reported in dogs or cats with primary pancreatic neoplasia. Thus currently there is no laboratory test for the diagnosis of pancreatic AC.

References and Suggested Reading Batchelor DJ et al: Prognostic factors in canine exocrine pancreatic insufficiency: prolonged survival is likely if clinical remission is achieved, J Vet Intern Med 21:54, 2007. Forman MA et al: Evaluation of serum feline pancreatic lipase immunoreactivity and helical computed tomography versus conventional testing for the diagnosis of feline pancreatitis,  J Vet Intern Med 18:807, 2004. Holm JL et al: C-reactive protein concentrations in canine acute pancreatitis, J Vet Emerg Crit Care 14:183, 2004. McCord K et al: A multi-institutional study evaluating the diagnostic utility of the Spec cPLTM and SNAP® cPLTM in clinical acute pancreatitis in 84 dogs, J Vet Intern Med 26(4):888, 2012. Spillmann T et al: Canine faecal pancreatic elastase (cE1) in dogs with clinical exocrine pancreatic insufficiency, normal dogs and dogs with chronic enteropathies, Eur J Comp Gastroenterol 5:1, 2000. Steiner JM, Williams DA: Serum feline trypsin-like immunoreactivity in cats with exocrine pancreatic insufficiency, J Vet Intern Med 14:627, 2000. Steiner JM et al: Sensitivity of serum markers for pancreatitis in dogs with macroscopic evidence of pancreatitis, Vet Ther 9:263, 2008. Steiner JM et al: Stability of canine pancreatic lipase immunoreactivity concentration in serum samples and effects of longterm administration of prednisone to dogs on serum canine pancreatic lipase immunoreactivity concentrations, Am J Vet Res 70:1001, 2009. Steiner JM, Rehfeld JF, Pantchev N: Evaluation of fecal elastase and serum cholecystokinin in dogs with a false positive fecal elastase test, J Vet Intern Med 24:643, 2010. Thompson KA et al: Feline exocrine pancreatic insufficiency: 16 cases (1992-2007), J Feline Med Surg 11:935, 2009. Wiberg ME, Nurmi AK, Westermarck E: Serum trypsin-like immunoreactivity measurement for the diagnosis of subclinical exocrine pancreatic insufficiency, J Vet Intern Med 13:426, 1999. Williams DA, Batt RM: Sensitivity and specificity of radioimmunoassay of serum trypsin-like immunoreactivity for the diagnosis of canine exocrine pancreatic insufficiency, J Am Vet Med Assoc 192:195, 1988.

CHAPTER 

136 

Exocrine Pancreatic Insufficiency in Dogs MARIA WIBERG, Helsinki, Finland

C

hronic diseases of the exocrine pancreas may affect pancreatic function and lead to inadequate production of digestive enzymes with associated maldigestion signs of exocrine pancreatic insufficiency (EPI). The exocrine pancreas has a large reserve in terms of secretory capacity, and clinical signs do not occur until about 90% of secretory capacity is lost. EPI in dogs can be the result of pancreatic acinar atrophy, chronic pancreatitis, pancreatic hypoplasia, and pancreatic neoplasia. EPI has been found in many different breeds, and breedspecific pathogenetic differences have been reported.

Etiopathogenesis Pancreatic acinar atrophy is by far the most common reason for the clinical signs of EPI. The breeds most  commonly affected with the acinar atrophy are German shepherds, rough-coated collies, and Eurasians. In these breeds, an autosomal-recessive inheritance model has been suggested. Thus far genetic studies have not been able to identify the genes involved (Clark et al, 2005; Proschowsky and Fredholm, 2007). Females and males usually are affected equally. Studies with German shepherds and collies suggest that pancreatic atrophy is a result of an autoimmunemediated atrophic lymphocytic pancreatitis, which gradually may lead to almost total destruction of pancreatic acinar tissue (Wiberg, Saari, and Westermarck, 2000). Typically the endocrine part of the pancreas is unaffected. A  long-term follow-up study of a German shepherd litter revealed that the disease was not congenital, and a polygenic inheritance pattern has been suggested (Westermarck, Saari, and Wiberg, 2010). Genetic predisposition to the disease and the typical histologic findings during the progression of acinar atrophy have been taken as primary evidence of the autoimmune nature of the disease. Wiberg, Saari, and Westermarck (1999b) divided the progression of acinar atrophy into subclinical and clinical phases. The subclinical phase is characterized by marked lymphocytic inflammation into a partially atrophied acinar parenchyma. Cytotoxic T cells are predominant when the tissue destruction is in progress. When the disease progresses to end-stage atrophy, the clinical phase of EPI develops. An atrophied pancreas is thin and transparent with no increase of fibrotic tissue. The natural progression of the atrophic pancreatitis can vary markedly. Clinical signs of EPI usually appear at 558

1 to 5 years of age but also can be seen in older dogs. Dogs may remain in the subclinical phase for years and sometimes for life (Wiberg and Westermarck, 2002). Markers that predict which dogs are likely to develop clinical disease or environmental factors that trigger disease have not been identified thus far. Chronic pancreatitis is the most common cause of EPI in cats and humans. In dogs, chronic pancreatitis has been recognized increasingly as a cause of EPI. Chronic pancreatitis usually affects older dogs, and breed-specific clinical and histopathologic features have been reported (Batchelor et al, 2007b; Watson et al, 2011). Unlike the situation of atrophic pancreatitis, in chronic pancreatitis usually a progressive destruction of the exocrine and endocrine pancreas is accompanied by fibrosis. Clinical signs are nonspecific gastrointestinal signs and sometimes are related to the development of diabetes mellitus. The congenital form of exocrine or exocrine and endocrine pancreatic hypoplasia sometimes is found in young puppies. EPI is reported rarely in association with pancreatic neoplasia.

Clinical Signs Typical clinical signs of EPI include increased fecal volume and defecation frequency, yellow or gray feces, weight loss, and flatulence. Other common signs are polyphagia; poorly digested, loose, and pulpy feces; or coprophagia. Signs of nervousness or aggressiveness may occur possibly because of abdominal discomfort caused by increased intestinal gas. Severe watery diarrhea is usually only temporary. Skin disorders also have been reported. Although the signs of EPI are considered typical, they are not pathognomonic for pancreatic dysfunction, because similar maldigestion signs may be observed in other small intestinal disorders.

Diagnosis Diagnosis of exocrine pancreatic dysfunction is based on typical clinical findings and confirmed with abnormal pancreatic function testing. Routine serum biochemistry profile and complete blood count often show unremarkable changes. Serum amylase and lipase activities are not useful in the diagnosis of EPI. Various pancreatic function tests that measure pancreatic enzymes in the blood and feces have been used to diagnose canine EPI. The diagnostic value of the tests has relied mostly on their ability

CHAPTER  136  Exocrine Pancreatic Insufficiency in Dogs to distinguish whether the clinical maldigestion signs are caused by EPI or a disease of the small intestine.

Serum Trypsin-like Immunoreactivity The measurement of serum canine trypsin-like immunoreactivity (TLI) has become one of the most commonly used pancreatic function tests to diagnose canine EPI (see Chapter 136). Serum TLI measurement is species and pancreas specific, with high sensitivity and specificity for diagnosing EPI. The reference range for canine TLI (cTLI) in healthy dogs is greater than 5.7 to 45.2 µg/L (RIA). In dogs showing clinical maldigestion signs of EPI, cTLI concentrations are usually very low (46 µmol/L) have been shown to be a sensitive (98%) and specific (89%) test for the detection of congenital or acquired PSVA in dogs (Gerritzen-Bruning, van den Ingh, and Rothuizen, 2006). Currently ammonia is the only toxin that can be measured clinically for the diagnosis of HE. The diagnostic use of blood ammonia is limited by the need for meticulous sample handling, including avoidance of hemolysis, use of cold heparinized tubes, transfer on ice, and refrigerated centrifugation and assay, all ideally within an hour of collection (Ruland, Fischer, and Hartmann, 2010.).

573

Diagnostic Imaging in the Evaluation of Hepatobiliary Disease The size, shape, position, opacity, and margins of the liver can be assessed on standard radiographs of the cranial abdomen. Hepatomegaly is associated with congestion (right-sided heart failure), vacuolar hepatopathy (glycogen, lipid, amyloid), infiltrative disease (neoplasia), extramedullary hematopoiesis, and inflammatory liver disease. Microhepatica may be seen with PSVA or chronic hepatitis/cirrhosis (dogs). Increased opacity may be noted secondary to mineralization within the biliary system (49% of choleliths) or hepatic parenchyma (granulomas, long-term hematomas, abscesses, neoplasia, chronic hepatopathies, or regenerative nodules). Gas may be within the biliary tree (emphysematous cholecystitis, cholangitis), portal vessels (severe necrotizing gastroenteritis), or hepatic parenchyma (hepatic abscesses). Ultrasonography enables differentiation among focal, multifocal, and diffuse disease; evaluation of the biliary system and portal vasculature; and procurement of tissue for hepatic histopathology (Gashen, 2009). Focal hepatic diseases include cysts, hematomas, abscesses, granulomas, regenerative nodules, primary and metastatic neoplasms, infarcts, and biliary pseudocysts. A large liver with diffuse hyperechoic parenchyma may be noted with fatty change (hepatic lipidosis) and vacuolar hepatopathy, whereas a small, hyperechoic liver may be seen with cirrhosis. Diffuse hypoechoic parenchyma may be noted in cases of hepatic congestion and suppurative hepatitis. Evaluation of the biliary tree and gallbladder may reveal a gallbladder mucocele, choleliths, and intrahepatic or extrahepatic bile duct dilation. A diffusely thick gallbladder wall is consistent with cholecystitis. A normal ultrasound scan does not preclude a diagnosis of hepatobiliary disease. In many cases of PSVA ultrasonography permits direct visualization of the shunting vessel. Ultrasonography is more sensitive for the detection of intrahepatic shunts (100%) than extrahepatic shunts (80% to 98%). The sensitivity of ultrasound for the diagnosis of PSVA is enhanced by duplex-Doppler or color-flow Doppler, although this requires a cooperative patient and operator patience for accurate interpretation. Reduced or reversed portal flow is seen with multiple acquired shunts secondary to portal hypertension. When combined, findings of a small liver, enlarged kidneys, and uroliths had a positive predictive value of a 100% for a congenital PSVA in dogs. Portal vein/aorta and portal vein/caudal vena cava values of greater or equal to 0.8 and 0.75, respectively, consistently ruled out an extrahepatic PSVA (d’Anjou et al, 2004). Ultrasound can be used to detect vascular complications of hepatic disease such as portal hypertension and portal venous thrombosis. Ultrasonographic signs of portal hypertension include the presence of ascites, multiple acquired shunts, and reduced or reversed portal blood flow (Buob et al, 2011). Ultrasonography is currently the best imaging modality to evaluate for EHBDO. Ultrasonographic signs of EHBDO include dilation of the cystic duct, common bile duct (>5 mm in cats), or intrahepatic bile ducts and identification of an intraluminal or extraluminal mass obstructing the biliary tract (Gaillot et al,

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SECTION  VI  Gastrointestinal Diseases

2007). The degree of gallbladder distention appears to be variable and thus should not be used as a sole criterion to diagnose EHBDO, particularly in cats. Scintigraphy may be a useful adjunct in cases of suspected EHBDO or PSVA. In scintigraphic imaging of the biliary tract, an intravenous 99mTc-iminodiacetic acid (technetium 99m) derivative is taken up by hepatocytes and subsequently undergoes biliary excretion. Using a cutoff of 180 minutes for the dye to enter the small intestine, the sensitivity of scintigraphy to identify complete EHBDO is high (83% to 100%), but the specificity is  lower because partial bile duct obstruction also may slow  dye excretion. Sensitivity remains similar, whereas specificity is increased markedly when the cutoff time is increased to 24 hours after injection. High serum bilirubin concentration did not reduce the diagnostic usefulness of scintigraphy. Transcolonic pertechnetate scintigraphy (TCPS) is used for the detection of PSVA. In TCPS 99mTc pertechnetate is administered rectally and is absorbed subsequently into the portal venous system. In normal animals radioisotope activity is detected in the liver before its detection in the heart. In animals with PSVA the radioisotope activity is detected in the heart before the liver. In dogs TCPS has a high positive predictive value for the diagnosis of PSVA and discriminates dogs with macroscopic PSVA from those with primary hypoplasia of the portal vein because TCPS is abnormal only in the former. Transplenic portal scintigraphy (TSPS) also can be  used to diagnose PSVA. Ultrasound-guided TSPS results  in higher radioisotope count densities, more consistent splenic and portal venograms, and a significant decrease in radiation exposure when compared with TCPS. TSPS misses cases of PSVA when the shunt originates distal to the splenic vein. The value of magnetic resonance imaging (MRI) and helical computed tomography in the diagnosis of hepatobiliary disease is currently under evaluation (Gashen, 2009). MRI has shown promise in the differentiation of benign from malignant focal hepatic lesions in canine patients. Magnetic resonance angiography and helical computed tomography angiography have been used in dogs for the diagnosis of PSVA and offer the added advantage of accurate anatomic characterization of the shunt. The diagnostic use of these modalities currently is limited by availability and cost.

Hepatic Biopsy Acquisition and Interpretation Indications for hepatic biopsy include persistent serial increases in liver enzymes, abnormal hepatic function tests, hepatomegaly of undetermined cause, ultrasonographic abnormalities in hepatic parenchyma, and evaluation for the presence of a breed-specific hepatopathy. Hepatic biopsy can be obtained by ultrasound guidance (needle biopsy) or exploratory or laparoscopy (wedge biopsy). The advantages of the latter two methods are the ability to grossly evaluate the liver, acquire large tissue samples, and quickly identify and control postbiopsy hemorrhage. When wedge biopsy is used as the standard, discordance between wedge and Tru-Cut biopsies may be

as high as 48% (Cole et al, 2002). However, the standard for any study evaluating the accuracy of hepatic biopsies is histopathologic assessment of the whole liver at necropsy. Thus any hepatic biopsy, no matter how it is obtained, must be interpreted in light of sampling error. Prebiopsy considerations should include the patient’s overall clinical status and the risk of hemorrhage. Acquisition of hepatic tissue is contraindicated in the presence of a hemodynamically unstable patient, coagulopathy, and encephalopathy. A PT, PTT, and platelet count should be performed. Tru-Cut biopsy should be avoided with elevations in PT and PTT of greater than 1.5 times normal and a platelet count of less than 80,000. A buccal mucosal bleeding time may improve the sensitivity of detecting bleeding deficiencies in cases of mild thrombocytopenia. Vitamin K is administered routinely 24 hours before hepatic biopsy. Fresh frozen plasma may be considered before biopsy in cases in which mild elevations in PT and PTT are noted. The method of biopsy acquisition is influenced by the size of the liver, the suspected diagnosis, and the clinical condition of the patient. Microhepatica and large-volume abdominal effusion are contraindications for percutaneous ultrasound-guided biopsy. In some conditions, such as primary hypoplasia of the portal vein and nodular hyperplasia, a wedge biopsy is often necessary to obtain a definitive diagnosis. In cases of diffuse vacuolar hepatopathy, inflammatory disease, or neoplasia, a diagnosis can be obtained with a percutaneous ultrasound-guided Tru-Cut biopsy (a 16-gauge needle in dogs and an 18-gauge needle in cats). Multiple biopsy samples (three to five) should be taken from different areas of the liver. In general hepatic biopsy is preferred over fine-needle aspiration (FNA) to characterize liver disorders. When compared with hepatic biopsy, discordance rates with FNA may be as high as 70%. However, in animals with bleeding disorders or large cavitary lesions or abscesses, ultrasound-guided FNA can be performed safely. In focal or diffuse hepatic disease (vacuolar or neoplastic) FNA may yield diagnostic samples. Occasionally FNA may identify an infectious agent that can be missed easily on histopathology. However, FNA cannot diagnose reliably necroinflammatory or vascular disease. Percutaneous cholecystocentesis has been shown to be a safe technique by which to obtain bile for cytology and culture. The clinician must understand the benefits and limitations of hepatic histopathology. The purposes of obtaining hepatic tissue are to (1) determine the category of disease (inflammatory, neoplastic, vascular, or vacuolar); (2) define the extent of the disease; (3) assess the duration of illness; and (4) provide tissue for special stains and culture to aid in the diagnosis of metabolic and infectious causes. Although histopathology may result in a definitive diagnosis in the case of metabolic disease (hepatic lipidosis) and neoplasia, more often certain reaction patterns are described, which then provide clues to the underlying etiology. Correct interpretation of the biopsy results requires dialogue with the pathologist and reevaluation of the patient’s history and clinical picture. A liver biopsy specimen represents only a small portion of the entire liver, and frequently even diffuse disorders have  an uneven distribution; therefore the clinician always

CHAPTER  140  Drug-Associated Liver Disease should be critical of whether the histopathologic diagnosis fits with the clinical picture. Several breeds of dogs have copper-associated hepatopathies (Hoffman, 2009). Evaluation of hepatic biopsy for diagnosis of copper-associated hepatic disease ideally requires semiquantitative staining of the biopsy material and quantitative analysis of hepatic copper content. Hepatic wedge biopsies are ideal, although adequate material can be obtained to carry out these measurements in needle biopsy samples. Normal hepatocytes do not take up much copper stain, and hepatic copper values are 200 to 400 PPM. Dogs with copper-associated hepatopathies have quantitative copper values in excess of 1500 PPM with copper deposits in many hepatocytes, particularly those away from areas of inflammation or in the centrolobular area.

References and Suggested Reading Berent AC, Tobias KM: Portosystemic vascular anomalies, Vet Clin North Am Small Anim Pract 39:513, 2009. Buob S et al: Portal hypertension: pathophysiology, diagnosis, and treatment, J Vet Intern Med 25:169, 2011. Center SA: Interpretation of liver enzymes, Vet Clin North Am Small Anim Pract 37:297, 2007.

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575

Cole TL et al: Diagnostic comparison of needle and wedge biopsy specimens of the liver in dogs and cats, J Am Vet Med Assoc 220:1483, 2002. d’Anjou MA et al: Ultrasonographic diagnosis of portosystemic shunting in dogs and cats, Vet Radiol Ultrasound 45:424, 2004. Gaillot HA et al: Ultrasonographic features of extrahepatic biliary obstruction in cats, Vet Radiol Ultrasound 48:439, 2007. Gashen L: Update on hepatobiliary imaging, Vet Clin North Am Small Anim Med 39:439, 2009. Gaskill CL et al: Liver histopathology and liver and serum alanine aminotransferase and alkaline phosphatase activities in epileptic dogs receiving phenobarbital, Vet Pathol 42:147-160, 2005. Gerritzen-Bruning MJ, van den Ingh TSGAM, Rothuizen J: Diagnostic value of fasting plasma ammonia and bile acid concentrations in the identification of portosystemic shunting in dogs, J Vet Intern Med 20:13, 2006. Hoffman G: Copper associated liver disease, Vet Clin North Am Small Anim Pract 39:489, 2009. Ruland K, Fischer A, Hartmann K: Sensitivity and specificity of fasting ammonia and serum bile acids in the diagnosis of portosystemic shunts in dogs and cats, Vet Clin Pathol 39:57, 2010. Unakami S et al: Molecular nature of three liver alkaline phosphatases detected by drug administration in vivo: differences between soluble and membranous enzymes, Comp Biochem Physiol B 88:111, 1987.

140 

Drug-Associated Liver Disease* LAUREN A. TREPANIER, Madison, Wisconsin

T

he liver is a common target of drug toxicity. It receives 25% to 30% of cardiac output and is the site of first-pass clearance of many orally administered drugs. Hepatic cytochrome P450s and other biotransformation enzymes can generate reactive metabolites, which may lead to local cytotoxicity, or haptenize liver proteins and trigger an immune response. Drugs also can inhibit transporter pumps in the sinusoidal or canalicular membranes, thus interfering with hepatocyte function and bile salt efflux. Two major patterns of drug-induced hepatotoxicity are recognized: cytotoxic (associated with hepatocyte necrosis) and cholestatic (which can be attributed to inhibition of biliary transporters, or mitochondrial injury with resulting steatosis). In humans, an R

*Data included in this chapter were supported in part by grants from Miravista Laboratories, the Waltham Foundation, and the Companion Animal Fund at the University of Wisconsin-Madison.

value is calculated to characterize hepatotoxicity by biochemical pattern, where R=

( ALT / Upper limit of normal) ( ALP / Upper limit of normal)

An R value greater than 5 indicates hepatocellular injury, an R less than 2 indicates cholestatic injury, and an R of 2 to 5 represents a mixed pattern.

Dose-Dependent Hepatotoxic Drugs For dose-dependent, or intrinsic, hepatotoxicity, toxicity increases with increasing dose in one or more species,  and virtually all members of a population or species are affected at high enough doses. Dose-dependent hepatotoxicity may be caused by the parent drug or by a metabolite generated reliably in the treated species (Figure 140-1). These reactions are relatively predictable, and therapeutic drug monitoring may be helpful in prevention. They

576

SECTION  VI  Gastrointestinal Diseases Parent drug or reliably generated metabolite

Oxidative stress Acetaminophen Azathioprine Azole antifungals P450 induction Phenobarbital?

Mitochondrial dysfunction Tetracyclines Amiodarone

Transporter inhibition Cholestasis of pregnancy

Figure 140-1  Dose-dependent, drug-associated hepatotoxicity

typically is caused by either the parent drug or a consistently generated metabolite. Drugs can inhibit transporter pumps and lead to a functional cholestasis; this occurs with endogenous hormone metabolites during pregnancy. Many drugs yield reactive metabolites that cause oxidative stress; examples include acetaminophen, azathioprine, and azole antifungals. For these compounds, antioxidant supplementation may be effective. Drugs that interfere with mitochondrial function can lead to steatosis from inhibition of fatty acid β-oxidation or may lead to more severe hepatocellular damage because of impaired cellular respiration. Finally, drugs that act as P450 inducers, such as phenobarbital, may mediate hepatotoxicity by chronic bioactivation of environmental toxins.

Azathioprine Azathioprine can lead to increases in ALT and/or ALP activities in some dogs; these abnormalities commonly are subclinical but may be accompanied by jaundice and clinical signs. Azathioprine liver injury is associated with the generation of oxidative metabolites and depletion of hepatic antioxidants in rodent models and can be prevented by pretreatment with N-acetylcysteine. Dogs treated with azathioprine should be monitored routinely for increases in liver enzyme activities. If glucocorticoids also are administered, liver enzyme interpretation can become clouded; discordant increases in ALT relative to SAP, or early increases in serum bilirubin, are cause for concern. Risk factors for azathioprine hepatotoxicity in dogs are not clear, but increases in ALT or ALP typically are reversible with simple dosage reduction. Based on what is known about azathioprine hepatotoxicity in other species, supplementation with glutathione precursors may be effective in preventing or reversing azathioprine hepatotoxicity in dogs, but this has yet to be evaluated.

Azole Antifungals

require a dose reduction but usually not permanent drug discontinuation.

Phenobarbital Hepatotoxicity from phenobarbital can range from subclinical increases in serum bile acids to clinical hepatopathy to fulminant liver failure (Dayrell-Hart et al, 1991). Signs typically develop after a year or more of pheno­ barbital treatment, and prolonged duration of administration is associated with degree of histologic injury  in epileptic dogs. Typical histologic findings in dogs  with clinical signs are bridging portal fibrosis, bile  duct hyperplasia, and nodular regeneration. Dogs with phenobarbital hepatotoxicity improve clinically after  phenobarbital dose reduction (Dayrell-Hart et al, 1991). However, liver enzyme abnormalities can develop in phenobarbital-treated dogs without histologic liver injury, and higher phenobarbital dosages and serum drug concentrations have not been correlated with the development of abnormal serum bile acids in epileptic dogs. These findings suggest that phenobarbital hepatotoxicity is dose dependent, with modifying factors that are not understood. One hypothesized mechanism of phenobarbital hepatotoxicity is induction of cytochrome P450 enzymes, with secondary bioactivation and hepatotoxicity of other drugs, dietary components, or environmental toxins. For example, phenobarbital increases the hepatotoxicity of carbon tetrachloride in dogs, of chloroform in mice,  and of acetaminophen in human hepatocytes. Phenobarbital hepatotoxicity therefore could be modulated by environmental exposures in individual dogs. Phenobarbital does not lead to either enzyme induction or hepatotoxicity in cats.

Ketoconazole, itraconazole, and fluconazole can lead  to increases in serum ALT in dogs, although clinical  signs such as jaundice are uncommon. Mild, clinically insignificant increases in ALT also have been reported  in cats treated with itraconazole and fluconazole. In  dogs with blastomycosis, higher dosages of itraconazole (10 mg/kg/day) were associated with a greater risk of  ALT abnormalities than 5 mg/kg/day, with no difference in efficacy (Legendre et al, 1996). Further, increases in ALT and ALP were correlated with itraconazole plasma concentrations, which supports a dose-dependent mechanism. In animal models, ketoconazole hepatotoxicity has been attributed to an oxidative metabolite, N-deacetyl ketoconazole, which leads to covalent binding to liver proteins and glutathione depletion. Fluconazole appears to be less hepatotoxic overall than either ketoconazole or itraconazole in humans and animal models. In dogs with blastomycosis, the author observed increases in serum ALT in 26% of dogs treated with itraconazole (median fold increase 2.7), and in 17% of dogs on fluconazole (median fold increase 1.5). The author has observed anecdotally increases in serum ALT during treatment with itraconazole, which have resolved after a switch to fluconazole during treatment for blastomycosis in dogs.

Acetaminophen Acetaminophen is a classic dose-dependent hepatotoxin in humans and dogs; doses greater than 150 to  250  mg/kg lead to acute centrilobular hepatic necrosis. In cats, hematologic toxicity predominates over direct liver toxicity. Acetaminophen is bioactivated to the reactive oxidized metabolite, NAPQI (N-acetyl-p-benzoquinone imine), which is detoxified by glutathione conjugation. This provides the rationale for treatment of overdoses with the glutathione precursor N-acetylcysteine (140  mg/ kg loading IV, then 70  mg/kg q6h for 7 treatments).

CHAPTER  140  Drug-Associated Liver Disease* Although N-acetylcysteine is most effective in humans when given within 8 hours of acetaminophen ingestion, this antidote still has beneficial effects on survival when given much later in the course of intoxication. S-adenosylmethionine (SAMe) also can be used for acetaminophen intoxication in dogs that can tolerate oral medications; the protocol that has been used successfully is a 40 mg/kg loading dose, followed by 20 mg/kg q24h for 7 days. Cimetidine has been recommended to inhibit oxidation of acetaminophen to NAPQI; however, this drug has no effect on NAPQI generation in vitro and is not effective in humans with acetaminophen overdose; cimetidine therefore is not recommended.

Amiodarone Amiodarone leads to clinically significant hepatotoxicity in about 45% of dogs treated for refractory atrial fibrillation and ventricular arrhythmias, a median of 16 weeks after starting maintenance therapy (Jacobs et al, 2000; Kraus et al, 2009). Predominant increases in ALT typically are observed, with or without hyperbilirubinemia and neutropenia. These abnormalities slowly resolve over 1 to 3 months after drug discontinuation. Toxicity in animal models has been attributed to two oxidative metabolites, mono-N-desethylamiodarone (MDEA) and di-N-desethylamiodarone (DDEA), which generate reactive oxygen species that uncouple oxidative phosphorylation and lead to mitochondrial damage. Because of the prevalence of hepatotoxicity and neutropenia, a baseline CBC and biochemical panel is recommended in all dogs before amiodarone initiation, with a recheck of liver enzymes after a loading period and monthly during treatment. The development of substantial increases in serum ALT is an indication for dose reduction or drug discontinuation.

Lomustine The alkylating agent lomustine, or CCNU, is associated with substantial increases in serum ALT (> fivefold baseline) in about 29% of dogs (Hosoya et al, 2009; Rassnick et al, 2010). Enzyme elevations can occur suddenly and are most common after 1 to 3 monthly doses of CCNU. Dogs also may develop modest hyperbilirubinemia. The risk of ALT elevations is greatest in the boxer breed and in younger dogs (≤5 years old). Clinical signs of hepatotoxicity occur in an estimated 6% of CCNU-treated dogs, are noted after a median of four doses, and are associated with a higher cumulative dosages (median 350 mg/m2) (Kristal et al, 2004). Liver histopathology shows portal aggregates of hemosiderinladen Kupffer cells, enlargement of hepatocyte nuclei, and hepatocyte vacuolization. Dose reduction or drug discontinuation (for severe enzyme elevations) is associated with improvement in ALT activities in most dogs. However, some dogs that were not identified until clinical signs developed have been euthanized as a result of progressive liver disease. The mechanism(s) for CCNU hepatotoxicity are not known. Because of the high incidence of biochemical hepatotoxicity associated with CCNU and the risk for

577

Parent drug CYPs FMOs Reactive metabolite Oxidative stress Methimazole Diazepam? Necrosis Apoptosis

Drug hapten with immune response Potentiated sulfonamides Felbamate?

Humoral Drug-specific response T cells

Figure 140-2  Although the pathogeneses of many idiosyn-

cratic hepatotoxins are not understood, the most common demonstrated mechanism is the generation of reactive metabolites that lead to oxidative stress and/or hapten formation. Reactive metabolites typically are generated locally in the liver by cytochrome P450s (CYPs), flavin monooxygenases (FMOs), or other pathways. These metabolites may bind to critical proteins and impair hepatocyte function or generate reactive oxygen species than damage hepatocyte membranes. Drug-protein adducts also can be processed and presented to the immune system in association with MHC molecules. In the presence of a “danger” signal such as oxidative stress, this antigen presentation may lead to clonal expansion of drug-specific T cells, and/or the generation of drug-specific antibodies that target hepatocyte proteins.

progression to hepatic failure it is critical to monitor liver enzymes and bilirubin in all dogs treated with CCNU, at a minimum before each subsequent dosage. Concurrent SAMe and silybin (Denamarin) therapy given to dogs treated with CCNU led to lower liver enzyme elevations and less clinical toxicity (Skorupski et al, 2011).

Idiosyncratic Hepatotoxicity Idiosyncratic hepatotoxicity reactions are more difficult to predict because they lead to toxicity in only a small proportion of patients at therapeutic dosages. Toxicity does not increase with dose in the general population (therefore they are not considered dose dependent),  but toxicity probably does increase with dose in susceptible individuals. Idiosyncratic hepatotoxicity often is caused by reactive metabolites that are variably generated among individuals (Figure 140-2). These reactive metabolites may cause oxidative stress, mitochondrial damage, or form haptens that trigger a humoral or T cell-mediated immunologic response. Although idiosyncratic drug reactions sometimes are called drug hypersensitivity reactions, they may or may not involve an adaptive immune response. Idiosyncratic drug reactions usually require discontinuation of the suspect drug, and structurally related drugs may cause a similar reaction.

Potentiated Sulfonamides Potentiated sulfonamides are the most common antimicrobials associated with idiosyncratic hepatotoxicity in the dog. All commercially available formulations have been implicated. Clinical signs usually are seen 5 to  30 days after starting sulfonamides, with a mean of 12 

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SECTION  VI  Gastrointestinal Diseases

days. A hepatocellular pattern may progress over several  days to cholestasis in some dogs; hepatic necrosis is  the predominant histologic lesion initially. Signs also may include fever (55% of cases), transient neutropenia, thrombocytopenia, hemolytic anemia, polyathropathy, proteinuria, keratoconjunctivitis sicca, skin lesions, or uveitis. Dobermans are overrepresented among dogs with idiosyncratic sulfonamide toxicity, although arthropathy and glomerulonephropathy, not hepatotoxicity, typically are reported in this breed. Sulfonamide antimicrobials are oxidized to form nitroso metabolites that covalently bind to proteins and act as haptens. Idiosyncratic sulfonamide toxicity is convincingly immune mediated in humans, with antidrug antibodies and drug- and metabolite-specific T cells documented. If potentiated sulfonamides must be prescribed, the client should be educated to look for any subtle signs of illness. Failure to discontinue sulfonamides at the time of initial development of adverse signs can lead to fatal outcomes. Although specific antidotes for sulfonamide hypersensitivity have not been evaluated, this author recommends supplementation with a glutathione precursor (SAMe or N-acetylcysteine, using the same protocols as for acetaminophen toxicity) and ascorbate (30 mg/kg q6-8h IV, empiric dosage), based on the finding that glutathione and ascorbate can reverse haptenization of the nitroso metabolite to canine liver microsomes in vitro (Lavergne and Trepanier, unpublished observations). Glucocorticoids may be considered in the subacute setting, particularly if a cholestatic pattern persists after drug discontinuation and support.

Carprofen Potential hepatoxicity from carprofen is well recognized among veterinary clinicians, with an estimated incidence of 1.4 cases per 10,000 dogs treated (0.05%). Clinical signs of acute hepatic failure are noted 5 to 30 days after drug initiation, with a median of 19 days (MacPhail et al, 1998). A predominant hepatocellular or mixed pattern is found. No dogs with carprofen toxicity have been reported with increased ALP activities in the absence of clinically significant concurrent increases in ALT. Bridging hepatic necrosis is the predominant histopathologic finding. Although Labrador retrievers were overrepresented in the initial report, this may reflect the high ownership of this breed because the syndrome could not be reproduced in Labradors under controlled conditions (personal communication, Pfizer Animal Health). Given the low incidence and abrupt onset of idiosyncratic hepatotoxicity from carprofen in dogs, routine monitoring of liver enzymes is not an efficient approach to preventing clinical toxicity. Owners should be advised to watch for subtle signs of illness during NSAID administration, to include inappetence, vomiting, diarrhea, lethargy, or dark urine. A normal ALT in the face of clinical illness essentially rules out carprofen hepatotoxicity.

Felbamate The antiepileptic drug felbamate can lead to marked increases in serum ALT in dogs concurrently treated with

phenobarbital (Dayrell-Hart et al, 1991). Four of 16 dogs developed clinical hepatopathies; in addition, serum phenobarbital concentrations increased in felbamate-treated dogs. This likely is due to an impairment of phenobarbital clearance by felbamate. Felbamate generates an oxidative metabolite, 2-  phenylpropenal (also called atropaldehyde), which is detoxified by glutathione. This metabolite is cytotoxic to hepatocytes in vitro, can bind tissues covalently, and leads to T cell stimulation in animal models. Based on the unfavorable safety profile, felbamate is not recommended, particularly in combination with phenobarbital, in dogs.

Zonisamide Acute hepatotoxicity recently has been reported in two dogs treated with the anticonvulsant zonisamide (Miller et al, 2011; Schwartz et al, 2011). In one dog, clinical signs began 3 weeks after drug initiation, with a mixed biochemical pattern. Abnormalities resolved with drug discontinuation. In a second dog, marked increases in ALT with hyperbilirubinemia were noted 10 days after zonisamide was started. This dog was euthanized because of hepatic failure; histopathology showed massive panlobular hepatic necrosis with marked periportal microvesicular steatosis. Further clinical experience is needed before the incidence of zonisamide hepatotoxicity is clear; however, dog owners and veterinary colleagues should be informed of this potential adverse drug reaction when zonisamide is prescribed. Clients should be alerted to watch for acute signs of illness; if noted, zonisamide should be discontinued and serum ALT should be evaluated.

Diazepam Diazepam represents a classic idiosyncratic hepatotoxin in cats, first recognized and reported in the mid-1990s (Center et al, 1996). Cats develop clinical signs with  sedation 5 or more days after drug initiation, with progression to jaundice and overt hepatic failure. Blood work shows dramatic increases in ALT activities in all cats. Marked centrilobular hepatic necrosis, with mild to marked biliary hyperplasia, is seen on liver biopsies. The syndrome of diazepam hepatotoxicity in cats has been reported with generic and brand name diazepam (Center et al, 1996) but has not been observed with parenteral diazepam administration as a premedicant. Unfortunately, the mechanism for this potentially fatal adverse drug reaction has not been explored. Subsequent reports of diazepam hepatotoxicity have since appeared on veterinary message boards (Veterinary Information Network) in cats prescribed oral diazepam for seizures or urethral spasm. Although toxicity appears to be relatively rare, there are safer alternative drugs for behavioral problems, seizures, and urethral spasm in cats.

Methimazole About 1% to 2% of hyperthyroid cats administered the antithyroid drug methimazole develop clinical evidence of hepatopathy with jaundice, typically in the first month

CHAPTER  140  Drug-Associated Liver Disease* of treatment (Peterson, Kintzer, and Hurvitz, 1988). These changes are distinct from “innocent” increases in ALT and ALP seen with untreated hyperthyroidism. Hepatopathies can demonstrate a predominantly hepatocellular or cholestatic pattern, with or without hyperbilirubinemia. These reactions usually are reversible with drug discontinuation but can be fatal if not detected promptly. Methimazole hepatotoxicity in animal models presents as dose-dependent centrilobular hepatic necrosis, which is manifested in the presence of glutathione depletion. Hepatotoxicity has been attributed to an oxidative metabolite, N-methylthiourea, which is generated by flavin monooxygenases. This pathway has yet to be evaluated in cats. Management of idiosyncratic methimazole toxicity in cats is focused ideally on prevention. Cats treated with methimazole should be screened for increases in ALT and ALP at a recheck visit during the first 4 weeks of treatment and at subsequent rechecks if clinical signs of lethargy or anorexia are noted. If cats develop adverse clinical signs, idiosyncratic toxicity (hepatopathy, blood dyscrasias, or facial excoriation) should be ruled out. The transdermal route does not seem beneficial in preventing idiosyncratic methimazole toxicity, including hepatotoxicity. Given the role of glutathione depletion in methimazole hepatoxicity in experimental models, the efficacy of glutathione precursors must be evaluated in the management of this adverse drug reaction.

Monitoring and Prevention Client education and clinician index of suspicion are  the mainstays of monitoring for, and recognizing, druginduced hepatotoxicity. For dose-dependent reactions, periodic clinical monitoring such as serum drug concentrations, liver enzymes, serum bilirubin, and bile acids are useful in detecting hepatopathies before clinical signs develop. For idiosyncratic drug-induced hepatopathies, routine blood work is an inefficient monitoring tool. Hundreds of patients would have to be screened to detect a single rare adverse reaction, and more importantly, recent normal blood work may not predict an acute onset of hepatic necrosis a few days later. Clinicians always should consider the possibility of an adverse drug reaction in ill patients that have started a new drug, especially within the previous 4 weeks. Although any drug potentially could cause an adverse event in a given patient, 

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the clinician should focus on drugs with a high prior probability of toxicity (i.e., those drugs previously associated with idiosyncratic hepatotoxicity in dogs, cats, or humans). Most cases of drug-associated liver disease are reversible with drug discontinuation; for severe fulminant cases, rapid recognition of a possible drug-induced etiology, followed by aggressive support appropriate to the drug in question, is essential to a good outcome.

References and Suggested Reading Center SA et al: Fulminant hepatic failure associated with oral administration of diazepam in 11 cats, J Am Vet Med Assoc 209:618, 1996. Dayrell-Hart B et al: Hepatotoxicity of phenobarbital in dogs: 18 cases (1985-1989), J Am Vet Med Assoc 199:1060, 1991. Hosoya K et al: Prevalence of elevated alanine transaminase activity in dogs treated with CCNU (Lomustine), Vet Comp Oncol 7:244, 2009. Jacobs G, Calvert C, Kraus M: Hepatopathy in 4 dogs treated with amiodarone, J Vet Intern Med 14:96, 2000. Kraus MS et al: Toxicity in Doberman Pinchers with ventricular arrhythmias treated with amiodarone (1996-2005), J Vet Intern Med 23:1, 2009. Kristal O et al: Hepatotoxicity associated with CCNU (lomustine) chemotherapy in dogs, J Vet Intern Med 18:75, 2004. Legendre AM et al: Treatment of blastomycosis with itraconazole in 112 dogs, J Vet Intern Med 10:365, 1996. MacPhail CM et al: Hepatocellular toxicosis associated with administration of carprofen in 21 dogs, J Am Vet Med Assoc 212:1895, 1998. Miller ML et al: Apparent acute idiosyncratic hepatic necrosis associated with zonisamide administration in a dog, J Vet Intern Med 25:1156, 2011. Peterson ME, Kintzer PP, Hurvitz AI: Methimazole treatment of 262 cats with hyperthyroidism, J Vet Intern Med 2:150, 1988. Rassnick K et al: A phase II study to evaluate the toxicity and efficacy of alternating CCNU and high-dose vinblastine and prednisone (CVP) for treatment of dogs with high-grade, metastatic or nonresectable mast cell tumours, Vet Comp Oncol 8:138, 2010. Schulz BS et al: Suspected side effects of doxycycline use in dogs—a retrospective study of 386 cases, Vet Rec 169:229, 2011. Schwartz M et al: Possible drug-induced hepatopathy in a dog receiving zonisamide monotherapy for treatment of cryptogenic epilepsy, J Vet Med Sci 73:1505, 2011. Skorupski KA et al: Prospective randomized clinical trial assessing the efficacy of Denamarin for prevention of CCNU-induced hepatopathy in tumor-bearing dogs, J Vet Intern Med 25:838, 2011.

CHAPTER 

141 

Acute Liver Failure SHARON A. CENTER, Ithaca, New York

A

cute liver failure (ALF) is an uncommon, rapidly progressive, often lethal condition reflecting sudden, or perceptively sudden, severe hepatocel­ lular necrosis or dysfunction associated with hyper­ bilirubinemia, coagulopathy, and evidence of hepatic encephalopathy (HE) (Nguyen and Vierling, 2011). As characterized in humans, HE manifests as a breadth of neurobehavioral or psychologic abnormalities ranging from overt to mild encephalopathy. No subjective or objective scoring system has been validated in compan­ ion animal patients, similar to criteria used in humans (Riordan and Williams, 1997). In humans with ALF, highgrade HE has a poor prognostic implication.

Causal Factors Identifying the cause of ALF has prognostic and therapeu­ tic implications but often remains enigmatic. However, a number of well-substantiated causes have been recog­ nized (Boxes 141-1 and 141-2). Hepatotoxic and idiosyn­ cratic drug reactions are most common, with environmental and plant toxins, infectious diseases, rare neoplastic dis­ orders, and other conditions less common. The indis­ criminant appetite of many dogs results in a greater risk of environmental toxin, hepatotoxic plant, or mycotoxin ingestion compared with cats.

Pathophysiology The liver has a high susceptibility to toxicity because of its location and central role in metabolic and detoxifica­ tion pathways. Susceptibility and severity of hepatobili­ ary injury is influenced by age, species, patient nutritional status, concurrent drug administration, antecedent disease, the presence of excessive hepatocellular transi­ tion metal storage, antioxidant status, hereditary factors, and current or prior exposure to the same or similar com­ pounds. Hepatic toxicity is the most commonly reported organ system toxicity associated with true adverse drug reactions that may be intrinsic or idiosyncratic (see Chapter 140). Metabolically generated toxins often derive from reactions catalyzed by the cytochrome P-450 system. Such toxins may be potentiated by microsomal enzyme inducers (e.g., phenobarbital, omeprazole), whereas toxic­ ity of some is impaired by microsomal enzyme blockers (e.g., cimetidine, chloramphenicol, ranitidine). Although pathophysiologic mechanisms leading to ALF vary depending upon the causal agent, oxidative injury often plays a critical role. Many toxins are metabolized to a secondary injurious product generating toxic electro­ philic adducts that interact with structural proteins, 580

enzymes, or nucleoproteins (aflatoxin, cycad, sulfon­ amides) or that induce lymphocytotoxic responses or FAS-induced apoptosis (Box 141-3). The capacity of the hepatic microenvironment to terminate injury and regen­ erate perfused nonfibrosed hepatic parenchyma varies with the inciting cause, whether the toxin incapacitates protein transcription, the nutritional status of the patient (inappetence reduces glutathione [GSH] concentrations), presence of antecedent liver injury, and for dogs the status of transition metal accumulation (iron, copper). In humans, genetic polymorphisms in keratins 8 and 18 that confer antiapoptotic effects in liver injury increase sus­ ceptibility to ALF; these are known to segregate with ethnicity (Strnad et al, 2010). There is no information regarding this phenomenon in dogs or cats. Susceptibility to certain drugs and toxins having a narrow therapeutic or exposure window may reflect innate (individual or species related) or acquired low hepatic GSH. The increas­ ing causal role of complementary alternative medications in ALF in humans is relatively uninvestigated in compan­ ion animals. All supplements or complementary alterna­ tive medications have risk for contamination with other undeclared botanicals or chemicals (Nguyen and Vierling, 2011).

Clinical and Clinicopathologic Features Progressive clinical features of ALF include abrupt onset of lethargy, inappetence, vomiting, weakness, dehydration, hypothermia, jaundice, bleeding tendencies, and hypo­ tension. Clinicopathologic tests reflect the type, rate, and zonal location of hepatocellular injury, development of acute splanchnic hypertension, and synthetic failure. Acute severe necrosis accompanied by zone 3 parenchy­ mal collapse (perivenous, adjacent to hepatic venule) causes remarkable transaminase release (alanine amino­ transferase [ALT] from hepatocellular cytosol, aspartate aminotransferase [AST] from mitochondria), whereas injury focused on zone 1 (periportal region) can lead to a combined early induction of alkaline phosphatase  (ALP) and γ-glutamyl transferase (GGT) and transaminase activities. Cats with diazepam-induced ALF also demon­ strate markedly increased CK activity attributable to skel­ etal and cardiac muscle necrosis (Center et al, 1996). Toxins binding with nucleoproteins can disrupt liver enzyme synthesis (block protein transcription), muting their diagnostic utility in detection of liver injury (e.g., aflatoxin, cyanobacteria [microcystin], cycad toxicity). Panlobular hepatic injury leads to rapid development of hypocholesterolemia, low protein C and antithrombin activities, low coagulation proteins, and prolonged

CHAPTER  141  Acute Liver Failure

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BOX 141-1 

BOX 141-2 

Drugs That May Cause Hepatic Injury in Dogs and Cats*

Toxins and Conditions That May Cause Severe Acute Hepatic Injury to Dogs and Cats*

Acetaminophend,c Acetylsalicylic acidc Androgenic anabolic steroidsc (methyltestosterone, mibolerone) Antineoplastic drugs (methotrexate, 6-mercaptopurine [azathioprine]d, L-asparaginase, mithramycin, doxorubicin) Amiodaroned Chloroformd Chlortetracyclinec CCNU (lomustine, chemotherapy)d Danazol (an impeded androgen)c Diazepamc Erythromycin Glucocorticoids Griseofulvinc Halothaned

Ketoconazoled,c Mebendazoled Methimazolec Methoxyfluraned Mitotane (OP’ DDD)d Oxibendazoled Phenols: in catsc (aspirin, benzoic acid, benzyl alcohol, hexachlorophene) Phenazopyridine Phenobarbitald Phenothiazinesd Phenylbutazoned Phenytoind Primidoned Rimadyl (carprofen)d Tetracyclinec Thiacetarsamided Tolbutamide Trimethoprim/sulfad Xylitold Zonisamided

*Note that the superscript d in the table refers to dogs; the superscript c refers to cats.

clotting times. Acute onset of transudative abdominal effusion reflects intrahepatic and splanchnic hyperten­ sion that may worsen upon administration of polyionic fluids necessary to maintain hydration and perfusion pres­ sure. Albumin lost with bleeding into the intestinal lumen and transudation into the abdominal cavity results in pro­ gressive hypoproteinemia and hypoalbuminemia. Admin­ istration of packed RBCs can rapidly escalate (by fivefold to tenfold) hyperbilirubinemia by delivery of pigment that must be conjugated and eliminated by the liver. Glucos­ uria discordant with hyperglycemia usually incriminates an acquired Fanconi’s injury (e.g., severe copper hepato­ toxicosis, NSAID injury [carprofen], leptospirosis) associ­ ated with proximal renal tubular necrosis; this usually is accompanied by the appearance of granular casts.

Prognosis The ability to predict survival in ALF is limited with non­ invasive assessments. The best noninvasive predictive measures include sequential assessment (every few days) of liver enzyme activity and concentrations of albumin, fibrinogen, cholesterol, blood urea nitrogen (BUN), total bilirubin, and monitoring for appearance and abatement of ammonium biurate crystalluria, specific drug- or toxinrelated crystalluria, glucosuria, and granular casts. Provi­ sion of fresh frozen plasma to abate bleeding tendencies complicates interpretation of coagulant and anticoagu­ lant proteins. During the regenerative phase of recovery, increased activity in ALP and GGT may reflect oval 

Environmental Toxins Amanita mushroomsd Aflatoxinsd/mycotoxinsd Blue-green algae (Cyanobacteria)d Chlorinated compounds Cycad (sago palm)d Heavy metals (Pb, Zn, Mn, Ar, Fe, Cu)d,c Phenolic chemicals (especially cats)c Gossypol from cottonseed Endotoxins/Infectious Agents Enteric organisms Clostridium perfringens Clostridium difficile gramnegative enteric bacteria Food poisoning bacteria E. coli Staphylococcus spp. Salmonella spp. Bacillus cereus (emetic toxin) Leptospirosis Toxoplasmosis Disseminated fungal infections Leishmaniasis

Nutritional/Herbal Products Atractylis gummifera Black cohosh Callilepis laureola Chaparral Comfrey extracts (pyrrolizidine alkaloids)d Chinese herbal medicines (difficult to characterize) Germander Greater celandine Green tea extract Herbalife (not all products) Hydroxycut (not all products) Lipoic acidc,d Kava Kavad Licorice Mistletoe Pennyroyal senna Usnic acid Valerian Xylitold Neoplasia Histocytocytic sarcomad Lymphosarcomad,c Massive hepatocellular carcinomad Leukemiad,c Mast cell neoplasiac

*Note that the superscript d in the table refers to dogs; the superscript c refers to cats.

BOX 141-3  Mechanisms of Hepatotoxic Injury 1. Altered physicochemical properties of membranes: cell   or organelles 2. Inhibition of membrane and cellular enzymes 3. Impaired hepatic uptake or export processes 4. Altered cytoskeletal function 5. Precipitation of insoluble complexes in bile 6. Altered cell calcium homeostasis 7. Metabolic conversion to reactive intermediates causing oxidative injury augmented by antecedent excessive hepatic copper or iron stores 8. Toxic adducts binding to nucleoproteins: Prohibits protein transcription Prohibits cell replication and tissue repair 9. Initiation of FAS-induced apoptosis 10. Molecular mimicry: leads to immunologic injury 11. Lymphocytotoxic responses

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SECTION  VI  Gastrointestinal Diseases

cell hyperplasia and development of so-called reactive cholangioles. With toxins causing zone 3 collapse (e.g., aflatoxicosis, cycad poisoning, acute severe copper hepa­ totoxicosis), acute onset intrahepatic portal hypertension can lead to splanchnic hypertension before formation  of acquired portosystemic shunts. This may lead to  critical and fatal diapedesis of blood into the alimentary canal in the absence of ulcerative lesions (Dereszynski et al, 2008). Persistent or recurrent severe hypoglycemia portends a grave prognosis; this indicates compromised  gluconeogenesis and depletion of tissue glycogen stores. Abdominal ultrasound often demonstrates only abdomi­ nal effusion in animals with ALF but can disclose massive hepatocellular carcinoma, inducing the syndrome or parenchymal nodules or hypoechoic parenchyma associ­ ated with diffuse lymphosarcoma. A liver biopsy is more helpful in predicting chance for recovery than noninva­ sive assessments but is hazardous during the coagulo­ pathic stage. Despite the diagnostic limits of small sample size, core needle biopsy samples are most appropriate owing to short anesthetic and collection time and limited tissue trauma. Needle aspirates of liver are used to rule out disseminated hepatic neoplasia. Needle aspirates or core biopsies require anticipatory treatment with vitamin K1 (see below) and DDAVP (dose of 0.5 to 5.0 µg/kg SC or diluted in 10 to 20 ml of saline and given IV slowly over 10 minutes during the perioperative period [e.g., before liver biopsy or during a bleeding crisis]).

Supportive Care Supportive care should include crystalloid fluid support with caution given to the patient’s tolerance and procliv­ ity for third space fluid transudation. Causal factors of ALF concurrently may impair endothelial integrity, promoting formation of edema and abdominal effusions. Propriety of hetastarch administration must be considered carefully in light of its antiaggregatory platelet effect that can heighten risk for critical hemorrhage. The recently intro­ duced Vetastarch colloid seemingly does not impose similar marked coagulative influence. Rather, infusion of canine fresh frozen plasma is preferred, although cost can be prohibitive in large-breed dogs. Vitamin K1 should be provided initially at three doses of 0.5 to 1.5 mg/kg q12h SC or IM. After that, it is administered as perceived neces­ sary in one of two ways: (1) (optimal method) based on PIVKA testing (more sensitive than routine bench coagu­ lation tests) or the dependent coagulation factors or (2) (more common method) assessed with routine prothrom­ bin or partial thromboplastin coagulation bench tests. Judicious supplementation of B-soluble vitamins and KCl in fluids thwarts development of thiamine deficiency (can resemble neurologic signs confused with HE, and pro­ motes lactic acidosis and hypoglycemia) and hypokale­ mia (that may promote hyperammonemia). Glucose supplementation should be provided as needed in fluids to abate hypoglycemia; a 2.5% or 5.0% dextrose supple­ ment is usually sufficient. Because splanchnic hyperten­ sion increases risk for enteric bacterial translocation, which can contribute to HE, broad-spectrum antimicrobi­ als are administered parenterally. A combination of ticar­ cillin, enrofloxacin, and metronidazole often is used

initially, if septicemia, suppurative hepatitis, leptospiro­ sis, or other infectious bacterial agents are considered possible causes of the ALF. Acute splanchnic hypertension is not associated with gastric ulceration in humans or companion animals. Although hypergastrinemia can accompany hepatic splanchnic hypertension, in humans this is not associated with increased gastric acid produc­ tion but rather reflects gastric mucosal edema and reduced gastric acid production. Consequently, routine adminis­ tration of H2 or HCl pump blockers is not endorsed. Rather, this treatment should be defined by examining vomitus for pH and blood. Control of emesis with cen­ trally acting antiemetics is recommended; metoclo­ pramide using constant rate infusion (customary dosing) has been used successfully. There is less experience with maropitant in ALF; this drug is partially metabolized in the liver, so the conventional dose recommendations are reduced. Sucralfate (slurry preparation) should be pre­ scribed for patients demonstrating hematemesis (1 to 2 g mixed with water q8-12h). Because ALF is associated with high risk for hepatic oxidant damage, N-acetylcysteine (NAC) should be administered IV over 20 minutes up to q6h (10% solution, nonpyrogenic filter, loading dose of 140 mg/kg, thereafter at a dose of 70 mg/kg). Chronic constant rate infusion of NAC should not be used to  avoid interfering with urea cycle ammonia detoxification (protonation of carbomyl phosphate). Current studies  of NAC utility in ALF because of a variety of toxins  suggest antioxidant and antiinflammatory benefits. When oral medications are tolerated, administration of vitamin E (10 U/kg of α-tocopherol q24h PO), bioavailable S-adenosylmethionine (SAMe) (20 mg/kg q24h PO), and a silibinin/phosphatidylcholine (PPC) combination (2 to 5 mg/kg q24h PO) are recommended, primarily for their antioxidant properties. However, vitamin E, SAMe, and silibinin/PPC also may modulate beneficially NF-κB and cell apoptosis signaling, and reduce hepatofibrogenesis; SAMe and silibinin/PPC may stimulate cell repair and DNA replication and improve membrane fluidity (enhanc­ ing cell signaling), and SAMe may provide a choleretic response that may hasten biliary elimination of infectious organisms or toxins. Whether there is a role for ursode­ oxycholate in ALF remains unclear. Treatment of HE by oral administration of nonabsorbable antimicrobials (e.g., neomycin, rifaximin) may modify beneficially the enteric biome reducing generation of HE toxins (Rivkin and Gim, 2011; Bajaj et al, 2012). Cleansing water enemas followed by a lactulose reten­ tion enema may reduce production and uptake of enteric ammonia. Activated charcoal by oral dose or enema may be warranted if a specific toxin potentially persists in  the alimentary lumen. Elimination of some toxins may be escalated by oral administration of cholestyramine, a binding resin. Nutritional support containing adequate protein levels for tissue repair should be provided. Paren­ teral alimentation may be needed in the recumbent, lethargic, and neuroencephalopathic animal unwilling or unable to eat. Use of an amino acid solution designed for support of humans with ALF (rich in branched-chain amino acids [BCAA]) can improve nitrogen balance and reduce the passage of aromatic amino acids (AAA) across the blood-brain barrier, where they function as false

CHAPTER  142  Chronic Hepatitis Therapy neurotransmitters (competition between BCAA and AAA at the blood-brain barrier). Special considerations are nec­ essary when parenteral nutrition is designed for a feline ALF patient owing to the unique carnivore requirements of cats (Morris, 2002). Clinicians should keep animals with progressive neurologic signs leading to confusion, lethargy, recumbency, seizures, and coma in a head-up posture (45 degrees), give them mannitol, and induce mild hypothermia to reduce critical brain edema that may lead to herniation. Severe, acute HE in ALF reflects acute astrocyte swelling secondary to accumulation of metabolic milliosmoles (e.g., alanine, lactate, glucose, glutamine, glycine), impaired mitochondrial function (by ammonia), increased permeability of the blood-brain barrier, oxidative injury, and inflammatory cytokines. Although salvage interventions are described in experi­ mental animal models of ALF, there is no information regarding their success in companion animals with ALF. Recent interest in development of extracorporeal hepaticbridge modules offer potential therapeutic options in the future that may sustain life until hepatocellular regenera­ tion initiates. For cats with ALF the following treatment is warranted: L-carnitine (250 mg q24h PO), taurine (250 to 500 mg q24h PO), vitamin B1 (100 mg q12h PO ini­ tially × 3 days, then q24h), and vitamin B12 (cobalamin). (B12 is first tested in plasma, administered 500 µg once, SC or IM before test results are available and then judi­ ciously repeated weekly based on test findings.) Vitamin K is given as previously recommended (see earlier). These supplements are recommended based on successful resus­ citative experience in cats with severe hepatic lipidosis (Center, 2005).

CHAPTER 

583

References and Suggested Reading Albretsen JC, Khan SA, Richardson: Cycad palm toxicosis in dogs: 60 cases (1987-1997), J Am Vet Med Assoc 213(1):99, 1998. Bajaj JS et al: Linkage of gut microbiome with cognition in hepatic encephalopathy, Am J Physiol Gastrointest Liver Physiol 302(1):G168, 2012. Bémeur C et al: N-acetylcysteine attenuates cerebral complica­ tions of non-acetaminophen-induced acute liver failure in mice: antioxidant and anti-inflammatory mechanisms, Metab Brain Dis 25(2):241, 2010. Center SA: Feline hepatic lipidosis, Vet Clin North Am Small Anim Pract 35(1):225, 2005. Center SA et al: Fulminant hepatic failure associated with oral administration of diazepam in 11 cats, J Am Vet Med Assoc 209 (3):618, 1996. Dereszynski DM et al: Clinical and clinicopathologic features of dogs that consumed foodborne hepatotoxic aflatoxins: 72 cases (2005-2006), J Am Vet Med Assoc 232(9):1329, 2008. Dunayer EK, Gwaltney-Brant SM: Acute hepatic failure and coag­ ulopathy associated with xylitol ingestion in eight dogs, J Am Vet Med Assoc 229(7):1113, 2006. Miller ML et al: Apparent acute idiosyncratic hepatic necrosis associated with zonisamide administration in a dog, J Vet Intern Med 25(5):1156, 2011. Morris JG: Idiosyncratic nutrient requirements of cats appear to be diet induced evolutionary adaptations, Nutr Res Rev 15:153, 2002. Nguyen NTT, Vierling JM: Acute liver failure, Curr Opin Organ Transplant 16:289, 2011. Riordan SM, Williams R: Treatment of hepatic encephalopathy, N Engl J Med 337:473, 1997. Rivkin A, Gim S: Rifaximin: new therapeutic indication and future directions, Clin Ther (7):812, 2011. Strnad P et al: Keratin 8 and 18 variants are associated with ethnic background, Gastroenterology 139:828, 2010.

142 

Chronic Hepatitis Therapy PENNY J. WATSON, Cambridge, Cambridgeshire, Great Britain

C

anine chronic hepatitis (CH) is defined by the World Small Animal Veterinary Association (WSAVA) Liver Standardization Group histologically as being characterized by hepatocellular apoptosis or necrosis, a variable mononuclear or mixed inflammatory cell infiltrate, and regeneration and fibrosis. This definition says nothing about temporal chronicity. Some authors suggest the same criteria for the term chronic hepatitis be used in animals as it is in humans: clinical or biochemical evidence of hepatocellular dysfunction in animals without improvement for at least 6 months. However, clinical and biochemical evidence of hepatic

dysfunction alone in the absence of hepatic histopathology is never sufficient to diagnose CH. Unfortunately, none of the clinical and biochemical tests available in dogs differentiates primary from secondary liver disease, and in fact secondary and reactive hepatopathies are much more common than primary hepatitis in dogs. Serum liver enzymes and even ultrasound imaging and liver function tests can be altered secondary to a variety of other diseases, particularly those in the splanchnic bed drained by the portal vasculature. These diseases can produce similar clinical signs to CH, with vomiting, diarrhea, and even ascites and posthepatic jaundice in some

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cases. Some form of liver biopsy is therefore essential for definitive diagnosis and most appropriate treatment of CH in dogs.

Etiology The most effective treatment for CH is to treat the primary etiology. However, although canine CH is common, it is a frustrating disease in dogs because the cause is often unknown. One recent pathology study suggested as many as 12% of dogs from first opinion veterinary practices had histologic lesions in the liver consistent with CH by the time of death from any disease (Watson et al, 2010). Any breeds and crossbreeds can suffer from CH, but studies of CH from various countries in various decades have noted increased breed prevalence, some of which are consistent between countries and decades and some of which have changed. Although not definitively proving an inherited basis for CH in certain dog breeds, these findings certainly are suggestive of a genetic basis to the disease. Potential and proven causes of canine CH are detailed in Table 142-1 and include copper storage disease, chronic drug toxicities, and a number of proven or suggested infectious agents. However, many cases remain idiopathic, and a number of these may have autoimmune hepatitis. This has not been proven conclusively in  canine CH; however, it is suspected from recent work in Doberman pinschers in Scandinavia and also may occur in other breeds. Some of the other idiopathic cases may have a currently unknown canine chronic hepatitis virus. This has been suspected for a number of years, since the first description of a transmissible “acidophil cell hepatitis virus” in Glasgow in the 1980s (Jarrett and O’Neil, 1985). Some canine CH cases look clinically and histologically similar to chronic viral hepatitis in humans, but the putative virus has yet to be identified. Therefore  currently it is difficult if not impossible for a clinician  or pathologist to determine whether a particular noncopper-associated canine CH case is potentially viral or autoimmune, which obviously has profound implications for treatment, particularly with immunosuppressive drugs.

Treatment Goals

TABLE 142-1  Known and Potential Causes of Chronic Hepatitis in Dogs Potential Cause

Evidence in Dogs

Copper storage disease

Proven and suspected in a number of breeds

Iron storage disease (hemochromatosis)

Recognized in humans. Anecdotally reported in dogs but no published evidence except in association with massive iron overload

Other storage disease

The liver is involved in a number of rare but recognized storage diseases, which have predominant metabolic and CNS signs α-1 antitrypsin deficiency is a locally common cause of chronic hepatitis in humans and has been suspected but not proven in Cocker spaniels

Autoimmune disease

Suspected but not clearly proven. Recent work in Doberman pinschers in Scandinavia supportive of a role in this breed

Chronic bacterial disease

Bartonella spp. have been identified in a small number of cases of chronic granulomatous hepatitis in dogs; other chronic bacterial infections could be possible, including chronic biliary tract infection with resistant organisms. There are two old reports of CH associated with hepatic infection with atypical leptospira and a single recent case report of CH associated with Ehrlichia canis

Chronic viral disease

Suspected but not proven. There may be variation in breed susceptibility to viral hepatitis, as in humans

Chronic toxic hepatopathy

Chronic alcoholism is a clear example in humans. Phenobarbital toxicity is a documented cause in dogs. Other chronic toxicities from environmental toxins or drugs should be considered, although most reported canine toxic hepatopathies are acute

The approach to treatment of canine CH is outlined in Figure 142-1. The aims of treatment of any dog with CH are the following: • To treat the underlying cause, if this can be identified • To try to slow progression of the disease even if the cause is not identified • To support liver function as long as possible and support the dog in positive calorie and nitrogen balance • To treat the complications of liver disease that affect quality and length of life The underlying goal in all cases is to try to prevent the progression of disease to the end stage (i.e., cirrhosis). The WSAVA Liver Standardization Group defines cirrhosis  as a diffuse process characterized by fibrosis of the liver

and the conversion of normal liver architecture into structurally abnormal nodules. The liver has a high reserve capacity, but when loss of hepatocytes and  fibrosis reduces liver function to less than 25% of normal, hepatic failure ensues, which is incompatible with life. Cirrhosis often is accompanied by the development  of portal hyper­tension, where increased resistance to  flow through the hepatic vasculature raises portal pressure, resulting in splanchnic congestion, development  of ascites, and often acquired portosystemic shunts  and hepatic encephalopathy (HE) (see Chapter 144). In humans, the development of portal hypertension in endstage liver disease is a poor prognostic indicator. This has not been demonstrated specifically in dogs, although it is

CHAPTER  142  Chronic Hepatitis Therapy

585

Clinical signs, blood test findings, and imaging suggestive of chronic hepatitis

Is there ascites?

No

Yes Consider diuresis with spironolactone. May add furosemide early. Diurese prior to biopsy if possible. Is there jaundice?

No

Yes Rule out prehepatic and posthepatic. Consider ursodeoxycholic acid  antioxidants (vitamin E; SAMe; silibin)

Is there evidence of GI bleeding?

No

Yes Consider sucralfate and omeprazole or ranitidine

Liver biopsy possible/available?

No

Yes Confirms chronic hepatitis

Supportive treatment only with digestible diet (preferably not protein-restricted); antioxidants; perhaps antibiotics. Do NOT use steroids, other immunosuppressives, or copper chelators without biopsy

Stain for copper: is significant amount of copper present and consistent with severity of disease?

No

Assess degree of fibrosis, type of inflammatory cell, and distribution (see text)

Mild Attempt to identify and treat cause. Consider steroids or colchicine as antifibrotic

Moderate to marked and bridging. May still reverse if can identify and treat cause. Only use steroids if indicated as high risk of portal hypertension, ascites, and GI ulceration

Yes Use copper chelators; antioxidants; low-copper diet; increase zinc when chelation finished (see Chapter 143)

Severe cirrhosis usually irreversible; treat clinical signs

Figure 142-1  Logical approach to treatment of canine chronic hepatitis.

known that ascites is a negative prognostic indicator in canine CH (Raffan et al, 2009). The overarching aim in treating canine CH is therefore to diagnose it early and prevent progression to end-stage cirrhosis because liver transplantation is not as yet an option. However, fibrosis of the liver is not inevitably progressive in one direction, and even early cirrhosis  can be reversible if the underlying cause is removed, as has been demonstrated clearly in humans with alcoholic and viral hepatitis. The goal in treating canine CH therefore should be to identify and treat the cause wherever possible.

Initial Treatment Considerations Canine CH is not one single disease but a syndrome caused by a number of known or potential etiologic agents. Therefore no one treatment is effective for all cases of canine CH. Optimal treatment of the individual case of canine CH requires careful analysis of all the evidence available to the clinician: history, clinical findings, diagnostic imaging, and blood test results, in addition to biopsy results if available. It is impossible and potentially dangerous to give specific treatments for CH (such as copper chelators and steroid or other immunosuppressive

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therapy) without biopsy confirmation of disease. If the owner does not permit a liver biopsy or the clinician believes it is too risky for that patient, therapy cannot  be optimized for the disease and should be supportive only. In those cases, nonspecific supportive therapies and  treatment of clinical signs as outlined at the end of this chapter are the goal. The clinician should use all the information available to optimize treatment for an individual case. In the clinical examination, blood results, and imaging, the clinician must assess the degree of loss of liver function and identify signs of biliary stasis, portal hypertension, acquired portosystemic shunts, ascites, gastrointestinal edema or ulceration, or protein-calorie malnutrition. In the liver biopsy, if available, the clinician should assess the amount and distribution of inflammation and the types of inflammatory cells involved, the degree and distribution of fibrosis, and the presence of any obvious cause including buildup of copper. Combining all this information allows optimal treatment of the patient.

Specific Therapy Every effort should be made to understand the cause  of the disease because this allows optimal treatment. This is possible only if a liver biopsy is available. The history may suggest a cause: for example, elevated liver enzymes in a young Bedlington terrier would suggest copper storage disease, but other causes remain possible. Abnormal liver function tests in a dog on chronic phenobarbital therapy suggest phenobarbital hepatotoxicity, but other causes are possible or hepatotoxicity could be  predisposed by an underlying copper storage disease  or other hepatopathy. Therefore a liver biopsy always should be obtained if considered to be safe for the patient. The clinician should try to get the most representative biopsy possible in that patient. As discussed in Chapter 139, a wedge biopsy at laparotomy or laparoscopy is usually more representative than a needle biopsy, and a fine-needle aspirate is rarely helpful and should not be used to make a diagnosis of chronic hepatitis. The liver biopsy always should be stained for copper  if CH is described on the hematoxylin-eosin stain. A section of liver also may be sent off for quantitation of hepatic copper concentration (see Chapter 143). The pathologist may elect to undertake a variety of other stains to try to elucidate the etiology of the disease.  In some cases a discussion between the clinician and pathologist is ideal to come to a consensus for a logical course of action. If a significant amount of copper is found in the biopsy, in proportion to the severity of the disease, copper storage disease should be suspected strongly and treated with chelation and dietary therapy as described in Chapter 143. If copper storage disease is ruled out, the type and distribution of inflammation present may suggest a cause for the disease. A strong neutrophilic component, particularly if it is periportal, may indicate a chronic hepatic or biliary tract infection, and consideration should be given to culturing bile or liver and ruling out chronic partial extrahepatic biliary obstruction or cholecystitis.  A granulomatous inflammatory response may warrant

consideration of polymerase chain reaction (PCR) for  Bartonella spp. or fluorescence in situ hybridization (FISH) analysis for a bacterial etiology. A dense lymphoplasmacytic inflammatory component indicates consideration of an autoimmune cause. However, lymphoplasmacytic infiltration is nonspecific chronic inflammation occurring with a number of causes. Currently differentiating autoimmune hepatitis from other causes is impossible, so the most difficult decision to make may be over the use of steroids or immunosuppressive agents. In viral disease, steroid treatment may reduce temporarily the amount of inflammation but also increases the viral load. In humans with viral hepatitis, the amount of liver damage is proportional to viral load, so immunosuppressive therapy is avoided. In veterinary medicine, with the exception of adenovirus, viral hepatitis has not been documented; as yet it is impossible to rule out clinically viral disease as a cause. Use of steroids requires a liver biopsy because there is no indication for use in noninflammatory fibrosis and cirrhosis. If steroids are used in these cases in the presence of portal hypertension, they increase the risk of serious consequences, including increased water retention and gastrointestinal ulceration. The evidence base for the efficacy of steroids in CH is small and relies almost entirely on one retrospective study, in which immunosuppressive doses of steroids improved survival time in 58 treated dogs compared with 37 untreated dogs (Strombeck, Miller, and Harrold, 1988). However, like all retrospective studies, this study had many sources of potential bias, including preexclusion of cases that survived less than a week, clinician selection of treatment option, and a high proportion of Doberman pinschers and cocker spaniels, which are breeds perhaps most likely to have autoimmune hepatitis. The question still remains as to whether corticosteroids are indicated in all dogs with CH and whether the ideal dose is immunosuppressive or antiinflammatory. Nonetheless, corticosteroid therapy should offer the best chance of survival in dogs with true autoimmune CH and so should not be withheld if the clinician and pathologist believe on the basis of liver biopsies that this is the most likely cause of disease in a particular dog. The author would start with 0.5 to 1 mg/kg per day in these cases and taper the dose over the following 2 to 4 weeks, while carefully monitoring clinical signs and hepatocellular enzymes. This author does not routinely use additional immunosuppressive drugs in CH because the evidence for immune-mediated disease remains weak, immunosuppressive agents may reduce hepatic regenerative ability, and there is potential increased risk of infectious complications. Furthermore, no evidence supports the use of antiviral drugs in dogs with CH as are used in humans with viral hepatitis. Nonspecific use of antivirals is very unlikely to be of benefit because specific antiviral therapy should be targeted at the virus involved.

Supportive Therapy Slowing Progression of Disease In most cases, the cause of canine CH is unknown.  In these cases, the clinician still can attempt to slow progression of disease. The most important aim in slowing

CHAPTER  142  Chronic Hepatitis Therapy disease progression is to slow fibrosis. In addition, care should be taken to support liver function long term by feeding an appropriate diet and avoiding hepatotoxic drugs wherever possible in specific treatment of the liver disease and in the treatment of other, unrelated diseases. For example, all nonsteroidal antiinflammatory drugs should be avoided in dogs with CH. Therefore, if they have concurrent life-limiting chronic joint disease, alternatives will have to be found. Slowing fibrosis remains a challenge. After many years of research in humans and rodents the development of  a truly effective antifibrotic drug for humans is lacking. The source of hepatic fibrosis is the hepatic stellate  cell or Ito cell that transforms when stimulated from a quiescent vitamin A–storing cell to a collagen-secreting myofibroblast with contractile properties. These cells may be stimulated directly or indirectly by cytokines from inflammatory cells. One of the arguments for the use of steroids in canine CH is that their antiinflammatory properties reduce cytokine release and stellate cell activation. Hepatic fibrosis also can be a protective strategy, attempting to wall off an insult (such as infectious agent or toxin), so reducing fibrosis without treating the cause may not always be ideal (e.g., it could allow more widespread dissemination of an infectious organism). Therefore treating the cause is the most effective way of treating fibrosis. Some limited anecdotal evidence suggests that colchicine used at a dose of 0.03 mg/kg q24h PO in early hepatic fibrosis in dogs may be beneficial, but many dogs develop anorexia and gastrointestinal signs on this drug, in which case it should be stopped because the efficacy remains uncertain. In many placebo-controlled studies treating fibrotic-associated liver disease in humans, colchicine has failed to show a benefit. Colchicine never should be used in cats. Angiotensin-receptor blockers  are being tested in humans for treatment of hepatic  fibrosis but with conflicting results in different studies. A recent study in rodents suggests spironolactone treatment reduces fibrosis and portal hypertension, so this drug may be having more than just a diuretic effect in dogs with chronic hepatitis (Luo et al, 2012). In addition, supportive therapy with antioxidants (S-adenosylmethionine, silybin, and vitamin E) and ursodeoxycholic acid may help reduce fibrosis (see later).

Treating Clinical Signs Treating the clinical signs of disease nonspecifically is a worthwhile aim in CH because it improves the quality of life of the patient. Ultimately, most dogs with CH die because the owners request euthanasia because of poor quality of life, so improving the quality of life also should improve life expectancy in these patients. The factors to consider and treat are the following: • Ascites: If present, this should be treated as detailed in Chapter 144 with spironolactone as the primary diuretic and addition of loop diuretics as necessary. • Vomiting, diarrhea, and evidence of GI ulceration: These are common in animals with portal hypertension and should be treated predominantly by careful feeding of frequent, small amounts to

587

provide nutrition for gut wall healing and avoidance of potentially ulcerogenic drugs such as steroids. H2 antagonists such as ranitidine or proton pump inhibitors such as omeprazole could be used, together with sucralfate, although evidence for their efficacy in ulceration resulting from portal hypertension is lacking. If an antiemetic is required, metoclopramide would be preferred to maropitant because the latter is metabolized in the liver. • Jaundice: When prehepatic causes and posthepatic obstruction have been ruled out, this should be treated with ursodeoxycholic acid and antioxidants. Ursodeoxycholic acid (4 to 15 mg/kg q24h PO total dose that can be divided q12h) has a large number of potential benefits in animals with CH including choleresis, displacement of toxic bile acids, and antioxidant properties. There are no contraindications to its use but, like all other therapies in canine CH, the evidence for its efficacy is sparse. However, it makes sense to use it. Use of antioxidants also is logical in this circumstance because refluxed bile damages mitochondrial membranes and is a strong oxidant toxin. A combination of S-adenosylmethionine, silybin, and vitamin E is advised. The clinician should try to choose nutraceuticals with proven bioavailability in dogs. A dosage of 20 mg/kg/day has been suggested for S-adenosylmethionine and 50 to 200 mg of silybin per dog per day, although the ideal dose for chronic liver disease is unknown. Vitamin E is usually dosed at 400 IU for a 30-kg dog, titrating accordingly to other sizes. • Hepatic encephalopathy (HE): This is not as prominent or easily recognized in dogs with CH as it is in young dogs with congenital portosystemic shunt. Nonetheless, it can be an important cause of confusion and unusual behavior in these animals because of the development of acquired portosystemic shunts secondary to portal hypertension. It should be treated carefully: marked protein restriction is not indicated in these dogs because they are likely to be suffering from proteincalorie malnutrition already. HE can be addressed by treating any underlying inflammatory trigger and also any precipitating gastrointestinal bleeding and giving a highly digestible, high-quality diet in small, frequent amounts. Antibiotic and lactulose therapy also may be considered. Dietary protein restriction is rarely necessary in these cases. More details of treatment of HE are given in Chapter 144. • Treatment of protein-calorie malnutrition: Many dogs with CH present in negative nitrogen balance. They are often thin with partial anorexia and vomiting and diarrhea, which contribute to nutrient malabsorption. It is therefore important to prioritize nutrition in the treatment of these patients. Ideally, they should be fed a highly digestible, high-quality diet in frequent, small amounts, and this diet should not be protein restricted. Prescription diets recommended for liver disease may be too low in protein in this context. Diets manufactured for intestinal disease are preferred because they are very

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digestible. However, ultimately, it may be a matter of feeding whatever the dog will eat, which is preferable to no food at all.

References and Suggested Reading Andersson M, Sevelius E: Breed, sex and age distribution in dogs with chronic liver disease: a demographic study, J Small Anim Pract 32:1, 1991. Bexfield NH et al: Breed, age and gender distribution of dogs with chronic hepatitis in the United Kingdom, Vet J 193:124, 2012. Friedman SL: Evolving challenges in hepatic fibrosis, Nat Rev Gastroenterol Hepatol 7:425, 2010. Jarrett WF, O’Neil BW: A new transmissible agent causing acute hepatitis, chronic hepatitis and cirrhosis in dogs, Vet Rec 116: 629, 1985. Luo W et al: Spironolactone lowers portal hypertension by  inhibiting liver fibrosis, ROCK-2 activity and activating NO/

CHAPTER 

PKG pathway in the bile-duct-ligated rat, PlosOne 7:e34230, 2012. Poldervaart JH et al: Primary hepatitis in dogs: a retrospective review (2002-2006), J Vet Intern Med 23:72, 2009. Raffan E et al: Ascites is a negative prognostic indicator in chronic hepatitis in dogs, J Vet Intern Med 23:63, 2009. Strombeck DR, Miller LM, Harrold D: Effects of corticosteroid treatment on survival time in dogs with chronic hepatitis: 151 cases (1977-1985), J Am Vet Med Assoc 9:1109, 1988. Watson PJ: Canine chronic liver disease: a review of current understanding of the aetiology, progression and treatment of chronic liver disease in the dog, Vet J 167:228, 2004. Watson PJ et al: Prevalence of hepatic lesions at post-mortem examination in dogs and association with pancreatitis, J Small Anim Pract 51:566, 2010. WSAVA Liver Standardization Group: WSAVA standards for clinical and histological diagnosis of canine and feline liver diseases, ed 1, Philadelphia, 2006, Saunders-Elsevier.

143 

Copper Chelator Therapy ALLISON BRADLEY, Fort Collins, Colorado DAVID C. TWEDT, Fort Collins, Colorado

Pathophysiology of Copper-Associated Liver Disease Copper is an essential component of metalloenzymes used in many metabolic functions, and the liver is  central in regulating copper body stores. Copper enters the body through the diet, with approximately 30%  to 60% absorbed in the small intestine, and the rest passing out through the feces. After hepatic uptake, it  is complexed with the transport protein ceruloplasmin, incorporated into hepatic cellular pathways, or bound  to hepatic metallothioneins. Metallothioneins are cytosolic proteins that store copper, thereby protecting the surrounding cell from its toxic effects. Biliary excretion  is the major determinant of copper homeostasis, with  about 80% of absorbed copper excreted in bile. When copper concentrations exceed hepatic metallothionein–complexing capabilities, hepatic injury results from free radical–induced hepatocellular necrosis or apoptosis. Abnormal accumulation of hepatic copper can be caused by a metabolic defect of copper metabolism, secondarily from cholestatic or hepatocellular disease resulting in decreased biliary excretion of copper, or from increased dietary intake of copper. Reduction of hepatic copper levels is fundamental  to treatment of copper-associated hepatic disease. The

mainstay of treatment for primary copper hepatopathy is typically a chelating agent, which is a ligand (or drug) that binds to a metal ion for the purpose of removing the metal from the body, generally by renal excretion. Adjunctive therapies include zinc, antioxidants, hepatoprotectants, and dietary restriction of copper intake.

Copper Chelating Agents Indications for Chelating Agents Therapy is indicated in cases with significant increases in hepatic copper concentrations. Ideally, quantification of hepatic copper should be performed; normal canine concentrations range from 200 to 400 µg/g of dry weight liver. A semiquantitative histochemical grading scheme estimating the amount of hepatic copper also has been described, with the amount of copper accumulation graded on a scale of 0 to 5+. The scoring system tends to approximate the magnitude of copper concentration in the liver. Chelation therapy given to patients incorrectly  diagnosed with copper-associated liver disease is detrimental. Therefore it is important to determine whether the hepatic copper accumulation is a primary condition leading to liver damage or secondary to cholestasis. 

CHAPTER  143  Copper Chelator Therapy Secondary hepatic copper accumulation using histochemical staining is located predominantly in zone 1 (periportal), whereas in dogs with primary copper hepatoxicity it is found in zone 3 (centrilobular). Generally, copper concentrations from cholestatic or hepatocellular disease are lower (e.g., 750 to 1000 µg/g or >3+ grade), and location (zone 3) should have chelation therapy directed at lowering hepatic copper. If the suspected primary copper deposition is mild, other therapies, such as oral zinc supplementation and low-copper diets, may be sufficient.

Commonly Used Chelators Penicillamine is the treatment of choice for humans with Wilson’s disease, a primary metabolic disease associated with abnormal hepatic copper accumulation (Wiggelinkhuizen et al, 2009). Given the available veterinary data and experience, it should also be the first-line treatment for dogs with primary copper storage disease. Penicillamine is a thiol, a compound with a sulfhydryl (SH) group, making the molecule an active metal chelating agent with a high affinity for copper. It forms a stable water-soluble complex with copper that is then excreted through the kidneys. Additional mechanisms of action may include formation of a nontoxic hepatic chelate; induction of synthesis of metallothionein, which will bind to free copper; weak antifibrotic activity via interference with procollagen cross-linking; and immunomodulatory effects. The latter two mechanisms may be of additional benefit in chronic hepatitis. The recommended initial dosage of penicillamine is 10 to 15 mg/kg q12h PO. It should be given on an empty stomach at least 1 hour before or 2 hours after meals to maximize absorption and reduce inactivation by chelating substances within the gastrointestinal tract. The most common side effect in dogs is nausea and vomiting, which is observed in about 30% of patients. The side effects often can be avoided by either reducing the  dose or giving the medication with a small amount of  food until the patient becomes accustomed to the medication. Dermatologic reactions have been observed occasionally in the dog. Penicillamine is reported to cause depletion of vitamin B6 in people. Although not reported in dogs, B vitamin supplementation with long-term use may be advisable. Because penicillamine is related to penicillin, patients with a known penicillin allergy should not be treated with this chelator. Finally, because of potential teratogenic effects, penicillamine should not be given to pregnant animals, and pregnant women should  avoid contact with the drug. Penicillamine is relatively 

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expensive, and using less-expensive compounding pharmacies is appealing; however, the purity and efficacy of the drug cannot be ensured. Trientine is a triethylene tetramine or 2,2,2-tetramine used as an alternative copper chelator in humans that do not tolerate penicillamine. Similarly, it may be an alternative in dogs that do not tolerate penicillamine. The exact mechanism of trientine is poorly understood, but it appears to have a copper-lowering effect similar to that of penicillamine when given to affected Bedlington terriers and normal dogs. Because it may lower serum copper levels more rapidly it is the preferred  treatment in cases of hemolysis resulting from copper toxicity. The recommended dosage in dogs is 10 to 15 mg/kg q12h PO given on an empty stomach. Trientine appears to be well-tolerated by dogs, with rare cases of renal toxicity and vomiting being uncommon. Trientine also should be regarded as a potential teratogen.

Other Chelators 2,3,2-tetramine is similar in structure to trientine but is reported to be more four to nine times more potent than trientine in normal dogs without reported toxicity (Allen, Twedt, and Hunsaker, 1987). It has been used successfully in treating a number of affected Bedlington terriers, including two with copper-associated hemolysis (Twedt, Hunsaker, and Allen, 1988). It is not commercially available at this time. Tetrathiomolybdate has been used in the treatment of Wilson’s disease and copper-associated neurologic signs. This chelator has four sulfur groups that bind copper, and its mechanism relies in part on biliary copper excretion, which could be defective in hepatic disease. It is unknown how effective this chelator would be in dogs with copper-associated hepatotoxicity. Other chelators used in veterinary medicine, such as disodium calcium ethylenediaminetetraacetic acid (EDTA), dimercaprol, and deferoxamine, are not beneficial in copperassociated hepatotoxicity.

Monitoring and Duration of Therapy Only general guidelines can be made regarding chelation therapy, and each case should be monitored carefully, because hepatic copper deficiency is deleterious to the patient. Affected Bedlington terriers and some Dalmatians have high copper concentrations (>3000 to 10,000 µg/g) and often require prolonged (years) or lifetime therapy because hepatic copper concentrations rarely return to normal in these dogs. One study found that hepatic copper levels in Bedlington terriers decreased an average of 900 µg/g per year. The authors generally treat until liver enzymes approach normal and then decrease chelation to once a day or every 48 hours. Other breeds with elevated hepatic copper may require only a short course of chelation therapy before beginning zinc and or diet therapy. For example, Labrador retrievers and Doberman pinschers with copper concentrations ranging from 1000 to 2000 µg/g hepatic copper may require only 3 to a maximum of 6 months of therapy. Quantitation of hepatic copper during therapy can provide important

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objective information of when to transition from active chelation to preventive maintenance therapy. Normalization of alanine aminotransferase (ALT) concentrations during chelation therapy may indicate that hepatic copper concentrations are below the hepatotoxic threshold. Following clinical improvement and proof of sufficient copper removal, either intermittent chelation or oral zinc (see below) may be sufficient. Dogs with chronic liver disease considered to have moderate secondary hepatic copper accumulation generally are not treated with chelation therapy but managed with specific therapy for the liver disease, low-copper diets, and possibly zinc therapy.

Adjunct Therapeutic Options Diet All dogs with moderate or greater copper accumulation should be placed on a low-copper diet. Most commercial diets contain too much copper for these affected  dogs. Diets created specifically for liver disease typically contain appropriately restricted copper levels (approximately 4 mg/kg diet), but this should be verified for  the exact formulation being prescribed. Most commercial dog foods contain ranges of 10 to 25 mg/kg diet. Copper-containing treats or vitamin-mineral supplements and high-copper foods, such as eggs, shellfish, liver and other organ meats, beans, mushrooms, nuts, and cereals, should be avoided.

Zinc Zinc decreases intestinal absorption of dietary copper by competing directly for uptake and by inducing synthesis of enterocyte metallothionein. The zinc-induced metallothionein preferentially binds to copper, becomes sequestered within the enterocyte, and is lost into the feces when the enterocyte is sloughed into the lumen during normal cell turnover. Zinc also induces production of hepatic metallothionein, which sequesters the copper in an innocuous form. Zinc therapy has been shown to reduce hepatic copper concentrations in dogs with breedassociated copper hepatopathy; however, its effect is slower than that of chelation, with several months required to achieve any reduction and several years for maximal therapeutic response. Accordingly, zinc is likely better as a maintenance therapy.

Concurrent zinc and chelation therapy traditionally has been avoided because the chelators likely bind zinc in the intestinal tract, leading to decreased activity of both substances. More recently, patients with Wilson’s disease reportedly have been treated successfully with trientine and zinc in combination. However, the authors’ current recommendation is to initiate treatment of affected dogs with a faster-acting chelator and transition to prophylactic zinc once hepatic copper concentrations approach normal levels. If concurrent therapy is elected, the zinc and chelator should be staggered to allow  for adequate chelator absorption. Zinc also may be considered in cases when cost or side effects preclude the  use of chelator therapy. Reported induction dosages are 100 mg/dog or 5 to 10 mg/kg of elemental zinc q12h PO for approximately 1 month, and then the dose or frequency is halved. Because hemolysis can occur when serum zinc concentrations are greater than 750 µg/dl, serum zinc levels should be monitored several weeks into the induction phase. Dosing should be adjusted to target a therapeutic level of about 200 µg/dl. Gastrointestinal upset is common; the zinc salt may affect tolerability, with gluconate being the most favorable.

References and Suggested Reading Allen KG, Twedt DC, Hunsaker HA: Tetramine cupruretic agents: a comparison in dogs, Am J Vet Res 48(1):28-30, 1987. Center SA: Pathophysiology of liver disease: normal and abnormal function. In Guilford WG, Strombeck DR, editors: Strombeck’s small animal gastroenterology, ed 3, Philadelphia, 1996, Saunders, p 597. Hoffmann G: Copper associated liver diseases, Vet Clin North Am Small Anim Pract 39:489, 2009. Rothuizen J: General principles in the treatment of liver disease. In Ettinger SJ, Feldman EC, editors: Textbook of veterinary internal medicine, ed 7, Philadelphia, 2010, Saunders, p 1629. Scherk MA, Center SA: Toxic, metabolic, infectious, and neoplastic liver disease. In Ettinger SJ, Feldman EC, editors: Textbook of veterinary internal medicine, ed 7, Philadelphia, 2010, Saunders, p 1679. Spee B, Arends B, van den Ingh T: Copper metabolism and  oxidative stress in chronic inflammatory and cholestatic liver  diseases in dogs, J Vet Intern Med 20:1085, 2006. Twedt DC, Hunsaker MS, Allen KGD: Use of 2,3,2-tetramine as a hepatic copper chelating agent for treatment of copper hepatotoxicosis in Bedlington terriers, J Am Vet Med Assoc 192:52, 1988. Wiggelinkhuizen M et al: Systematic review: clinical efficacy of chelator agents and zinc in the initial treatment of Wilson disease, Aliment Pharmacol Ther 29:947, 2009.

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144 

Ascites and Hepatic Encephalopathy Therapy   for Liver Disease NICK BEXFIELD, Cambridge, Great Britain

Ascites Pathophysiology Ascites is the accumulation of fluid within the peritoneal cavity, and in liver disease this is usually a result of portal hypertension (PH). Hypoalbuminemia also can contribute to ascites formation in animals with reduced hepatic function, although it is unusual for hypoalbuminemia alone to cause ascites. PH, the sustained increase in blood pressure in the portal system, results from an increased intrahepatic resistance combined with increased portal blood flow. Increased intrahepatic resistance results  from architectural distortion (fibrous tissue, regenerative nodules), sinusoidal endothelial dysfunction leading  to impaired intrahepatic sinusoidal relaxation, and intrahepatic vascular shunts. With the development of PH, fluid is driven into the interstitial space, and when the capacity of the regional lymphatics is overwhelmed, ascites develops. The development of ascites is worsened by the splanchnic vasodilation that accompanies PH. This vasodilation results in pooling of blood in the abdomen, leading to a decrease in circulating volume, and when ionotrophic and chronotropic compensation fails, systemic hypotension results. This cumulates in activation of the renin-angiotensin-aldosterone system (RAAS), and volume expansion, which further increases hydrostatic pressure in the portal vasculature. PH is seen most commonly in dogs with chronic liver disease, although it occasionally occurs with acute liver disease; therefore the most common cause in dogs is chronic hepatitis progressing to cirrhosis. The presence of ascites is a poor prognostic indicator in dogs with chronic hepatitis, with a survival from the time of diagnosis of 0.4 months, compared to 24.3 months for nonascitic dogs. Because cats rarely get advanced liver fibrosis or cirrhosis, the development of PH and therefore ascites is uncommon in this species.

Therapy for Ascites Diuretics Despite PH, ascitic animals actually have systemic hypotension and increased renal sodium retention because of reduced glomerular filtration rate and increased activation of the RAAS. Activation of the RAAS results in the

release of aldosterone and increased sodium retention in the distal renal tubules. The aldosterone antagonist spironolactone is the diuretic of choice for the treatment of hepatogenic ascites. Spironolactone competes with aldosterone for its intracellular receptor sites, thus promoting sodium excretion and potassium retention in the renal tubules. Therapy with spironolactone at a dose of 2 mg/ kg q24h PO is the initial therapy for animals with ascites resulting from PH (Figure 144-1). The dose of spironolactone can be increased gradually every few days to a maximum of 4 mg/kg q24h PO. Some animals may benefit from twice-daily therapy. Spironolactone can have a relatively slow onset of activity in humans, taking up to 14 days to cause diuresis; this also may occur in cats and dogs. In cases that are refractory to spironolactone, or when a more rapid resolution of ascites is required, furosemide (1 to 2 mg/kg q12h PO) also can be used.  If there is no response to this dose of furosemide, it  can be increased incrementally. Therapy with furosemide rather than spironolactone has been shown to precipitate  more complications in humans with ascites, however. Importantly, serum electrolyte concentrations, especially sodium and potassium, should be monitored daily during the first few days of diuretic therapy, and every few weeks to months thereafter. Hypokalemia should be addressed as soon as possible as it can precipitate hepatic encephalopathy (HE) (see later). Body weight, abdominal girth (measure girth at level of the second lumbar vertebra with a tape measure), and hydration status as well as hematocrit and serum creatinine also should be monitored when on diuretic therapy. A safe loss of 0.5% to 1.0% body weight per day has been suggested for humans. Body weight reductions of 5% per day are dangerous and indicate the need for veterinary examination. When ascites has been mobilized adequately, intermittent use of diuretics is advised and guided by fluid reaccumulation. Administration of a diuretic two or three times per week is often sufficient to control fluid accumulation. Abdominocentesis Abdominocentesis should be avoided if possible because the removal of large volumes of relatively protein-rich fluid can cause significant hypoalbuminemia, potentially leading to worsened fluid re-formation. Hypoalbuminemia also may lead to protein catabolism and HE. 591

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SECTION  VI  Gastrointestinal Diseases Start spironolactone 2 mg/kg PO q24h Assess body weight, abdominal girth, hydration status Assess electrolytes during the first few days of therapy Good response

Poor response

Continue spironolactone till resolution of ascites Use spironolactone intermittently, approximately 2-3 times per week Assess electrolytes, hematocrit, serum creatinine every few weeks

Add furosemide 1-2 mg/kg PO q12h Continue spironolactone 2 mg/kg PO q24h Poor response Gradually increase spironolactone up to 4 mg/kg PO q24h Gradually increase furosemide up to 4 mg/kg PO q12h Assess electrolytes every 24-48 hours

Good response Good response Good response

If ascites remains unresponsive Perform therapeutic abdominocentesis Administer colloids or plasma prior to and during paracentesis Commence diuretics and sodium restriction Restrict patient’s mobility

Consider introducing a sodium-restricted diet Avoid salty snacks Good response

Good response

Monitor weight, abdominal girth Assess electrolytes, hematocrit, serum creatinine every few weeks

Figure 144-1  A flow diagram describing the management of ascites in patients with liver disease.

Therapeutic abdominocentesis is indicated if significant ascites is impairing mobility or causing respiratory compromise and is refractory to medical management. Fluid removal has the beneficial effects of improving cardiac function and stimulation diuresis. These effects are due to reductions of intraabdominal pressure, which compromises venous return. Administration of colloids or plasma before and during abdominocentesis is also advisable; this helps to prevent hypovolemia and worsening hypoalbuminemia as fluid shifts back into the abdomen. An infusion of 10 ml/kg of hetastarch over 3 hours is required, with abdominocentesis performed after the first 30 minutes of the infusion. Fluid removal is completed over 30 to 60 minutes. Dietary Sodium Restriction Dietary sodium restriction also is advocated in the management of ascites, although in humans this alone  is inadequate. Recommendations for sodium restriction in the diet vary from 0.1% to 0.3%, or less than 0.05 g/100 kcal; this can be established by feeding a prescription or homemade diet. However, dietary sodium restriction can result in several complications, including hypovolemia, renal hypoperfusion, and compensatory polydipsia, which may worsen hyponatremia. Salt restriction, if performed, should be gradual, and patients  should be monitored for complications of azotemia and hyponatremia.

Hepatic Encephalopathy Pathophysiology Hepatic encephalopathy (HE) is a neurophysiologic disorder of the central nervous system (CNS) that develops

as a result of hepatic dysfunction. HE is usually a result of congenital and acquired portosystemic shunting of blood, and the reserve capacity of the liver in dogs is usually enough to prevent HE in liver disease without collateral circulation. Cats cannot make the essential amino acid arginine, an intermediate of the hepatic urea cycle, and deficiency causes inadequate detoxification of ammonia. HE therefore may occur in cats without shunting and as a result of fasting. Clinical signs are variable, from those of acute HE, which can lead to cerebral edema, increased intracranial pressure, and brain herniation, to those of chronic HE, which may include behavioral changes, or subtle signs such as depression, anorexia, and lethargy. Most signs are consistent with neuroinhibitory effects, although excitatory signs such as aggression and hyperexcitability also develop. The pathogenesis of HE is multifactorial and still not understood completely. When portosystemic shunting exists, a number of toxic substances gain entry into the peripheral and cerebral circulation. In liver failure, the permeability of the blood-brain barrier also may be increased, allowing normally excluded substances to access the brain. The most commonly implicated and studied encephalopathic agent is ammonia. The effects of increased CNS ammonia are inhibitory and are due to glutamate depletion, altered glutamate receptors, blockade of GABA receptors, altered amino acid membrane transport, inhibition of Na/K-dependent ATPase, and impaired cerebral energy metabolism. A variety of other substances have been implicated in the pathogenesis  of HE including short-chain fatty acids, aromatic and branched-chain amino acids, abnormal or false neurotransmitters, tryptophan, methionine, phenols, and bile acids.

CHAPTER  144  Ascites and Hepatic Encephalopathy Therapy for Liver Disease

Therapy The main goals of therapy are to decrease the formation of gut-derived encephalotoxins, especially ammonia, with the hypothesis that the colon is the main source of this ammonia production. Therefore the mainstays of current therapy are a combination of protein-restricted diets, oral antibiotics to suppress bacterial populations that produce encephalopathic toxins, and local-acting agents to reduce gastrointestinal uptake of ammonia. However, emerging evidence from human medicine questions the efficacy of these commonly used treatment recommendations. For instance, studies suggest that the colon is not the main source of ammonia production, but in fact it originates from the obligate intestinal catabolism of glutamine by small intestinal enterocytes. Moreover, if dietary protein is highly digestible and not in excessive amounts, it should be digested in the small intestine and so not reach the colon. Controlled trials have not been performed in animals to determine the optimal treatment for HE and so current recommendations are based on anecdotal evidence. However, correction of acid-base abnormalities and the elimination of precipitating factors (Box 144-1) are a vital part of successful therapy. Emerging evidence also suggests that inflammatory cytokines are synergistic with ammonia in precipitating HE and that controlling inflammation in

BOX 144-1  Precipitating Factors for Hepatic Encephalopathy Increased production of ammonia in the gastrointestinal tract • A high-protein meal • Undigested protein in the colon • Constipation • Gastrointestinal bleeding or ingestion of blood • Azotemia Increased systemic generation of ammonia • Blood transfusions, especially of stored blood • Protein-calorie malnutrition leading to breakdown of endogenous body protein • Feeding a poor-quality protein Factors affecting the uptake and metabolism of ammonia in  the CNS • Metabolic alkalosis (only the nonionized form of ammonia penetrates neuronal membranes. In alkalosis, the reaction equilibrium [NH3 + H+ ↔ NH4+] shifts to the left, making more nonionized ammonia available) • Hypokalemia (potassium shifts from cells in exchange with H+. The resulting H+ shift causes alkalosis and the production of more nonionized ammonia) • Hypoglycemia (potentiates the activity and production of other neurotoxins) • Inflammation (inflammatory cytokines can be directly neurotoxic and synergistic with ammonia) • Infections (fever and increased protein catabolism) • Sedative and anesthetic drugs (interact with various neurotransmitters)

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other organs is an important part of managing the patient with HE. Diet Dietary manipulation is the key to the successful management of HE. Studies in humans and animals with acquired portosystemic shunts (PSSs) and dogs with experimental PSSs have shown a higher protein requirement than normal subjects. The current recommendation is therefore to feed patients with congenital or acquired PSSs with normal to slightly increased amounts of protein. Feeding a protein-restricted diet results in protein-calorie malnutrition, resulting in the breakdown of endogenous protein, which may worsen HE. The protein source should be high quality and highly digestible to minimize the amount of undigested protein reaching the colon to be converted into ammonia. High-quality proteins include dairy products, chicken, or soya. Diets manufactured for dogs with liver disease may be protein restricted and should be supplemented with high-quality protein. Alternatively, a veterinary diet designed for intestinal disease can be used because these contain high-quality and highly digestible protein. Animals also should be fed several times per day and with small amounts of food. Fat should be fed in normal amounts unless clinical steatorrhea develops, and the carbohydrate source should be highly digestible. Zinc supplementation also may be beneficial in the dietary management of HE because zinc is a vital component of many enzymes in the urea cycle and in muscle metabolism of ammonia. Lactulose Lactulose (β-galactosidofructose) is a semisynthetic disaccharide that passes into the colon, where it is degraded by bacteria into short-chain fatty acids (SCFAs). The SCFAs, primarily acetic and lactic acid, acidify the colon, trapping ammonia as ammonium ions (NH4+). Lactulose also promotes an osmotic diarrhea, so reducing the  time colonic contents are acted on by intestinal bacteria. SCFAs also are used as an energy source by colonic  bacteria, causing them to incorporate more ammonia  into their own bacterial proteins. Lactulose (cats 2.5 to 5.0 ml q8-12h PO; dogs 2.5 to 15 ml q8-12h PO) is  used with dose adjustment to produce two to three soft stools per day. Lactulose is sweet tasting and so not tolerated by some cats and dogs. An alternative is lactitol (β-galactosidosorbitol), available in some countries as a powder to add to food (500 mg/kg q6-8h PO, adjusted  to produce two to three soft stools per day), although  its efficacy in the management of HE has not been  evaluated extensively. Antibiotics Antibiotics can be used if dietary therapy alone or in combination with lactulose does not control the signs  of HE. Drugs effective against anaerobic organism such  as metronidazole 7.5 mg/kg PO q12h, or amoxicillin  10 mg/kg PO q8-12h should be selected. The dose of metronidazole is lower than that normally suggested because excretion of this drug may be compromised in patients with liver disease. Antibiotics effective against gram-negative, urea-splitting bacteria, such as neomycin

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SECTION  VI  Gastrointestinal Diseases

sulfate 20 mg/kg PO q8-12h also may be used. The latter drug is probably best reserved for acute, rather than longterm, management of HE as intestinal bacteria become resistant to neomycin. Moreover, neomycin’s adverse effects include nephrotoxicity and ototoxicity. Metronidazole and amoxicillin have an added advantage over neomycin because they are absorbed systemically and therefore may protect against bacteremia. In human medicine, rifaximin, an oral rifamycin-based antibiotic, is the currently preferred antibiotic because of its superior safety profile, although it has not been studied in dogs or cats with HE.

CHAPTER 

References and Suggested Reading Buob S, Johnston AN, Webster CRL: Portal hypertension: pathophysiology, diagnosis, and treatment, J Vet Intern Med 25:169, 2011. Sanyal AJ et al: Portal hypertension and its complications, Gastroenterology 134:1715, 2008. Shawcross DL et al: Ammonia and the neutrophil in the pathogenesis of hepatic encephalopathy in cirrhosis, Hepatology 51:1062, 2010. Shawcross D, Jalan R: Dispelling myths in the treatment of hepatic encephalopathy, Lancet 365:431, 2005.

145 

Portosystemic Shunts KAREN M. TOBIAS, Knoxville, Tennessee

P

ortosystemic shunts (PSS) are vascular anomalies that divert blood from the abdominal to the  systemic venous circulation while bypassing the hepatic sinusoids. Products absorbed from the intestines are delivered to the heart without undergoing the extraction and detoxification processes normally performed  by hepatocytes. This reduction in hepatic blood flow  and function leads to decreases in protein production and glycogen storage, reticuloendothelial dysfunction, and altered metabolism of ammonia and other toxins. PSS can occur as congenital anomalies or may develop secondary to liver disease and portal hypertension. Although clinical signs from multiple acquired shunts must be managed medically, congenital PSS have been treated successfully with surgery in many dogs and cats. Congenital portosystemic shunts (CPSS) usually occur as single large vessels, although some animals have two or more shunts. Common types of CPSS include intrahepatic portocaval shunts, such as a patent ductus venosus and extrahepatic portocaval or portal-azygos shunts. In a small percentage of dogs with CPSS, the prehepatic portal vein is absent. CPSS are considered heritable in many breeds. Multiple acquired shunts develop secondary to liver disease and/or causes of portal hypertension. They are small, tortuous vessels that frequently join the caudal vena cava around the base of the mesentery or the renal veins.

Breeds most commonly affected with extrahepatic CPSS are Yorkshire terriers, Havanese, Maltese, Dandie Dinmont terriers, pugs, and miniature schnauzers. Intrahepatic CPSS are found primarily in large-breed dogs such as Irish wolfhounds and in medium-sized breeds such as Australian shepherds and Australian cattle dogs. General clinical signs of CPSS include small stature, weight loss or failure to gain weight, polydipsia, and anesthetic or tranquilizer intolerance. Neurologic dysfunction from hepatic encephalopathy (HE) is seen in most animals with CPSS and may include lethargy,  restlessness or pacing, ataxia, head pressing, circling, seizures, behavioral changes, and amaurotic blindness. Precipitating factors of severe neurologic signs (HE) include protein overload, hypokalemia, alkalosis, hypovolemia, hypoxia, gastrointestinal hemorrhage, infection, azotemia, constipation, drugs, and transfusion of stored red cells. Gastrointestinal clinical abnormalities may include anorexia, vomiting, diarrhea, or pica and, in large-breed dogs, evidence of gastrointestinal bleeding such as melena or hematemesis. Some dogs have no apparent signs or signs of only lower urinary tract disease or urinary tract obstruction. Many cats have hypersalivation and seizures, and some have unusual coppercolored irises.

Signalment, History, and Clinical Signs

Routine Laboratory Tests

CPSS usually are diagnosed in immature animals, although a few animals are diagnosed at 10 years of age or older.

In dogs, common blood work abnormalities include microcytosis and decreases in blood urea nitrogen,

Diagnosis

CHAPTER  145  Portosystemic Shunts protein, albumin, glucose, and cholesterol. Serum alanine aminotransferase and alkaline phosphatase may be increased. Increase in alkaline phosphatase is most likely from bone growth because cholestasis is not usually a feature in animals with CPSS. Cats with CPSS may have normal albumin, glucose, total protein, and cholesterol concentrations but usually have increased liver enzymes. Up to half of dogs with CPSS have prolonged partial thromboplastin times; however, this usually does not result in a clinically significant problem. Urine abnormalities include low urine specific gravity, ammonium biurate crystalluria, and occasionally abnormal urine sediment suggestive of cystitis secondary to crystalluria or (urate) urolithiasis. Some dogs may have silent urinary tract infections; therefore urine culture is performed routinely in many animals. Common hepatic histologic changes in animals with CPSS include lobular atrophy, increased numbers of hepatic arterioles and bile ductules because of proliferation or tortuosity, decreased number or size of intra­ hepatic portal tributaries, and deposition of lipid and pigment within cytoplasmic vacuoles (lipogranulomas). These pathologic changes are variable and also can be seen in dogs with congenital portal vein hypoplasia  with secondary microvascular dysplasia (PVH-MVD)  that do not have CPSS and in dogs with other hepatic diseases such as noncirrhotic portal hypertension (see Chapter 146).

Liver Function Tests Results of bile acids, ammonia, and protein C activity provide additional information about liver function. Serum bile acids are measured after a 12-hour fast and again 2 hours after a meal. Bile acid concentrations are usually greater than 75 µmol/L in dogs with CPSS but also can be increased with any significant liver disease. Occasionally postprandial bile acid concentrations are less than the prefasting sample (in approximately 20% of dogs) because of spontaneous interdigestive gallbladder contraction. Most animals with CPSS also have increased ammonia concentrations, particularly if measured 6 hours after feeding or after oral or rectal administration of ammonia (ammonia tolerance test). Concentrations of blood ammonia are not well correlated with severity of hepatic encephalopathy, and ammonia concentrations may be normal with effective medical treatment. Ammonia can be increased falsely with improper sample handling. Protein C is a component of the coagulation cascade that decreases clot formation. In normal dogs, protein C activity is at least 70%. Protein C activity is decreased in many dogs with severe liver disease and in most dogs with CPSS but is usually normal (>70%) in most dogs with PVH-MVD.

Diagnostic Imaging Common findings on survey radiographs include a small liver and enlarged kidneys. Urate calculi are usually not visible unless combined with other compounds such as struvite or calcium.

595

Often CPSS can be identified on ultrasonography by experienced operators, particularly if color-flow Doppler is available. The combination of small liver, large kidneys, and uroliths is highly suggestive of shunting in dogs, and dogs and cats with extrahepatic shunts have reduced portal vein-to-aorta ratios. Extrahepatic CPSS can be more difficult to diagnose with ultrasonography because the patient is usually small and structures such as ribs and intestines can obscure the vessel. Nuclear scintigraphy with technetium 99m provides a diagnosis of shunt or no shunt. If the radionuclide is injected directly into the spleen, the operator often can tell where the shunt terminates, how many shunts are present, and whether they are likely to be congenital or acquired. Normal shunt fraction is less than 5% for transsplenic scintigraphy and less than 15% for per rectal. Isolation for 12 to 24 hours usually is required in animals undergoing rectal scintigraphy. Direct injection of contrast into the splenic or jejunal veins (portovenography) usually provides excellent information regarding the presence, number, and location of shunts; however, at most practices a celiotomy is required to obtain the images. In addition, some CPSS are not visible on portograms performed in dorsal or right lateral recumbency. Computed tomographic (CT) angiography is considered the standard for definitive diagnosis of CPSS and is particularly useful for preoperative planning in animals with intrahepatic CPSS and hepatic arteriovenous malformations. Magnetic resonance angiography also can be used to detect shunts, but it is more expensive and image quality is not as good.

Differential Diagnoses Single congenital portosystemic shunts must be differentiated from neurologic conditions such as hydrocephalus and epilepsy and from other primary hepatic diseases, including congenital PVH-MVD and multiple acquired shunts secondary to portal hypertension. Differentiation usually is based on results of advanced imaging; however, history, clinical signs, and results of blood work also may be helpful. Conditions other than CPSS should be suspected when neurologic or other clinical signs do not resolve with medical management of the HE. Unlike animals with CPSS, ascites is a common finding on physical examination or ultrasonography in dogs with portal hypertension secondary to severe hepatocellular disease or hepatic arteriovenous malformations. With development of multiple acquired PSS, these animals have increased shunt fractions on scintigraphy. Congenital portal vein hypoplasia is found in many small breeds predisposed to CPSS. Although results of liver biopsy are the same for both conditions, laboratory changes are usually less severe in dogs with PVH-MVD, unless noncirrhotic portal hypertension is present (see Chapter 146). Dogs with PVH-MVD are more likely to have normal red cell size (MCV); glucose, albumin, total protein, and cholesterol concentrations; and urine specific gravity and fewer if any at all clinical signs than dogs with CPSS. In addition, 90% to 95% of dogs with PVH-MVD have normal protein C activity and 81% 

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SECTION  VI  Gastrointestinal Diseases

have postprandial bile acids less than 75 µmol/L at the author’s institute. Results of scintigraphy, portography, and CT angiography are usually normal in dogs with PVH-MVD.

Medical Management of Portosystemic Shunts All animals with CPSS should receive medical management to improve their physical condition and treat or prevent hepatic encephalopathy (see Chapter 144). Dietary protein is restricted moderately to reduce substrates for ammonia formation by colonic bacteria. Caloric requirements should be calculated based on ideal body weight because patients with shunts may be thin or have poor muscle development. At least 30% to 50% of dietary calories should be provided as easily digested, complex soluble carbohydrates; and diets for dogs and cats should contain 15% to 30% and 20% to 40% fat, respectively, on a dry matter (DM) basis. Crude protein requirements in dogs with liver disease are approximately 2.11 g per kilogram of body weight per day. On a dry matter basis, commercial liver diets range from 14% to 18% protein for dogs and 31% to 32% for cats, respectively. Soybean meal and dairy proteins often are recommended protein sources because of their high digestibility. If homemade diets are used, zinc, fat-soluble vitamins, and vitamins B and C should be  supplemented and components that precipitate hepatic encephalopathy (e.g., manganese) should be limited. Lactulose is given to animals showing signs referable to hepatic encephalopathy. Dosages should be regulated so that feces are soft but formed; in toy breed dogs a common dose is 1 to 2 ml q8-12h PO. Although usually administered orally, lactulose can be given by enema in obtunded or seizing animals. Yogurt with active cultures can be substituted in place of lactulose to alter colonic flora. Nutraceuticals used to treat animals with CPSS include S-adenosylmethionine (SAMe), vitamin E, and milk thistle (silymarin). Benefits of these compounds may include hepatoprotective, antioxidant, and antiinflammatory effects and improved hepatic function. Unfortunately, no controlled studies describe effectiveness of yogurt or nutraceuticals in the management of CPSS in dogs or cats. Gastrointestinal hemorrhage (see Chapter 123), intestinal parasites, and cystitis should be treated appro­ priately. Gastrointestinal ulcers have been reported preoperatively, particularly in large-breed dogs with intrahepatic CPSS, and even after successful closure of a shunt and may require long-term management with proton pump inhibitors. Urate uroliths may respond to lowprotein diets; renal calculi reportedly have dissolved after shunt ligation. In severely encephalopathic animals, medical management includes correction of fluid, electrolyte, and glucose imbalances as needed. Enemas with water and lactulose may be used to reduce colonic bacteria and substrates. Fresh frozen plasma or hetastarch may be required  in patients with coagulopathy or decreased oncotic pressure, respectively. Once animals can swallow, oral antibiotics effective against urease-producing bacteria (e.g., neomycin or metronidazole) can be administered to

decrease colonic bacterial populations; clinicians should be aware of the potential toxicity of these drugs. Seizures unrelated to hypoglycemia or hyperammonemia are treated initially with intravenous benzodiazepines. Some clinicians prefer low-dose midazolam over intravenous diazepam, which contains a propylene glycol–carrying agent that requires liver metabolism. However, at the author’s institute, diazepam is used successfully to acutely halt seizures in dogs with CPSS. Once seizures are controlled, loading doses of, and continued treatment with, anticonvulsants such as phenobarbital, levetiracetam, zonisamide, or potassium or sodium bromide are recommended, particularly if continued seizure activity is anticipated. In a retrospective study by Fryer et al, postoperative seizures were reported in 4 of 84 dogs that did not receive preoperative levetiracetam before extrahepatic CPSS attenuation compared with 0 of 42 that received preoperative levetiracetam. Preoperative seizures are reported in 23% of cats; those with a history of frequent seizures are placed on levetiracetam, zonisamide, or phenobarbital for several weeks before surgery.

Prognosis with Medical Management With proper medical management, weight and quality of life stabilizes or improves with treatment in most animals; however, long-term mortality rates of medically treated animals are higher than those of animals undergoing shunt attenuation. In a study by Watson and Herrtage (1998), 52% of dogs were euthanized with a median survival time of 10 months. At least one third of dogs  did well with medical management as the sole method  of treatment, however, with many living to 7 years of  age or older. Shorter duration of survival was correlated with intrahepatic shunt location, younger age at onset initial signs, greater severity of clinical signs (e.g., hepatic encephalopathy), and lower blood urea nitrogen (BUN) concentration. Some dogs developed progressive hepatic fibrosis and subsequent portal hypertension. In a more recent report by Greenhalgh et al (2010), 52% of dogs receiving medical treatment were still alive at the completion of the study, and 30% of medically treated dogs died of shunt-related causes. In comparison, 88% of surgically treated dogs were alive at the end of the study, and 10% of surgically treated dogs died of shuntrelated causes. Median survival time for medically or surgically treated dogs that died was 164 days. Age at the time of diagnosis was not correlated with survival. With medical management alone, survival time of cats with CPSS, particularly those that are neurologic, is usually less than 2 years. Dogs and cats with multiple acquired PSS are managed medically.

Surgery Once patients have been managed medically for several weeks, attenuation of CPSS is recommended to improve long-term outcome. Options include acute ligation with suture; gradual occlusion with ameroid constrictors,  cellophane banding, or hydraulic occluders; or embolization with coils (most commonly for intrahepatic  CPSS). Because shunt closure with ameroid constrictors

CHAPTER  145  Portosystemic Shunts or cellophane bands relies on inflammatory reaction and subsequent scar tissue formation, use of antiinflammatory or immunosuppressive doses of glucocorticoids should be avoided after surgery. Complication and mortality rates are highest in animals that undergo shunt ligation; therefore gradual occlusion or coil embolization is preferred. Excellent outcomes are seen in 80% to 85% of dogs undergoing gradual shunt occlusion, although bile acids remain mildly to moderately increased in many dogs because of concurrent PVH-MVD. Prognosis for successful surgical treatment is best for dogs with extrahepatic shunts, for animals that undergo complete shunt occlusion, and for those that present with urinary tract signs and no hepatic encephalopathy. Prognosis is not related to age but is poorer in animals with severe preoperative hypoalbuminemia, hypoproteinemia, anemia, or leukocytosis. Perioperative complications are reported in less than 15% of dogs undergoing coil embolization of intrahepatic CPSS, and long-term survival rate is more than 87%, as long as the dogs are maintained on lifelong antacid (e.g., omeprazole) therapy to prevent gastrointestinal ulceration. Good or excellent long-term outcome is reported in about 75% of cats that survive surgery; however, many have postoperative complications. The most common is neurologic dysfunction, including generalized seizures and central blindness in up to 28% and 44% of cats, respectively. Blindness usually resolves in 2 months.

Postoperative Care Portal hypertension is uncommon when gradual attenuation is performed. Most animals need analgesics, such as opioids, for the first 24 to 48 hours. Sedation with dexmedetomidine or a low dose (0.01 to 0.02 mg/kg IM) of acepromazine may be necessary if dogs are vocalizing  or abdominal pressing because these activities increase portal pressure and hyperexcitability. Acepromazine does not appear to lower seizure threshold in PSS patients,  but its effects may be prolonged, so careful dosing is critical. About 25% of toy breed dogs develop hypoglycemia despite concurrent intravenous treatment with dextrosecontaining fluids. Patients with nonresponsive hypoglycemia, poor anesthetic recovery, or signs of circulatory disturbances (decreased systolic pressure, increased capillary refill time, poor peripheral pulses, pale mucous membranes) may require treatment with one or more doses of steroids (0.02 to 0.1 mg/kg dexamethasone sodium phosphate IV). Seizures have been reported in 3% to 18% of dogs and 8% to 22% of cats after shunt attenuation. They usually are seen within 48 hours after surgery but may occur as late as 96 hours. Lethargy, restlessness, frantic or aggressive behavior, facial twitching, ataxia, muscle fasciculation, blindness, and abnormal vocalization are often apparent before generalized seizure activity. Etiology is unknown, and affected animals usually do not respond to fluids, dextrose, lactulose, or enemas. Single seizures are treated with a bolus of diazepam or midazolam to effect, correction of any hypoglycemia, and administration of lactulose retention enemas in case there is an underlying encephalopathy. If seizures recur, the animal

597

is given an additional bolus of benzodiazepine, anesthetized with propofol (5 to 8 mg/kg), and maintained on a propofol continuous rate infusion (0.1 to 1 mg/kg/min). Intubation may be required in some dogs. Phenobarbital can be started concurrently (3 to 8 mg/kg IV loading dose, then 2 to 2.5 mg/kg IV or IM q12h); patients are switched to oral phenobarbital (2 mg/kg q12h) once awake. Alternatively, levetiracetam can be administered intravenously (20 mg/kg) followed by oral administration (20 mg/kg q8h) once the patient is awake. Mannitol (1 g/ kg IV) is administered every 6 hours to reduce intracranial swelling. Electrolyte and glucose abnormalities are corrected, and supportive care (e.g., maintenance fluids, body rotation, eye lubrication, oral cleansing) is provided. Partial or total parenteral nutrition should be considered in patients that have been fasted more than 48 hours. Lactulose can be administered as a retention enema if hepatic encephalopathy cannot be ruled out. Propofol infusion is discontinued after 12 to 24 hours; if the animal seizes during recovery, it is reanesthetized for another 12 to 24 hours and supportive care is continued. Differentiating anesthetic recovery from fulminant seizures can be difficult during the propofol weaning process, and sedation may be required to reduce anxiety. In a few cases, the author has used successfully an acepromazine or dexmedetomidine continuous-rate infusion during propofol recovery or in place of propofol to prevent seizure reoccurrence. Prognosis is poor for animals with persistent postoperative seizures. Those that survive usually improve neurologically over weeks to months, although incoordination and partial visual deficits may persist. Portal hypertension occurs most frequently after  acute ligation or overly aggressive coil embolization. Treatment includes intravenous fluids, hetastarch, broadspectrum systemic antibiotics, and fresh frozen plasma and low-molecular-weight heparin if coagulation times are prolonged. For some dogs, clinical signs resolve with supportive therapy; others may require removal of the attenuating device. Medical management is continued after surgery until liver function improves. Frequently animals can be gradually weaned off of lactulose 2 to 6 weeks after the surgery unless they are constipated or clinical signs recur. Bile acids, protein C activity, complete blood count, serum chemistry, and urinalysis are evaluated 3, 6, and 12 months after the surgery to assess liver function. Protein in the diet can be increased gradually once bile acids are near normal. In dogs with mildly increased bile acids  and normal albumin, it may be necessary to monitor clinical response to diet change to determine whether protein content can be increased gradually. Animals with persistently increased bile acids or ammonia concentrations can be treated with a combination of silymarin and SAMe to improve hepatic function and regeneration. Animals with persistent clinicopathologic abnormalities may require further workup (e.g., scintigraphy or CT  angiography and liver biopsy) to determine the underlying cause (Figure 145-1). For many dogs, bile acids never normalize after CPSS attenuation because of concurrent PVH-MVD. In those dogs, measurement of bile acids  is discontinued and liver function instead is monitored  by evaluation of albumin, total protein, BUN, liver

598

SECTION  VI  Gastrointestinal Diseases Recheck CBC, chemistry, bile acids, protein C

Normal

Abnormal

Continue protein-restricted diet / lactulose; start nutraceuticals; and retest in 3 months

No clinical signs

Clinical signs present

Bloodwork changes moderate to severe

Repeat scintigraphy

Negative for shunting

Positive for shunting

Bloodwork abnormal

Discontinue medical management

Bloodwork changes are mild

Wean off medical management and monitor response Liver biopsy positive for PVH-MVD

CT, portogram, or ultrasound to define shunt type

Second CPSS or persistent shunting through original CPSS

Multiple acquired shunts

Continue medical management based on animal and owner; check CBC, chemistry, U/A periodically; and discontinue bile acid measurements

Consult with surgeon about necessity of second surgery

Figure 145-1  Algorithm for evaluation of animals with single congenital shunts 3 months after surgery.

enzyme, glucose, and cholesterol concentrations; MCV; urinalysis; and protein C activity. Controlled studies comparing effects of various medical treatments on long-term outcome of animals after CPSS attenuation are lacking; therefore management of asymptomatic animals with mild to moderate increases in bile acids is determined on a case-by-case basis and often is based on response to therapy and owner preference.

References and Suggested Reading Bajaj JS et al: Probiotic yogurt for the treatment of minimal hepatic encephalopathy, Am J Gastroenterol 103:1707, 2008. Berent A, Tobias K: Hepatic vascular anomalies. In Tobias KM, Johnston SA, editors: Veterinary surgery: small animal, St Louis, 2011, Elsevier, p 1624. Berent A, Tobias K: Portosystemic vascular anomalies, Vet Clin North Am Small Anim 39:513-541, 2009.

Flatland B: Botanicals, vitamins, and minerals and the liver: therapeutic applications and potential toxicities, Compend Contin Educ Pract Vet 25:514, 2003. Fryer KJ et al: Incidence of postoperative seizures with and without levetiracetam pretreatment in dogs undergoing portosystemic shunt attenuation, J Vet Intern Med 25:1379, 2011. Greenhalgh SN et al: Comparison of survival after surgical or medical treatment in dogs with a congenital portosystemic shunt, J Am Vet Med Assoc 236:1215, 2010. Proot S et al: Soy protein isolate versus meat-based low-protein diet for dogs with congenital portosystemic shunts, J Vet Intern Med 23:794, 2009. Tobias KM, Rohrbach BW: Association of breed with the diagnosis of congenital portosystemic shunts in dogs: 2,400 cases (1980-2002), J Am Vet Med Assoc 223:1636-1639, 2003. Toulza O et al: Evaluation of plasma protein C activity for detection of hepatobiliary disease and portosystemic shunting in dogs, J Am Vet Med Assoc 229:1761, 2006. Watson PJ, Herrtage ME: Medical management of congenital portosystemic shunts in 27 dogs—a retrospective study, J Small Anim Pract 39:62, 1998.

CHAPTER 

146 

Portal Vein Hypoplasia (Microvascular Dysplasia) ANDREA N. JOHNSTON, Ithaca, New York CYNTHIA R.L. WEBSTER, Grafton, Massachusetts

I

n normal dogs approximately 70% of the blood flow to the liver is delivered by the portal circulation, with the remaining 30% derived from the hepatic artery. Hepatopetal blood flow from the portal system enters the portal triad, traverses the sinusoids, and returns to the systemic circulation via the hepatic veins. A spectrum of congenital hepatic vascular anomalies involving the hepatic portal vasculature exists in the dog. Macroscopic portosystemic vascular anomalies (PSVA) occur as single vessels within (intrahepatic) or outside (extrahepatic) the liver that shunt blood from the portal to the systemic circulation (see Chapter 145). Hypoplasia of the portal vein (also known as microvascular dysplasia, or MVD) is a microscopic intrahepatic vascular abnormality in which portal venous blood is diverted into the hepatic veins within the intrahepatic microcirculation (Allen et al, 1999; Center, 2008; Christiansen et al, 2000; Rothuzien et al, 2006; Schermerhorn et al, 1996). Originally called MVD, in 2004 the World Small Animal Veterinary Association (WSAVA) Liver Standardization Group renamed the syndrome primary hypoplasia of the portal vein (PHPV) (also referred to as portal vein hypoplasia [PVH]) because the association felt MVD was part of a group of congenital disorders (excluding PSVA) associated with the PVH resulting in hepatic parenchymal hypoperfusion. Although it is clear that some dogs with congenital portovascular disease have true hypoplasia (atresia) of the extrahepatic portal vein, it is not clear whether all dogs with the syndrome recognized as MVD have hypoplastic vessels. PVH/MVD may occur independently or concurrently with PSVA. Multiple small-breed dogs are at increased risk for PVH/MVD, including many of the same breeds predisposed to PSVA. These breeds include Cairn terriers, Tibetan spaniels, Maltese, Havanese, Yorkshire terriers, Norfolk terriers, and miniature schnauzers. A small-breed genotyping initiative underway at Cornell University in these breeds has established that macroscopic or microscopic portovascular anomalies occur in 30% to 80% of those breeds (Center S, personal communication). They found the incidence of PVH/MVD exceeds PSVA 30 : 1 in all breeds that were studied. Genotyping data suggest that the PSVA/PVH/MVD trait is allelic and may represent an ancestral founder mutation. An autosomal incomplete penetrant or polygenic mode of inheritance is most consistent with trait transmission.

Clinical Features Dogs with PVH/MVD are typically asymptomatic. They have none of the clinical features seen in dogs with PVSA, such as small body stature, neurobehavioral signs consistent with hepatic encephalopathy (amaurosis, head pressing, staring, vocalizing, seizures, lethargy, and coma), intermittent gastrointestinal signs (anorexia, vomiting, diarrhea), or urinary signs (polyuria/polydipsia, stranguria, hematuria, pollakiuria). Rarely dogs may exhibit drug intolerance to substances metabolized or extracted by the liver. These drug sensitivities often are noted initially at the time of neutering. Reports of PVH/MVD dogs with neurobehavioral and gastrointestinal signs can be found in the veterinary  literature (Allen et al, 1999; Christiansen et al, 2000). Although initial clinical impressions were that dogs with PVH/MVD could be subdivided into asymptomatic and symptomatic groups, some symptomatic PVH/MVD dogs actually may represent PSVA dogs in which the vascular anomaly escaped detection or dogs with other disorders such as noncirrhotic portal hypertension (NCPH) (see later) or ductal plate abnormalities, which share some clinical and histologic features with PSVA/PVH/MVD. The latter is differentiated from primary vascular disease by the presence of intense cytokeratin positive bile duct profiles on hepatic biopsy.

Clinical Pathology The hallmark of PVH/MVD is the presence of increased total serum bile acids in a dog that is otherwise clinically normal. Diagnosis requires ruling out the presence of a PSVA. Although increases in total serum bile acids are relatively lower in dogs with PVH/MVD as compared with PSVA, the degree of elevation cannot be used to differentiate the two disorders because of the potential for overlap in bile acid values. Complete blood count, serum biochemistry, and urinalysis typically are normal in dogs with PVH/MVD, with occasional mild increases in serum aminotransferases. In contrast, dogs with PSVA may have an RBC microcytosis, hypocholesterolemia, low BUN and creatinine, hypoglycemia, and ammonium biurate crystalluria. If readily available, plasma protein C level may aid in the differentiation of PSVA and PVH/MVD because it typically is subnormal with PSVA (protein C < 70% in 599

600

SECTION  VI  Gastrointestinal Diseases

88% of dogs) and normal with MVD (protein C ≥ 70% in 95% of dogs) (Toulza et al, 2006). The low protein C levels in PSVA likely reflect hepatic hypoperfusion and not synthetic failure; attenuation of the anomalous vessel results in normalization of these values.

Diagnostic Imaging Abdominal ultrasound is an easily accessible imaging modality that can identify features consistent with PSVA. Dogs with PVH/MVD typically have normal abdominal ultrasound examinations. With an experienced operator, the use of color-flow Doppler, and adequate restraint of the patient (which often requires sedation), the sensitivity of ultrasound to identify a macroscopic extra- or intraPSVA can be as high as 98% (d’Anjou et al, 2004). In addition to visualization of the anomalous vessel, other signs suggestive of a PSVA on ultrasound include the presence of a small hypovascular liver, turbulence in the portal vascular, renomegaly, urolithiasis, and a portal vein-to-aorta ratio less than 0.65 in a dog without portal hypertension. Unfortunately, a normal ultrasound examination does not definitively exclude PSVA, so additional imaging may be necessary to make a diagnosis of PVH/ MVD. Transplenic portal or per rectal portal scintigraphy can be used to confirm the presence of portosystemic shunting (either congenital or acquired) with a sensitivity and specificity approaching 100% (Sura et al, 2007). In these procedures, small volumes of technetium 99m pertechnetate are administered to the sedated patient per rectum or transcutaneously into the spleen, and distribution of the radioactivity within the portal and systemic circulation is monitored with a computer-linked gamma camera. Dogs with PVH/MVD have a normal or mildly increased shunt fraction with these techniques, whereas dogs with PSVA usually have a shunt fraction greater than 60% (Center, 2008). Transplenic scintigraphy is a minimally invasive and relatively cost-effective secondary imaging modality often used by the authors as a second-line modality after ultrasound has failed to find a PSVA. In the authors’ (CRLW) hospital a clinically normal dog with increased total serum bile acids but normal CBC, biochemical profile, urinalysis, abdominal ultrasound, and transplenic portal scintigraphy routinely is given a diagnosis of PVH/MVD without pursuing additional diagnostics (Box 146-1).

BOX 146-1  Typical Findings in Dogs with   Microvascular Dysplasia Absence of clinical signs Increased total serum bile acids Normal CBC, biochemistry panel, and urinalysis Normal protein C activity Normal abdominal ultrasound Normal transplenic and per rectal scintigraphy

Additional imaging modalities to aid in the identification of a PSVA include contrast-enhanced multiphase magnetic resonance angiography and three-dimensional multidetector computed tomography angiography. Both techniques are noninvasive and accurate methods of visualizing PSVA; however, both require patient sedation or anesthesia, have limited availability in general practice, and are relatively expensive. It is presumed that the appearance of a liver with PVH/MVD would be normal; however, no large-scale studies have described the computed tomography (CT) or magnetic resonance imagery (MRI) appearance of PVH/MVD. Normal radiographic mesenteric portography is the standard for excluding the presence of a PSVA. This requires abdominal exploratory and direct mesenteric injection of an iodinated contrast agent. Portography in dogs with MVD is essentially normal, although there may be failure of some regions of the liver to opacify with contrast or abnormally long retention of contrast in other areas.

Hepatic Biopsy A diagnosis of MVD cannot be made by evaluation of hepatic histopathology (Rothuzien et al, 2006). The histopathologic changes associated with MVD are identical to those seen with PSVA and reflect chronic hypoperfusion of the liver (Figure 146-1). These features include juvenile or underdeveloped portal triads with hepatic arteriolar reduplication (increased number of profiles), small or absent portal veins, prominent central venous musculature, lobular atrophy, dilation of perivenular lymphatics, disorganized hepatic sinusoids, and multifocal lipogranulomas surrounding hepatic venules. Accurate histopathologic diagnosis of PSVA/PVH/MVD often requires surgical or laparoscopic wedge biopsy specimens collected from multiple liver lobes. Because the microscopic lesions can be inconsistent among liver lobes and subtle in dogs with PVH/MVD, lesions may be missed with single-lobe or small-needle biopsies. At least three liver biopsies should be taken from three different liver lobes to better identify this condition histologically. In general the workup to differentiate MVD from PSVA usually does not require hepatic biopsy.

Treatment and Prognosis Because dogs with MVD typically are asymptomatic and nothing suggests that PVH/MVD is progressive, dogs with the disorder generally do not require any therapy. Caution should be exercised with use of drugs that require extensive hepatic metabolism. Occasionally, in the dog with increases in serum transaminases, treatment can be initiated with hepatic cytoprotective agents such as ursodeoxycholate or S-adenosylmethionine, and liver enzymes should be monitored periodically. Although studies with long-term follow-up in dogs with PVH/MVD are lacking, anecdotal experience suggests that the disease is not progressive. This is supported by the diagnosis of the condition in asymptomatic Cairn terriers at up to 8 years of age (Schermerhorn et al, 1996).

CHAPTER  146  Portal Vein Hypoplasia (Microvascular Dysplasia)

Bile duct

601

Bile duct

Arteriole Arteriole

Portal vein

A

B Figure 146-1  Hepatic histopathology in dogs with chronic hypoperfusion. A, A normal portal triad with one portal vein, hepatic artery, and bile duct. B, A typical portal triad from a dog with chronic hepatic hypoperfusion that shows portal vein attenuation and hepatic arteriolar reduplication.

Portal Vein Hypoplasia and Microvascular Dysplasia Versus Vascular Disease with Portal Hypertension Within the WSAVA classification of PHPV, some symptomatic dogs show the stereotypical histologic picture of chronic hypoperfusion seen with PSVA/PVH/MVD but also have portal hypertension. Some of these dogs have true hypoplasia (atresia of the portal vein). Others have a clinical syndrome that has been referred to as noncirrhotic portal hypertension (NCPH), idiopathic hepatic fibrosis, hepatoportal fibrosis, and PHPV in the veterinary literature (Bunch, Johnson, and Cullen, 2011; Buob, Johnston, and Webster, 2011; Rothuizen et al, 2006; van dan Ingh, Rothuizen, and Meyer, 1995). In humans NCPH is an acquired vasculopathy of the small and medium branches of the portal vein associated with exposure to toxins absorbed from the gastrointestinal tract (e.g., lipopolysaccharide, some drugs), autoimmune disorders, and prothrombotic states. Veterinary cases of NCPH/PHPV may be due to primary hypoplasia of the intrahepatic portal vasculature or may be a consequence of a similar congenital or acquired disorder in hepatic perfusion. The clinical features in dogs with NCPH/PHPV are different than those seen in PSVA/PVH/MVD. Typically dogs with this disorder are young (100 mg/kg), cardiac arrhythmias are possible. The adverse effects may be both dose and route dependent. If the drug is injected intravenously, CNS effects are more likely because of rapid and high blood concentrations. The metabolism of theophylline may be inhibited by erythromycin, enrofloxacin, and cimetidine. Interactions with fluoroquinolones other than enrofloxacin have not been investigated. At our institution, the dosage interval is generally doubled for patients treated with enrofloxa­ cin. The metabolism of theophylline may be increased by rifampin and phenobarbital, which may necessitate increasing the dose if these drugs are used together. As a phosphodiesterase inhibitor, theophylline shares a mech­ anism with the cardiac drugs pimobendan and sildenafil. Potentiation of effects is possible if these drugs are used

Mechanism of Action In patients with inflammatory airway diseases, glucocor­ ticoids have potent antiinflammatory effects on the bron­ chial mucosa. Glucocorticoids bind to receptors on cells and inhibit the transcription of genes for the production of mediators involved in airway inflammation (cytokines, chemokines, adhesion molecules). The result is a decrease in the synthesis of inflammatory mediators such as pros­ taglandins, leukotrienes, and platelet-activating factor. Although these inflammatory mediators are significantly suppressed, mast cells are not affected by glucocorticoids. Glucocorticoids also enhance the action of adrenergic agonists on β2-receptors in the bronchial smooth muscle, either by modifying the receptor or augmenting muscle relaxation after a receptor has been bound. Corticoste­ roids prevent down-regulation of β2-receptors and may be synergistic when used with β2-agonists. Glucocorticoids and theophylline used together also appear to be synergistic.

Antiinflammatory Drugs Glucocorticoids Glucocorticoids are used most often to decrease inflam­ mation associated with inflammatory airway diseases, particularly allergic or idiopathic feline or canine bron­ chitis. Their role in the treatment of asthma and chronic bronchitis in people continues to be studied extensively, and although few in number, reports in veterinary medi­ cine support their use. For treatment of asthma in people, inhaled corticosteroids are recognized as the most effec­ tive maintenance therapy available. Glucocorticoids are also used in the treatment of other inflammatory respira­ tory diseases such as eosinophilic bronchopneumopathy, tracheobronchomalacia, and chronic (lymphoplasma­ cytic) rhinitis. Although they are not a direct treatment, they may also improve clinical signs related to inflamma­ tion associated with diseases such as dirofilariasis or neoplasia.

Clinical Use The clinical effectiveness of glucocorticoid therapy for chronic respiratory disease is enhanced by treating with a sufficient dose for a sufficient period of time before beginning to taper the dosage to low-dose, alternate-day therapy. Once inflamed, the respiratory mucosa is sensi­ tized to react with a greater inflammatory response to subsequent insults, which may include simply irritants in the air. When the initial course of treatment is continued for 2 to 3 weeks before tapering is begun, the ultimate dose of glucocorticoids needed for good control of signs long term is often much less than that that required for moderate control of signs with a more rapid taper. Dogs.  Oral prednisolone or prednisone is usually the drug of choice for dogs. A typical antiinflammatory

626

SECTION  VII  Respiratory Diseases

dosage is 0.5 to 1.0 mg/kg twice daily. Improvement in clinical signs is expected within a week. If improvement is seen, this dosage is continued for 2 to 3 weeks and then gradually tapered by 25% to 33% every 1 to 2 weeks, as long as signs remain controlled. The ultimate goal is an every-other-day schedule at the minimum effective dose. Cats.  Because cats are somewhat resistant to glucocor­ ticoids, higher dosages have been used than in dogs. Oral prednisolone at initial dosages of 2 to 4 mg/kg/day has been used for inflammatory diseases, with expected response and tapering of dose as described earlier for dogs. For cats, prednisolone is often recommended instead of prednisone because of concern that either prednisone is not well absorbed or there is a deficiency in the conversion of prednisone to the active form pred­ nisolone; however, supportive data have been reported only in preliminary form. Because of difficulty in giving oral medications to cats, many veterinarians have admin­ istered 20 mg per cat of a long-acting formulation, meth­ ylprednisolone acetate (Depo-Medrol) intramuscularly. The effects of one injection may persist for 3 weeks. The negative aspect of this approach is the inability to achieve stable remission and minimize long-term exposure to sys­ temic glucocorticoids. Adverse effects are common with long-term treatment, and those of particular concern for patients with respiratory disorders include weight gain, muscle weakness, and potential predisposition to pulmo­ nary thromboembolism or infection. In addition, gluco­ corticoids may exacerbate or increase the risk of congestive heart failure in cats, possibly through increased plasma glucose concentrations and an increase in plasma volume leading to cardiac overload (Ployngam et al, 2006), and the development of diabetes mellitus.

Drug

Brand Name

Dose Delivered

Beclomethasone dipropionate

Vanceril

40 or 80 µg per puff

chamber (10 seconds) have reduced need for oral pred­ nisolone. In one study, inhaled fluticasone reduced bron­ chial hyperresponsiveness and bronchoconstriction in cats with bronchitis (Kirschvink et al, 2006). Inflamma­ tory cells and prostaglandins in bronchoalveolar lavage fluid were also reduced. Inhaled steroids also have been effective in the management of bronchitis in dogs. Delivery options for MDI drugs in veterinary patients were described earlier in the discussion of inhalant therapy using the bronchodilator albuterol. Fluticasone is the agent most often administered because of its  high potency and low systemic effects. MDIs can deliver fluticasone doses that range from 220 µg to 44 µg. For example, a 110-µg dose of fluticasone for a cat is delivered in one puff from a 110-µg MDI. In a study com­ paring dosages in cats, lower dosages of 44 µg twice daily were as effective as higher dosages (Cohn et al, 2010). However, this study used a mild, allergy-induced model of feline airway disease that may not reflect typical clini­ cal cases. Our institution usually initiates therapy at a dosage of 110 to 220 µg of fluticasone twice daily in cats or dogs. Cats with marked signs are concurrently pre­ scribed systemic prednisolone for 2 weeks. As with  systemic glucocorticoids, the initial MDI dosage is con­ tinued for at least 2 to 3 weeks, and signs should be in remission before tapering (decreasing frequency or dose) is attempted. In people, fluticasone has a systemic absorption of only 18% to 26%, and there are extensive first-pass effects and high protein binding that prevents significant sys­ temic active blood concentrations if it is swallowed after delivery. Therefore, clinical effects are mostly confined to the airways, and the systemic action is minimized. In cats, flunisolide was studied for its systemic effects after administration by inhalation (Reinero et al, 2006). Although there was some suppression of the hypothalamicpituitary-adrenal axis (indicating some systemic absorp­ tion), systemic effects on immune cells (lymphocytes and lymphocyte function) were not observed, which demon­ strated that inhaled flunisolide is capable of producing a local effect in the airways with minimal effects on the systemic immune system. Another adverse effect is the development of localized dermatitis either from the mask or from the topical effects of the potent steroid. Demo­ dectic mange mites and dermatophytes have been  identified in some cases, but simply discontinuing the glucocorticoid by inhaler generally results in rapid resolu­ tion. In these patients, systemic glucocorticoids are instituted. The canisters of MDI glucocorticoids are much more expensive than prednisone or prednisolone. There is also the investment in the spacer and mask. For patients without a contraindication for systemic steroids, it is rea­ sonable to carry out a therapeutic trial with an oral glu­ cocorticoid before transitioning to MDI administration.

Flunisolide

AeroBid

250 µg per puff

Leukotriene Inhibitors

Fluticasone propionate (most potent)

Flovent

44, 110, or 220 µg per puff

Triamcinolone acetonide

Azmacort

75 µg per puff

Leukotrienes, such as leukotriene D4, contribute to airway inflammation, produce bronchoconstriction, and increase airway wall edema in people but have not been demon­ strated to be important mediators in feline asthma.

Topical Corticosteroids (Metered Dose Inhalers) Glucocorticoids are among the most valuable drugs for managing asthma in people. For people, an MDI is used to deliver the drug topically to avoid systemic adverse effects. Examples of aerosolized corticosteroids are listed in Table 151-1. Fluticasone is the most potent (18 times the potency of dexamethasone) and is the one used most often in veterinary medicine. When glucocorticoids are delivered topically with these devices, systemic adverse effects are minimized but not eliminated. Cats with bronchitis given inhaled corticosteroids twice a day and allowed 5 to 7 breaths from the spacing

TABLE 151-1  Examples of Corticosteroids Available in Metered Dose Inhalers

CHAPTER  151  Respiratory Drug Therapy Therefore, the leukotriene inhibitor class of drugs may not have a role in treatment of feline respiratory disease. Their use has not been explored in dogs.

Other Antiinflammatory Drugs Nonsteroidal antiinflammatory drugs are not recom­ mended for the treatment of inflammatory airway and parenchymal diseases in people, and there is no evidence to support their use for these diseases in dogs or cats. Traditionally N-acetylcysteine has been considered a mucolytic drug (discussed further later), but it has been investigated for the treatment of respiratory diseases such as idiopathic pulmonary fibrosis in people because of its effects as an antioxidant and its possible effects on remod­ eling. No clear indication for this drug exists to date. Azithromycin and other newer macrolide antibiotics are being studied in human medicine based on trials showing improvement in some chronic inflammatory airway dis­ eases (bronchitis, asthma, bronchiectasis, cystic fibrosis) with long-term use. It is unclear whether antiinflamma­ tory properties of these drugs or antimicrobial effects against poorly characterized organisms are playing a  role. Omega-3 fatty acid supplementation may also be  of nonspecific benefit through its role in dampening inflammation.

Expectorants and Mucolytic Drugs The expectorants comprise a diverse group of compounds. Their proposed benefits include increased output of bron­ chial secretions, enhanced clearance of bronchial exudate, and promotion of a more productive cough. Unfortu­ nately, few clinical studies have documented efficacy for any of these drugs in people. The mechanism of action for stimulation of mucous secretions is via a vagally medi­ ated reflex action on the gastric mucosa. Examples of expectorants are various salts of iodide. Volatile oils such as eucalyptus oil and oil of lemon are believed to increase respiratory tract secretions directly. Their clinical efficacy in veterinary medicine is unknown. Guaifenesin is typically classified as a muscle relaxant in anesthesia and as an anesthetic adjunct but at appro­ priate doses it also may have an expectorant effect. The mechanism of action is uncertain, but it is possible that guaifenesin stimulates bronchial secretions via vagal pathways or accelerates particle clearance from the airways. Although many over-the-counter cough reme­ dies contain guaifenesin, efficacy has been questioned because most preparations do not contain a large enough dose. Formulations now used in people (but not evalu­ ated in animals) employ higher doses than older over-thecounter drugs. Most older over-the-counter formulations contain doses of 100 mg; higher-dose formulations for people include Mucinex (600- and 1200-mg tablet), Mucinex D (with pseudoephedrine), and Mucinex DM (with dextromethorphan). Mucolytic agents are desirable for patients with volu­ minous, tenacious mucous secretions that cannot be cleared with mucociliary transport and cough. Because there are no proven, safe, effective drugs to accomplish this goal, the primary means of treatment include

627

maintenance of systemic hydration, nebulization with physiologic saline solution (which has mucolytic proper­ ties), and physical therapy. Acetylcysteine is a mucolytic agent available as a 10% solution that can be nebulized for administration to patients. Its mucolytic effect is caused by an interaction of the exposed sulfhydryl groups on the compound with disulfide bonds on mucoprotein. However appealing its mucolytic potential may be, its use is greatly limited by its irritant effects on the respiratory mucosa. When administered in nebulized form to cats, it may induce bronchoconstriction. Anecdotally reported uses of systemically administered acetylcysteine in veterinary medicine include intrave­ nous administration to dogs with severe bronchopneu­ monia, particularly small puppies or bulldogs with a hypoplastic trachea, in which mucus appears to repeat­ edly obstruct the trachea. It has also been administered orally to dogs or cats with idiopathic pulmonary fibrosis based on some studies in people. Although there is no clear benefit to this treatment in people, and no studies in dogs or cats, there is little else to offer these patients. In people, a dose of 600 mg PO three times daily has been used, which is approximately 8 to 9 mg/kg. For both these indications, it is quite possible that antioxidant properties account for any benefit that may be seen. Oral acetylcysteine can be obtained from nutrition or health food stores.

Decongestants Decongestants are used to “dry up” mucous membranes. They have few indications in veterinary medicine. Decon­ gestants are sympathomimetic drugs that stimulate the α-adrenergic receptors, causing local vasoconstriction and a decongestant effect. Short-acting topical agents include phenylephrine and phenylpropanolamine, which are common ingredients in over-the-counter nasal sprays (e.g., Neo-Synephrine). In veterinary medicine, these products are applied topically to decrease bleeding associ­ ated with some surgical procedures (e.g., nasal turbinate surgery in dogs) and rhinoscopy, and for short-term man­ agement of severe congestion associated with feline upper respiratory tract infections. Some topical decongestants, such as oxymetazoline (Afrin) and xylometazoline (Dristan), are particularly long-acting. Caution should be exercised when using the topical products for long periods. Rebound inflammation and hyperemia may occur when the action of the drug diminishes, resulting in a worsen­ ing of the problem. The systemic use of adrenergic ago­ nists as decongestants has been a common practice in human medicine for decades. The systemic decongestant phenylpropanolamine hydrochloride is used for treating urinary incontinence in dogs and approved formulations are available for dogs (Proin Chewable Tablets). However, a beneficial effect is rarely seen in dogs or cats with rhi­ nitis, and their use is not recommended.

Antibacterial Drugs Antimicrobial therapy for bacterial respiratory infections includes treatment for conditions such as pneumonia

628

SECTION  VII  Respiratory Diseases

(airway origin or hematogenous), aspiration pneumonia, bacterial bronchitis or tracheobronchitis, pyothorax, and rhinitis/sinusitis. An accurate diagnosis is essential, because a common error is to administer antibiotics for conditions that do not require an antibiotic. Diffusion of antibiotics to the airways has been the subject of considerable discussion and controversy. Anti­ biotic concentrations in interstitial (tissue) fluid predict the active concentration necessary for treating most infections. These concentrations are equivalent to the protein-unbound (free) drug concentrations in plasma. However, the respiratory tract presents another challenge— the diffusion of antibiotics across the blood-alveolar barrier (also referred to as the blood-bronchus barrier in some publications). The concentration of drug that pen­ etrates the blood-alveolar barrier is represented by the concentrations in the epithelial lining fluid (ELF), which may be an important site of infection in pneumonia. Although drug concentration in the ELF may be better for predicting efficacy than lung or plasma concentra­ tions, this assumption has some flaws. Healthy ELF assessed in experimental animals may not represent the actual environment during clinical infection. The impor­ tance of adequate antibiotic concentrations in ELF not­ withstanding, lung infection can disrupt the alveolar wall and invade the interstitial space. Some lung infections are also borne hematogenously and invade the airway via the interstitium. After pneumonia is established, the drug concentration in the area of consolidation may be more equivalent to that in the interstitial (tissue) fluid than the ELF. In reality, both concentrations may be important to evaluate: interstitial fluid drug concentrations may be predictive of respiratory tissue concentrations during infection, but drug concentrations in ELF may be more predictive of drug concentrations in airway secretions and may be helpful in eradicating infecting agents that colonize the airways. Drug concentrations in ELF are probably more important for macrolide antibiotics (e.g., azithromycin) for which ELF concentrations far exceed concentrations in plasma. Properties that favor penetra­ tion to the ELF include high lipophilicity, high potency of the drug (low minimal inhibitory concentration), and the concentration of free (unbound) drug in the intersti­ tial fluid. Drugs such as macrolides (erythromycin, azithromy­ cin), tetracyclines, and fluoroquinolones appear to achieve adequate concentrations in ELF. The β-lactam antibiotics, especially the highly protein-bound drugs, and aminoglycosides do not reach high concentrations in the ELF but may diffuse into the interstitial space to achieve effective concentrations in the presence of infec­ tion. Inflammation that occurs in pneumonia produces leakage of drugs into the ELF regardless of which drug is selected. Another approach for enabling drugs to reach infec­ tions colonizing the airways is nebulization. There is no evidence supporting the benefit of this route of antibiotic treatment in veterinary medicine, and its use is based on anecdotal reports. Potential indications for this route are limited to bacterial tracheal or bronchial infection and adjunctive treatment for management of bacterial pneu­ monia. It is not sufficient treatment alone for pneumonia.

In veterinary medicine, nebulization of antibiotics is gen­ erally used for administration of aminoglycosides to the airways, which minimizes concerns of systemic toxicity. Treatment for Bordetella bronchiseptica has been suggested using gentamicin 50 mg in 3 ml of sterile water, nebu­ lized for 10 minutes, and delivered by face mask twice daily for 3 days (Bemis and Appel, 1977). Although this treatment resulted in decreased numbers of Bordetella in the airways for up to 3 days, numbers returned to pre­ treatment levels by 7 days. It is not known if the formula­ tion of the drug is important in veterinary patients. Typically in veterinary patients the injectable solutions are used. But in human medicine, antibiotics for nebuli­ zation are specifically formulated without preservatives or other excipients that might produce airway inflammation or bronchoconstriction and are matched to particular nebulizers. These human medications are more expensive than injectable solutions. Risks of antibiotic administra­ tion via nebulization include bronchospasm and environ­ mental contamination, with potential exposure of the administrator. Bronchodilators should be on hand in case of acute distress. The nebulizer unit must be properly cleaned and the sterility of administered fluids main­ tained to avoid nebulizing additional pathogens into the airways. Treatment of specific respiratory tract infections is reviewed in other chapters in this section.

References and Suggested Reading Bach JE et al: Evaluation of the bioavailability and pharmacoki­ netics of two extended-release theophylline formulations in dogs, J Am Vet Med Assoc 224:1113, 2004. Barnes PJ: Theophylline: new perspectives for an old drug, Am J Respir Crit Care Med 167:813, 2003. Bemis DA, Appel MJG: Aerosol, parenteral, and oral antibiotic treatments of Bordetella bronchiseptica infections in dogs, J Am Vet Med Assoc 170:1082, 1977. Cohn LA et al: Effects of fluticasone propionate dosage in an experimental model of feline asthma, J Feline Med Surg 12:91, 2010. Gingerich DA, Rourke JE, Strom PW: Clinical efficacy of butor­ phanol injectable and tablets, Vet Med Small Anim Clin 78:179, 1983. Guenther-Yenke CL et al: Pharmacokinetics of an extended release theophylline product in cats, J Am Vet Med Assoc 231:900, 2007. Kirschvink N et al: Inhaled fluticasone reduces bronchial respon­ siveness and airway inflammation in cats with mild chronic bronchitis, J Feline Med Surg 8:45, 2006. KuKanich B: Pharmacokinetics of acetaminophen, codeine, and the codeine metabolites morphine and codeine-6-glucuronide in healthy Greyhound dogs, J Vet Pharmacol Ther 33:15, 2010. KuKanich B, Papich MG: Plasma profile and pharmacokinetics of dextromethorphan after intravenous and oral administra­ tion in healthy dogs, J Vet Pharmacol Ther 27:337, 2004. Papich MG: Handbook of antimicrobial therapy for small animals, St Louis, 2011, Saunders. Ployngam T et al: Hemodynamic effects of methylprednisolone acetate administration in cats, Am J Vet Res 67:583, 2006. Reinero CR et al: Inhaled flunisolide suppresses the hypothalamicpituitary-adrenal axis, but has minimal systemic immune effects in healthy cats, J Vet Intern Med 20:57, 2006. Takahama K, Shirasaki T: Central and peripheral mechanisms of narcotic antitussives: codeine-sensitive and -resistant coughs, Cough 3:1, 2007.

CHAPTER 

152 

Feline Upper Respiratory Tract Infection JYOTHI V. ROBERTSON, Davis, California KATE HURLEY, Davis, California

F

eline upper respiratory tract infection (URI) is frequently identified in high-density populations, including those in breeding catteries and animal shelters. This clinical syndrome is inextricably linked to stress, crowding, and poor husbandry. Consequently, adopting effective preventive strategies is essential to combatting this disease in both household pets and large feline populations.

Causes and Primary Agents Feline URI is a multifactorial disease with a primarily viral origin and secondary bacterial components. Feline herpesvirus type 1 (FHV-1) and feline calicivirus (FCV) cause approximately 80% of all URIs in cats, but the relative importance of each contributing pathogen varies with context. FHV-1 is an antigenically stable DNA virus, whereas FCV is an RNA virus with multiple strains of varying virulence. Both viruses maintain carrier states, both are readily spread by fomites, and droplets can be transmitted up to 5 ft by forceful sneezing. FHV-1 shedding is closely associated with stress. In the United States, FHV-1 is the principal pathogen causing most shelter-acquired URIs, and once infected, most cats develop latent chronic infections. In one study, the percentage of cats shedding FHV-1 increased from 4% of cats on day 1 to more than 50% on day 7 of their shelter stay (Pedersen et al, 2004). Accordingly, cats are most commonly diagnosed with URI during their second week in a shelter. Intermittent shedding occurs after stress-induced reactivation of FHV-1. URI signs are manifest during recrudescence in 50% of cats. In contrast, FCV shedding is not linked to stress and has greater prevalence in long-term sanctuaries and large, stable populations, including hoarding situations. One recent study documented the prevalence of FCV in longterm sanctuary cats with and without clinical signs to be more than double that in shelter cats with and without clinical signs (McManus et al, 2011). The relative importance of FCV in sanctuary settings is likely due in part to dissemination of multiple mutating strains in a constant population. Less commonly, the bacterial agents Chlamydophila felis, Bordetella bronchiseptica, Mycoplasma spp., and Streptococcus canis have been implicated in primary disease. Respiratory pathogens have a synergistic effect, and  there is increased likelihood that cats harbor multiple

pathogens when clinically ill. However, all pathogens associated with URI have been isolated from both healthy and clinically affected cats, so identification of a microorganism does not necessarily implicate it as the primary cause of illness.

Risk Factors Any factor that elicits stress has the potential cause clinical signs of URI by reactivating latent feline herpesvirus. For the household pet, the addition of a new animal, a recent move, or a trip to the veterinarian could be enough to cause recrudescence. For cats entering animal shelters, the cumulative effect of many stressors compounded with a new environment, can lead to viral shedding. A cat’s length of stay, or time spent in the shelter, is directly linked to development  of URI, and, conversely, development of URI leads to increased lengths of stay. Crowded conditions, poor housing, loud noises, and new foods make cats more susceptible to illness. Notably, the single-compartment feline cages commonly used in shelters are directly linked to stress and, by extension, illness (Kessler and Turner, 1999). These housing units provide insufficient floor space, which limits a cat’s ability to exhibit normal feline behaviors (e.g., stretching, hiding, grooming), and lack sufficient separation of bedding, food, and litter. Cats in animal hoarding situations often manifest clinical signs of feline URI. When multiple cats from a single household are diagnosed with severe or chronic URI over an extended period, the clinician should  obtain a thorough history and evaluate the housing environment.

Clinical Signs The magnitude of evidenced clinical signs depends on the immune status of the cat, the specific pathogens or strains involved, infecting dose, presence of coinfections, and the environment. A list of clinical signs associated with the most common URI pathogens is provided in Table 152-1. The organisms listed in this table can cause overlapping clinical signs. Thus a particular clinical manifestation does not implicate a specific pathogen as the  cause of disease. Synergism among pathogens may lead to more severe clinical signs in cats harboring multiple pathogens. 629

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TABLE 152-1  Clinical Signs Associated with Major Pathogens

a baseline for comparison. In this manner, URI incidence, prevalence, and rates serve as overall indicators of the welfare of a cat population (Hurley, 2004).

Pathogen

Clinical Signs

Treatment

Feline calicivirus

Rhinitis, stomatitis, oral ulceration, conjunctivitis, polyarthritis, lower airway disease, virulent systemic disease—systemic vasculitis

Feline herpesvirus type 1

Rhinitis, stomatitis, conjunctivitis, keratitis, facial dermatitis, corneal ulcerations, corneal sequestrum

Bordetella bronchiseptica

Conjunctivitis, tracheobronchitis, pneumonia

Chlamydophila felis

Conjunctivitis, mild upper airway signs; can cause severe disease in conjunction with other respiratory pathogens

Most cases of feline URI are self-resolving within 2 weeks. Because of the disease’s viral origin, blanket application of antibiotics in group settings is not recommended. Rather, the instigating risk factors should be remedied to prevent cats from acquiring illness through exposure or reinfection. Supportive treatment that may be provided includes fluid rehydration therapy, humidification of  the environment, and administration of appetite stimulants such as cyproheptadine HCl (1 to 2 mg per cat, q12-24h PO).

Diagnosis The diagnosis of acute feline URI is based on clinical signs often coupled to a triggering event. Diagnostic testing is warranted in individual cats, in cases of chronic disease, and in populations in which disease manifestations are unusually severe or frequent. It is important to consider noninfectious differential diagnoses for URI signs, including neoplasia, inflammatory polyp, foreign body, trauma, cleft palate, chronic rhinosinusitis, oronasal fistula, and fungal infection. Preexisting immunosuppression caused by feline leukemia virus or feline immunodeficiency virus infection should be considered in previously untested cats. It is also emphasized that although viral or bacterial culture or DNA detection can be used to confirm the presence of a potential pathogen, a positive test result does not confirm causality. Additionally, oculonasal or oropharyngeal swabs submitted for sampling are likely to contain some normal flora. Real-time polymerase chain reaction (RT-PCR) is one test used to evaluate potential infectious primary causes of URI. However, RT-PCR results must be interpreted with caution, especially in individual cases. Currently, a positive PCR test result cannot distinguish between the inciting cause of disease, commensals, and vaccine strains. In the future, quantitative RT-PCR tests may be available to differentiate acute infection from carrier states. A negative test result helps rule out an acute infection with a particular infective agent but not a carrier state, because shedding can be sporadic. In group settings, sampling a minimum of 5 to 10 affected cats or 10% of the population early in the course of disease should be considered. Positive test results should be interpreted in the context of the expected prevalence of the organism in that population. In severe outbreaks, in which cats are euthanized or are dying from disease, histopathologic analysis and necropsy should be performed to determine the underlying cause and guide risk assessment. Monitoring of disease prevalence, incidence, duration, and severity is critical for assessing the success of URI control measures. These data also provide

Antibiotics Antibiotics are often administered to treat secondary bacterial infection or to target known or suspected primary or coinfecting bacteria. Doxycycline (5 mg/kg q12h PO or 10 mg/kg q24h PO) is commonly chosen to treat  suspected infection with Bordetella, Chlamydophila, and Mycoplasma spp. Doxycycline (in particular doxycycline hyclate) should be compounded into a liquid form, since it has been linked to esophagitis and esophageal strictures in cats. Dry pills can be crushed and suspended in  a variety of products, including milk or corn syrup  or other sweet-tasting liquid. Formulations should be used within 7 days. Pills (and possibly even liquids) should be followed with a bolus of liquid (6 ml). Other commonly chosen antibiotics with dosages are listed in Table 152-2. A broad-spectrum antibiotic that includes gramnegative coverage may be administered when there is no response to initial therapy or when secondary bacterial infection is the main target of treatment. If the patient does not improve after 5 to 7 days of treatment, treatment plans should be adjusted and a change in antibiotics considered. In general, antibiotics should be administered until resolution of clinical signs, rather than for a specified duration. An exception to this rule is chronic cases of URI or disease known to be caused by Chlamydophila infection, which will require a longer treatment course (2 to 3 months) beyond the resolution of clinical signs. If antibiotic therapy fails after two courses of antibiotic treatment, further diagnostic testing may be warranted  to rule out other causes of illness or underlying immunosuppression.

Antivirals Lysine is an essential amino acid that interferes with FHV replication in vitro. When used as adjunctive or palliative therapy in client-owned cats, it is administered as a bolus of 500 mg twice daily (Maggs, 2010). Lysine was found to be ineffective as a preventative in shelter populations when administered in food (Maggs et al, 2007; Rees and Lubinski, 2008). Treatments specifically targeting FHV-1 and FCV are currently under study but are beyond the scope of this chapter.

CHAPTER  152  Feline Upper Respiratory Tract Infection

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TABLE 152-2  Commonly Administered Antibiotics for Feline Upper Respiratory Tract Infection Antibiotic

Dose

Comments

Amoxicillin/clavulanate

13.75 mg/kg q12h PO or 62.5 mg per cat q12h PO

Broad spectrum; disrupts cell wall; not effective against Mycoplasma

Azithromycin

15 mg/kg q24h PO

Relatively broad spectrum

Doxycycline

5 mg/kg q12h PO or 10 mg/kg q24h PO

Provides good coverage for primary bacterial respiratory pathogens including Bordetella, Chlamydophila, Mycoplasma spp. Administer as liquid suspension, or flush with water after administration

Cephalexin

22 mg/kg q8h PO

First-generation cephalosporin; active against gram-positive organisms; not effective against Mycoplasma

Clindamycin

10 mg/kg q24h PO

Lincosamide antibiotic; active against anaerobes; penetrates bone; effective against Bordetella, Mycoplasma, Chlamydophila Administer as liquid suspension, or flush with water after administration

Enrofloxacin

2.5-5.0 mg/kg q24h PO

Broad spectrum; effective against Chlamydophila, Mycoplasma Do not exceed 5 mg/kg/day

Minocycline

5 mg/kg q12h PO

Similar to doxycycline, less commonly used

Pradofloxacin

7.5 mg/kg (liquid suspension) q24h PO

Similar to enrofloxacin but better coverage of Mycoplasma spp. and anaerobes; less ophthalmic concerns

PO, Orally.

Prevention Strategies to Combat Crowding Since crowding is a primary cause of illness in animal shelters, adopting strategies that maintain the population at a number that is appropriate for the facility size and staffing capacity are critical to reducing the incidence of URI. Shelters must have sufficient staff, housing units, and time to care for all animals in their facility. Decreasing the length of stay for each individual cat by ensuring that it is moved through the facility quickly will decrease exposure to disease and increase the organization’s ability to save more animals. Decreasing lengths of stay will notably also reduce the overall shelter population and further combat crowding. Figure 152-1  Example of a porthole between cages that allows

Housing Solutions to Reduce Stress

separation of litter from food and bedding.

Housing impacts many aspects of the health and wellbeing of those cats in confinement; therefore, simple improvements can greatly reduce disease in multicat facilities. Purchasing double-compartment housing units or installing portholes in existing cages allows separation of litter from food and bedding and increases the overall square footage of living space while minimizing animal handling (Figure 152-1). Hiding boxes or a simple towel draped over a cage can greatly reduce stress in cats and thereby decrease the incidence of disease (a towel or cage cover is preferred if floor space is limited). Cats should be housed away from dogs, and cats in different age groups should not be mixed in housing units.

Vaccination Natural infection does not create long-term immunity  for any of the common URI pathogens. Therefore, while vaccination may diminish the severity of clinical signs and reduce pathogen shedding, it does not prevent infection or development of the carrier state. Both modified live virus (MLV) and inactivated virus subcutaneously administered vaccines are available for FHV-1 and FCV, formulated as combination vaccines with and without feline panleukopenia vaccine (feline viral rhinotracheitis and calicivirus [FVRC] and feline viral rhinotracheitis, calicivirus, and panleukopenia [FVRCP], respectively.

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Intranasal MLV two-way (FVRC) or three-way (FVRCP) vaccines also are available. A modified live intranasal vaccine is available for feline Bordetella and both modified live and inactivated vaccines are available for Chlamydophila felis in conjunction with the FVRCP vaccine. Use of these vaccinations is not recommended unless those pathogens have been diagnosed specifically in a feline population or a pet is at known risk of exposure. Cats living in high-density populations such as animal shelters should receive an MLV FVRCP vaccination (first vaccination at 4 to 6 weeks, then q2wk until 16 to 18 weeks). The intranasal MLV FVRC (two-way) vaccine may be administered to kittens as early as 2 weeks of age in animal shelters or other high-risk facilities where there is rampant URI.

References and Suggested Reading Hurley KF: Implementing a population health plan in an animal shelter: goal setting, data collection and monitoring, and

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policy development. In Miller L, Zawistowski S, editors: Shelter medicine for veterinarians and staff, Ames, IA, 2004, Blackwell Publishing, p 211. Kessler MR, Turner DC: Effects of density and cage size on stress in domestic cats (Felis silvestris catus) housed in animal shelters and boarding catteries, Anim Welf 8(3):259, 1999. Maggs DJ: Antiviral therapy for feline herpesvirus infections, Vet Clin North Am Small Anim Pract 40(6):1055, 2010. Maggs DJ et al: Effects of dietary lysine supplementation in cats with enzootic upper respiratory disease, J Feline Med Surg 9(2):97, 2007. McManus CM et al: Prevalence of upper respiratory pathogens in four management models for unowned cats in the southeast United States, Research Abstract Program of the 2011 ACVIM Forum, Denver, CO, June 15-18, 2011 (abstr). Pedersen NC et al: Common virus infections in cats, before and after being placed in shelters, with emphasis on feline enteric coronavirus, J Feline Med Surg 6(2):83, 2004. Rees TM, Lubinski JL: Oral supplementation with l-lysine did not prevent upper respiratory infection in a shelter population of cats, J Feline Med Surg 10:510, 2008.

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Canine Infectious Respiratory Disease Complex JANE E. SYKES, Davis, California

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anine infectious respiratory disease is a widespread problem where large numbers of dogs are collectively housed indoors, as in shelters, commercial dog colonies, and breeding facilities. In shelter environments, canine infectious respiratory disease complex (CIRDC), also known as kennel cough or canine infectious tracheobronchitis, delays rehoming and may result in unmanageable costs related to treatment, quarantine, and isolation. CIRDC can develop in pet dogs after contact with large numbers of other dogs at dog parks, at canine sporting events such as fly ball, or during dog behavior classes. It also can occur after dogs (or their owners) visit veterinary hospitals, boarding facilities, or pet daycare centers. With the widespread clinical application of molecular diagnostic assays, it has become increasingly apparent that the number of infectious agents that can damage the canine respiratory tract is much larger than previously recognized. Most cases are viral in origin. Viruses believed to play a role in canine contagious respiratory disease include canine herpesvirus (CHV), canine adenovirus type 2 (CAV-2), canine distemper virus (CDV), canine

parainfluenza virus (CPiV), canine respiratory coronavirus (CRCoV), and canine influenza virus (CIV). CIV appears to have originated from an equine H3N8 influenza virus that first emerged in racing greyhounds in Florida and has spread across the United States through dog-to-dog transmission. CRCoV was first identified in a rehoming kennel in the United Kingdom and also appears to be widespread in the United States. It is distinct from canine enteric coronavirus. Finally, a pneumovirus (canine pneumovirus) also may be involved in CIRDC, but more research is required to determine the significance of this agent. Coinfections with multiple viruses and bacteria such as Mycoplasma spp., Bordetella bronchiseptica, and Streptococcus equi subspecies zooepidemicus are common and contribute to an increased severity of disease. Studies in England have suggested that Mycoplasma cynos may be a primary pathogen (Rycroft et al, 2007), but whether this is true in other countries is unclear. Other Mycoplasma spp. may be more likely to represent normal flora  that invade opportunistically. Although the majority of the canine respiratory pathogens have a worldwide

CHAPTER  153  Canine Infectious Respiratory Disease Complex distribution, their relative prevalence varies from year to year and among geographic locations. Even within a state or city, predominant pathogens may differ from one shelter and boarding kennel to another. Mycoplasma spp. and the enveloped viruses CDV, CHV, CPiV, CRCoV, and CIV survive poorly in the environment and are susceptible to a variety of disinfectants. Despite this relative fragility, direct contact with organisms that persist even for a short time in the environment may be important for transmission in densely housed canine populations. CAV-2 is a nonenveloped virus and has the potential to survive several weeks on fomites. Other microorganisms that may persist in the environment and may be transmitted on fomites include B. bronchiseptica and S. equi subspecies zooepidemicus. There are a large number of strains of B. bronchiseptica, varying in virulence and in host specificity. Nevertheless, strains that infect dogs can be passed to cats and vice versa. Shedding of B. bronchiseptica by both dogs and cats may continue intermittently for at least a month and sometimes several months after infection. Survival inside of phagocytes may allow for evasion of the immune system and help to explain persistent infections. S. equi subspecies zooepidemicus has been isolated from shelter dogs in outbreaks of severe pneumonia and may contribute to an increased severity of disease when present in coinfections with respiratory viruses. Both B. bronchiseptica and S. equi subspecies zooepidemicus have been uncommonly reported to infect humans. B. bronchiseptica has caused primary respiratory illness in immunocompromised people.

Diagnosis Generally it is not possible to identify the cause of transmissible respiratory disease in dogs based solely on clinical features. Each pathogen produces a similar spectrum of clinical signs. Occasionally, a specific causative diagnosis may be strongly suspected based on the presence of particular clinical signs, such as footpad hyperkeratosis or chorioretinitis in dogs with distemper, or dendritic corneal ulceration in dogs infected with CHV. However, the high prevalence of coinfections and increased severity of disease when multiple pathogens are present complicates diagnosis. In addition, other noncontagious causes of respiratory disease in dogs (such as inflammatory airway disease, respiratory tract neoplasia, or fungal pneumonia) can produce signs that resemble transmissible respiratory disease. A history of exposure to other dogs can increase suspicion for a diagnosis of CIRDC. Most dogs experience self-limiting disease. Attempts to obtain a causative diagnosis should be made when disease persists for longer than 7 to 10 days or is complicated by secondary bacterial pneumonia. The latter may be accompanied by mucopurulent ocular or nasal discharge, fever, lethargy, and inappetence. When only one pet dog is affected, the diagnosis is further complicated by the fact that pathogens associated with CIRDC also can be isolated from healthy dogs. Thus the clinical significance of a positive test result for one of these pathogens may be unclear. When outbreaks occur in shelters or the pattern of endemic respiratory disease changes, attempts to make

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a causative diagnosis are indicated. Oropharyngeal, conjunctival, and nasal swabs or airway lavage specimens may be submitted for aerobic bacterial culture, for Mycoplasma culture, and for molecular diagnostic testing. In an outbreak situation, collection of multiple specimens from both affected and healthy dogs in the affected area facilitates diagnosis and interpretation of positive test results. Virus isolation also is available from some specialized veterinary diagnostic laboratories. Organism detection methods, such as polymerase chain reaction (PCR) assay or virus isolation, are best used early in the course of illness (e.g., the first 1 to 3 days) or in exposed dogs that have not yet developed clinical signs. Use of a combination of serologic and organism detection methods may also facilitate diagnosis when outbreaks occur. In shelter situations or in outbreaks in which severe disease occurs, necropsies can provide valuable information and should be performed by a veterinary pathologist as soon as possible after death or euthanasia. Tissues should be submitted for histopathologic analysis (in formalin), bacterial and viral cultures (fresh tissue), and PCR testing for respiratory viruses and bacteria (fresh or frozen tissue). For dogs that develop chronic bronchitis or bronchopneumonia, a full physical examination, complete blood count, and thoracic radiographs are indicated, and if  possible, specimens for aerobic bacterial culture and susceptibility testing, Mycoplasma culture, and molecular diagnostic testing should be collected using bronchoscopy and bronchoalveolar lavage. Tracheal lavage is acceptable if bronchoscopy is not possible or affordable; in some cases collection of an airway specimen may not be possible because of patient condition, and empiric antimicrobial drug therapy must be used.

Treatment and Prognosis Uncomplicated CIRDC in dogs resolves without treatment in most cases, regardless of the underlying cause. Thus if a dog has signs of respiratory disease that have been present for fewer than 7 to 10 days and remains bright and has good appetite, no treatment may be necessary. In some patients (such as those with bordetellosis), cough may persist for as long as 10 to 30 days. Cough suppressants such as hydrocodone could be used in dogs with a nonproductive, honking cough that occurs throughout the day and night, but these drugs are not indicated for all dogs because they can suppress normal clearing mechanisms and contribute to pneumonia. Cough suppressants should not be used in dogs with a productive cough. Use of a harness or gentle leader rather than a neck collar for leash walking also may reduce cough. Removing affected animals to reduce stress and coinfections may be beneficial, especially in overcrowded environments with poor hygiene. Antimicrobial treatment is indicated when there is evidence of bacterial infection, such as mucopurulent ocular and nasal discharge, lethargy, decreased appetite, and radiographic evidence of bacterial bronchopneumonia, such as pulmonary alveolar infiltrates and consolidation. Young puppies (2500 pmol/L) despite clear lungs and normal respiratory rates. In symptom-based classification schemes, these dogs probably are classified as having CHF, but in the ABCD classification they probably are categorized as having stage B2 disease with airway complications. The authors’ approach to management of these dogs is to initiate treatment with enalapril or benazepril (0.25 mg/kg q12h for 1 to 2 weeks then 0.5 mg/kg q12h thereafter) along with low-dose furosemide (~1 to 2 mg/ kg once daily PO) to contract the plasma volume. In most cases the cough improves if it is caused by bronchial compression (or early CHF). If the cough returns weeks or months later or if respiratory rate increases at home (to >40 breaths/min), then radiographs are repeated, the dog is reclassified as stage C, and standard four-drug therapy for CHF is initiated as described previously. It should be emphasized that failure of the cough to respond to a low dose of a diuretic and a full dose of  an ACE inhibitor should prompt reconsideration of the diagnosis; in particular, the clinician should rule out chronic bronchitis, bronchomalacia, and other airway diseases (including laryngeal disease and tracheal collapse), as well as pulmonary parenchymal disorders (pneumonia, neoplasia, heartworm disease). These patients ideally are evaluated by radiography and fluoroscopy or even by computerized tomography. It may be helpful to obtain a second opinion about the interpretation of the thoracic radiographs from a radiologist or cardiologist. If CHF is unlikely, appropriate respiratory diagnostic testing (e.g., bronchoscopy with cytologic analysis and culture of airway specimens) should be offered. When diagnostic testing is limited by client concerns, a trial course of doxycycline or prednisone may be instructive (and may relieve signs related to infection or noninfective bron­ chitis). Cough suppressants, especially codeine-derived agents, can be prescribed as a last resort for symptom relief.

Hospital Management of Acute Congestive Heart Failure— Clinical signs of left-sided or biventricular CHF can be life-threatening. These dogs have respiratory distress  and hypoxemia at presentation. A number of standard treatment approaches have proven useful for acute  management of these patients. If the patient’s condition is stable enough to allow minimal manipulation, placement of an intravenous catheter in a peripheral vein and attachment of ECG monitoring leads at the outset of therapy makes patient management and monitoring easier. The combination of intravenous furosemide, oxygen, and a nitrovasodilator (topical nitroglycerine or sodium nitroprusside) closely followed by pimobendan represents the initial treatment plan and is applicable to most cases of CHF regardless of cause. Most dogs are distressed and sedation is beneficial; butorphanol is used most often (0.25 mg/kg IM, repeated in 30 to 60 minutes if needed). When this protocol is used, diuresis is initiated, oxygen saturation is increased, ventricular loading is reduced, the

CHAPTER  176  Management of Heart Failure in Dogs tendency toward pulmonary edema is decreased, myocardial contractility is supported, and anxiety is relieved. If the patient becomes heavily sedated, the torso is positioned in sternal recumbency, the neck is extended and the chin supported with a towel or soft pad, and nasal oxygen prongs (or cannula) are inserted to deliver oxygen. Thoracocentesis should be performed if moderate to large pleural effusions are clearly evident. After administration of an initial IV bolus of 2 mg/kg furosemide, the dose, route, and frequency of the drug can be adjusted to the clinical response (respiratory rate, anxiety level, auscultation findings). In life-threatening or poorly responsive pulmonary edema a constant-rate infusion of furosemide along with aggressive afterload reduction with sodium nitroprusside also should be considered (see Chapter 175 for administration guidelines). This is especially useful when there is MR because the regurgitant volume will be decreased by load reduction. Less potent and less controllable alternatives to sodium nitroprusside are oral hydralazine or an ACE inhibitor.

Cardiogenic Shock The findings of pulmonary edema or pleural effusion with severe hypotension (BP < 80 mm Hg), along with other indicators of low cardiac output (pallor, hypothermia, depression, elevated blood lactate) are highly  suggestive of cardiogenic shock. Dogs with DCM (often Doberman pinschers) represent the typical case. Other potential causes of cardiogenic shock include myocardial infarction and pulmonary embolus as might occur following treatment for adult heartworms or after formation of a large pulmonary thrombus. Although initial treatment is generally the same as that discussed in the  previous section (furosemide, oxygen, nitroglycerine, pimobendan), there are other therapeutic considerations. First, these hypotensive patients often are very depressed, so sedation is needed only infrequently. Second, the clinician should determine if centesis is necessary because dogs with cardiogenic shock can have both pulmonary edema and large cavity effusions. Third, volume infusion (i.e., fluid therapy) is not appropriate to raise BP because it will only worsen edema; furthermore, diuretics and venodilators can further depress BP, so other treatments are needed to stimulate cardiac output. A catecholamine can be given to provide cardiac support by stimulating contractility, increasing cardiac output, and facilitating diuresis. Dobutamine (or dopamine) is administered as a constant-rate IV infusion starting at 2.5 µg/kg/min, and the infusion is increased by 1 to 2 µg/kg/min every 15 to 30 minutes until systolic BP is 90 mm Hg or higher (see Chapters 3 and 175). This end point generally is reached at an infusion rate of 5 to 10 µg/kg/min, although higher rates may be needed. Once the BP is stable, other vasoactive drugs, such as nitroprusside or an ACE inhibitor, can be added to unload the left ventricle. After 24 to 48 hours of dobutamine therapy, the dobutamine infusion rate is reduced by 50% every 2 to 4 hours, and once the dosage has been lowered to approximately 1 to 2 µg/kg/min, the infusion is discontinued. By that time the dog should be taking oral drugs, including the inodilator pimobendan, which can

783

be administered as cotherapy because it exerts a potent inotropic effect via a different cellular mechanism.

Arrhythmias in Congestive Heart Failure In HF complicated by hemodynamically significant ventricular or supraventricular arrhythmias, antiarrhythmic drugs are needed, and referral to a critical care center with a cardiologist on staff generally is the best option if it is available and the owner is willing. Common arrhythmias in CHF are isolated atrial and ventricular premature complexes, atrial fibrillation, and ventricular tachycardia. Atrial fibrillation can precipitate CHF in a canine patient in previously stable condition. This problem usually is managed with heart rate control as opposed to cardioversion (to normal rhythm; see Chapter 171). Rate control involves initiation of oral digoxin (0.005 to 0.0075 mg/kg q12h PO) followed within 24 hours by up-titration of oral diltiazem. Diltiazem is administered until a hospital heart rate of less than 180 beats/min is achieved (optimally a resting rate of 120 to 140 beats/ min). Effective treatment of CHF also is useful because it allows for some withdrawal of sympathetic tone with attendant reduction of ventricular rate response. Initial doses of 0.5 to 1 mg/kg PO of standard diltiazem can be increased with each sequential dose to a total daily dose of approximately 6 mg/kg (in two or three divided doses, depending on the formulation used). Rate response is best evaluated by 24-hour (Holter) ECG monitoring once a stable home dosage has been established. Average daily heart rates in the range of 90 to 110 beats/min are probably evidence of good control in a dog with CHF. Electrical cardioversion from atrial fibrillation to sinus rhythm has been used by some in managing this arrhythmia (see Web Chapter 60), but the authors’ experience is that dogs with CHF usually revert back to atrial fibrillation in a short time, so the authors mainly recommend rate control in their practices. Isolated premature ventricular complexes are not treated in CHF cases. However, sustained runs of rapid ventricular tachycardia require treatment to maintain BP and are managed initially with boluses of lidocaine (2-mg/ kg IV boluses; 40- to 60-µg/kg/min IV infusion). Mexiletine (5 to 8 mg/kg q8h PO) is an oral alternative to lidocaine. Antiarrhythmic drugs are a problem in the setting of HF because they depress myocardial function. Lidocaine and mexiletine are the safest in this regard, but reduced hepatic blood flow could lead to drug accumulation and toxicity (tremors, vomiting, seizures). Ensuring that the patient is well oxygenated and that serum electrolyte values (especially potassium and magnesium) are normal also is important. Use of digoxin is contraindicated in this setting. When possible, a cardiologist should be consulted about management approaches and associated risks. It also is useful to gauge the client’s expectations and concerns because some simply accept the risk of sudden cardiac death, especially if antiarrhythmic drug therapy is likely to exacerbate CHF or induce adverse effects such as anorexia, vomiting, or hepatic toxicity. With regard to other hospital and long-term treatment options, injectable procainamide is available in some locales and can be effective in the hospital, but it is a

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negative inotropic drug and also may result in peripheral vasodilation, lowering BP. Since sotalol has β-blocking actions, it should be used with caution in the setting of CHF, although sometimes there are no other options, and the negative inotropic effect may be partly managed with concurrent administration of pimobendan. Initial dosages of sotalol should be conservative (~1 mg/kg q12h PO). Amiodarone is another consideration (see Chapter 175), but its use requires diligent monitoring for toxicity and it is not devoid of negative inotropic effects.

References and Suggested Reading Atkins CE et al: Results of the veterinary enalapril trial to prove reduction in onset of heart failure in dogs chronically treated with enalapril alone for compensated, naturally occurring mitral valve insufficiency, J Am Vet Med Assoc 231(7):1061, 2007. Atkins C et al: ACVIM consensus statement: guidelines for the diagnosis and treatment of canine chronic valvular heart disease, J Vet Intern Med 23:1142, 2009.

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BENCH (BENazepril in Canine Heart disease) Study Group: The effect of benazepril on survival times and clinical signs of dogs with congestive heart failure: results of a multicenter, prospective, randomized, double-blinded, placebo-controlled, longterm clinical trial, J Vet Cardiol 1(1):7, 1999. COVE Study Group: Controlled clinical evaluation of enalapril in dogs with heart failure: results of the Cooperative Veterinary Enalapril Study Group, J Vet Intern Med 9(4):243, 1995. Häggström J et al: Effect of pimobendan or benazepril hydrochloride on survival times in dogs with congestive heart failure caused by naturally occurring myxomatous mitral valve disease: the QUEST study, J Vet Intern Med 22(5):1124, 2008. Kvart C et al: Efficacy of enalapril for prevention of congestive heart failure in dogs with myxomatous valve disease and asymptomatic mitral regurgitation, J Vet Intern Med 16(1):80, 2002. Summerfield NJ et al: Efficacy of pimobendan in the prevention of congestive heart failure or sudden death in Doberman Pinschers with preclinical dilated cardiomyopathy (the PROTECT Study), J Vet Intern Med 26(6):1337, 2012.

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Chronic Valvular Heart Disease in Dogs JOHN E. RUSH, North Grafton, Massachusetts SUZANNE M. CUNNINGHAM, North Grafton, Massachusetts

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hronic valvular heart disease (CVHD) is the most common acquired heart disease in dogs, with an overall cumulative incidence of more than 40%. CVHD often results in congestive heart failure (CHF). Cardiac disease is an important cause of morbidity and mortality in dogs, responsible for approximately 10% of all canine deaths and with a higher incidence in some breeds of dogs such as the cavalier King Charles spaniel. The mitral valve most commonly is affected in CVHD, but concurrent tricuspid valve disease often is noted. Most veterinarians are very familiar with CVHD; thus the goal of this chapter is to discuss and highlight some important concepts about this disorder, consider frequently discussed topics, and review recent developments in diagnosis and therapy.

Etiology, Pathology, and Pathophysiology The cause of CVHD currently is unknown, although a genetic tendency to develop the disease has been proven in the cavalier King Charles spaniel and suspected in

other breeds. As the field of canine cardiac genetics continues to develop, it is likely that specific genes causing or contributing to the development of CVHD will be identified. In addition, poorly defined environmental and epigenetic factors likely play a role in the rate of onset or severity of the disease. Advanced myxomatous degeneration leads to grossly thickened and shortened valve leaflets with curled, nodular margins (Figure 177-1). Valvular hemorrhage and calcification may be seen. There is fibrosis of the valves, loss of collagen fibers, and an accumulation of acid-staining glycosaminoglycans within affected valves. Chordae tendineae often are affected and may become thickened, stretched, or ruptured, which allows portions of the diseased valve leaflets to bulge or prolapse into the atrial chamber. Electron microscopy has documented great variation in endothelial cell size and morphology of affected valves, with focal loss of the endothelial layer, collagen exposure, and activation of valvular interstitial cells. It is not clear which of these findings is a result of the disease and which might be a cause or contributor to

CHAPTER  177  Chronic Valvular Heart Disease in Dogs

Figure 177-1  Gross pathologic image of the mitral valve from a dog with advanced chronic valvular heart disease. The left atrium has been opened allowing visualization of the atrial surface of the valve. Note the severely thickened, shortened leaflets and the retracted, nodular leaflet edges.

disease progression. CVHD historically has been considered a noninflammatory, myxomatous degeneration of the atrioventricular valve, but there is growing interest in the role that serotonin or other inflammatory mediators may play in accelerating the pathologic development of the disease. There is one report of elevated C-reactive protein concentrations in the serum of affected dogs, which suggests a possible role of low-grade systemic inflammation in the progression of the disease (Rush et al, 2006). Another study evaluating genomic expression patterns in the valves of dogs with CVHD confirmed activation of several pathways involved in cell signaling, inflammation, and extracellular matrix activation, with several inflammatory cytokines and serotonin– transforming growth factor-β pathways identified as contributory to the development of the degenerative process in the valve (Oyama and Chittur, 2006). Increased serum serotonin levels have been found in dogs with CVHD, and increased autocrine production of serotonin, as well as up-regulation of the serotonin receptor 5HT-R2β, has been detected in affected valves. Increased serotonin signaling or decreased clearance can activate mitogenic pathways in valvular interstitial cells, resulting in their transformation to a more active myofibroblast phenotype. These activated interstitial cells are believed to play a role in pathologic valve remodeling via increased deposition of glycosaminoglycans, collagen turnover, and expression of transforming growth factor-β1 and other signaling molecules (Oyama and Levy, 2010). Further research into the role that serotonin pathways play in the pathogenesis of the valvular remodeling accompanying CVHD is ongoing. In addition to valvular abnormalities, many dogs with CVHD have histopathologic lesions in the myocardium, including small foci of myocardial fibrosis and necrosis, as well as more widespread intramural coronary arteriosclerosis (Falk et al, 2006). The role that arteriosclerosis, myocardial fibrosis, and microinfarction resulting from occlusion of these arteriosclerotic lesions might play 

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in the progression toward ventricular dilation, systolic dysfunction, and CHF is not well understood at this  time, but these lesions seem to offer possible alternative avenues for investigation as treatment or interventional opportunities. Progressive valvular thickening leads to poor leaflet coaptation and worsening valvular regurgitation with progressive dilation and eccentric hypertrophy of the atria and ventricles. As the regurgitant fraction increases, forward cardiac output may diminish, and compensatory neurohumoral pathways are activated (e.g., adrenergic activation, enhanced renin-angiotensin-aldosterone system activity) in an attempt to restore blood pressure and maintain tissue perfusion. As long as the dilated left atrium remains sufficiently compliant to accept the regurgitant blood volume, CHF does not develop, although coughing may occur due to left main-stem bronchial compression. Increased left ventricular filling pressure eventually precipitates CHF as the volume of regurgitated blood becomes overwhelming; chordal rupture suddenly increases the regurgitant fraction; and the limits of left atrial or ventricular compliance are exceeded, or the left ventricular myocardium starts to fail. Atrial rhythm disturbances, including atrial fibrillation, also can contribute to cardiac dysfunction and precipitation of CHF. The onset of decompensated CHF typically is manifested by the development of pulmonary edema in mitral valve disease. Chronic left-sided heart failure often leads to postcapillary pulmonary hypertension (PHTN), which further strains the right side of the heart and leads to signs of right-sided CHF with accumulation of ascitic fluid and possibly pleural effusion. In some dogs, there is evidence of severe PHTN beyond that explained simply by elevated pulmonary venous pressures.

Clinical Evaluation of Dogs with Chronic Valvular Disease CVHD is identified most commonly in middle-aged or older dogs of small to medium-sized breeds. Although primary valvular disease also occurs in large-breed dogs, dilated cardiomyopathy is a more common cause of CHF in these breeds than is CVHD. When large-breed dogs develop CVHD, concurrent myocardial failure, evidenced by global systolic dysfunction and inadequate left ventricular hypertrophy, often is noted relatively early in the disease. The incidence of CVHD is higher in male dogs than in females (1.5 : 1).

Clinical Presentations in Chronic Valvular Disease Most dogs are first diagnosed with CVHD based on the finding of a cardiac murmur in the absence of any signs of cardiac decompensation. The period between first detection of a murmur and onset of clinical signs generally is years. As the disease advances, many dogs develop a cough as the first sign of CVHD, caused by either early CHF or left atrial enlargement leading to main-stem bronchial compression. Panting, dyspnea, exercise intolerance, weight loss, weakness, and syncope are additional causes for a visit to a veterinarian. Specific triggers that

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cause a sharp increase in fluid retention or decrease in cardiac performance may precipitate CHF. These include increased dietary intake of salty foods, vigorous exercise or exertion in the previous 48 hours, recent onset of a rapid tachyarrhythmia, overzealous fluid therapy, general anesthesia, and potentially glucocorticoid administration.

Evaluation of Asymptomatic Dogs with a Heart Murmur Many dogs with CVHD have an audible murmur for years before the onset of cardiac decompensation and CHF (see Table 177-1 for the American College of Cardiology/ American Heart Association [ACC/AHA] staging classification). An extra systolic sound known as a midsystolic click is often detected before the onset of this murmur and has been associated with mitral or tricuspid valve prolapse; this is a sign of early CVHD. With rare exceptions, clinically significant CVHD is accompanied by a holosystolic murmur of medium to loud intensity. Point of maximal murmur intensity is over the left apex with radiation dorsally and to the right in most cases. In most dogs the intensity of the murmur is correlated roughly with the severity of mitral regurgitation (MR) as long as arterial blood pressure is normal. Thus in dogs with soft murmurs of MR the volume of regurgitation is unlikely to result in clinical signs; however, once a loud murmur is present, one cannot readily predict the onset of CHF in a given dog.

TABLE 177-1  Modified ACC/AHA Classification Scheme ACC/AHA Stage

Patient Population

Stage A

Patient at high risk of developing heart disease with no current identifiable structural cardiac abnormality (e.g., Cavalier King Charles spaniels with no cardiac murmur)

Stage B

Patients with structural cardiac disease but no past or present clinical signs of heart failure   Stage B1: Asymptomatic patients with no echocardiographic or radiographic evidence of cardiac remodeling   Stage B2: Asymptomatic patients with echocardiographic or radiographic evidence of cardiac enlargement

Stage C

Patients with past or present clinical signs of heart failure secondary to structural cardiac disease

Stage D

Patients with end-stage heart failure that are refractory to standard therapies (high-dose furosemide, ACE-I, and pimobendan)

Modified from Atkins C et al: ACVIM consensus statement: guidelines for the diagnosis and treatment of canine chronic valvular heart disease, J Vet Intern Med 23:1142, 2009; and Hunt SA et al: ACC/AHA guidelines for the evaluation and management of chronic heart failure in the adult: executive summary: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee to revise the 1995 Guidelines for the Evaluation and Management of Heart Failure). J Am Coll Cardiol 38:2101, 2001.

When a murmur is auscultated in a dog without clinical signs, baseline testing can be offered to the owner and often is helpful for comparison at subsequent examinations (see Table 177-2 for American College of Veterinary Internal Medicine [ACVIM] consensus recommendations on diagnostic testing). At a minimum the client should be clearly informed of the presence of the murmur and the fact that the disease ultimately may progress to CHF. Baseline testing ideally should include thoracic radiography to assess for cardiomegaly and optimally echocardiography to confirm the diagnosis and help assess cardiac size and function. A baseline B-type natriuretic peptide  or N-terminal prohormone B-type natriuretic peptide (NT-proBNP) level also may be helpful in disease staging, and an NT-proBNP concentration above 1500 pmol/L indicates a higher chance of cardiac decompensation in the next 6 to 12 months. A blood pressure measurement is indicated to exclude systemic hypertension, which might accelerate progression of MR. If hypertension is identified, an underlying cause such as renal or adrenal disease should be sought. Baseline laboratory evaluation should include, at a minimum, assessment of hematocrit, total solids, serum creatinine level, and urinalysis. However, a complete blood count, full serum chemistry analysis, urinalysis, and possible urine protein : creatinine ratio are recommended in hypertensive animals or dogs with other signs of systemic disease.

Evaluation of Dogs with Signs of Cardiac Dysfunction Once heart failure develops, a range of clinical presentations are possible, related to the degree and duration of valvular dysfunction. In an acute setting clinical signs usually are pulmonary or behavioral and may include cough, tachypnea, retching or gagging, nocturnal dyspnea, orthopnea or reluctance to settle down, and sometimes either excessive clinginess or social isolation. Less commonly, abdominal distention from ascites may be present, or the client may detect a “racing heart.” Exertional collapse or syncope may be the initial sign of heart disease and can occur as a result of significant arrhythmias, secondary to low cardiac output, in association with a vasovagal reflex (neurocardiogenic) response, or following a coughing spell (tussive syncope). In our experience syncope can be seen at the time of the initial presentation of heart failure, and syncope in this setting likely has a reflex-mediated or vasovagal component. Moderate to severe PHTN also has been associated with syncope in dogs with CVHD. Some dogs exhibit decreased exercise tolerance and weight loss for weeks to months before the onset of CHF, but these are often overlooked and rarely are the cause of a trip to a veterinarian.

Physical Examination Pulmonary auscultation may reveal loud bronchovesicular sounds that can progress to pulmonary crackles with the onset of alveolar edema. The latter may be particularly prominent over the hilar or caudal lung fields on inspiration. Hepatomegaly and ascites may be evident in dogs with right-sided CHF from advanced tricuspid

CHAPTER  177  Chronic Valvular Heart Disease in Dogs

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TABLE 177-2  2009 ACVIM Consensus Recommendations for the Diagnosis and Treatment of Canine Chronic Valvular Heart Disease Modified ACC/AHA Classification

Diagnosis

Treatment

Stage A

• Yearly auscultation of small-breed dogs at risk of CVHD • Yearly screening by a cardiologist for breeding animals or those at very high risk

• No drug therapy • No dietary therapy • Remove from breeding program those animals with early onset (85 mm Hg or MAP >60 • Measure serum creatinine before and after 24-72 hr • Consider mechanical ventilation Chronic Therapy • Up-titrate furosemide dose as needed to decrease signs of congestion, if use not limited by renal azotemia • Monitor creatinine 12-48 hr after dose increases • Start or continue spironolactone (0.25-2.0 mg/kg PO q12-24h) • Avoid β-blockade in the presence of congestive signs

regurgitation (TR) or mitral disease with postcapillary PHTN. Jugular venous distention is commonly appreciated in dogs with ascites. Often the femoral pulses are easily palpated and prominent, even at the time of onset of CHF. Irregularities in pulse rate and strength may be

noted in association with an arrhythmia. In animals with CHF the heart rate usually is elevated or in the uppernormal range, and sinus arrhythmia typically is absent, although this is variable. The ventricular apex beat is hyperdynamic and is progressively shifted caudally from

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the fifth intercostal space with increasing disease severity. If present, a precordial thrill also is palpable over the left apex. A louder murmur or more pronounced thrill on the right hemithorax typically indicates concurrent TR and PHTN. There may be a left ventricular heave or apical thrust. There may be other abnormalities since most CVHD patients are geriatric; therefore a complete physical examination is warranted.

Thoracic Radiography Thoracic radiographs are essential to the management of CVHD. The earliest characteristic findings on thoracic radiographs are mild left ventricular enlargement and left atrial enlargement, which may be best noted as an auricular prominence on the dorsoventral view at the 2- to 3-o’clock position. Left atrial and left ventricular enlargement elevate the trachea and carina on the lateral radiographic projection, with a decrease in the angle between the trachea and the thoracic spine. The left main-stem bronchus may become elevated and compressed in cases of moderate to severe left atrial enlargement. There is straightening of the caudal cardiac border and loss of the caudal cardiac waist. Pulmonary venous dilation occurs; this finding may be best appreciated in the cranial lung fields in the lateral view. Distended pulmonary veins (and arteries in severe cases) also can be identified in the caudal lung fields on the dorsoventral or ventrodorsal projections. Early pulmonary edema is seen as a diffuse increase in interstitial density in the hilar or caudal lung fields, progressing to perihilar densities with air bronchograms corresponding to alveolar edema. Cardiogenic pulmonary edema appears to have a propensity for the right caudal lung fields in some dogs, and this finding may be noted on the dorsoventral view. With TR and right-sided or biventricular CHF, the cranial aspect of the trachea may be elevated, the caudal vena cava increases in size, and small-volume pleural effusion may be noted. Not only is radiographic evaluation useful for monitoring cardiac chamber size and documenting CHF, but it also serves to guide therapy and exclude other disorders. Pneumonia can develop in an older dog with CVHD and CHF; thus, in a patient with new signs or a poor response to therapy, infection or another problem such as lung cancer should be considered. Chronic bronchitis also is common in many dogs with CVHD and occasionally can be recognized by the presence of severe bronchial patterns or bronchiectasis. The rate of increase in vertebral heart score has been shown to accelerate in the 6 to 12 months before the onset of CHF; thus sequential monitoring of radiographs may be helpful in predicting impending heart failure (Figure 177-2).

Electrocardiography Electrocardiographic findings can include evidence of left ventricular hypertrophy, widened P waves of left atrial enlargement (P mitrale), and, infrequently, P pulmonale (P wave > 0.4 mV). P pulmonale is seen more frequently in dogs with concurrent respiratory disease. ST-segment slurring or depression, which may result from myocardial disease, ischemia, or hypoxia, is evident in some dogs

with left ventricular hypertrophy. Sinus rhythm or sinus tachycardia is typical of dogs with CVHD and CHF. Atrial arrhythmias, especially atrial premature depolarizations, are common. Atrial fibrillation develops in some dogs with marked atrial enlargement. On the other hand, ventricular arrhythmias are relatively uncommon in animals with compensated disease, and even in dogs with CHF ventricular ectopy is far less common than in animals with dilated cardiomyopathy.

Echocardiography Echocardiography is valuable in assessing cardiac structure and function, although thoracic radiography is more useful in identifying CHF. Valvular thickening and valvular prolapse into the atria can be appreciated early in the course of disease (Figure 177-3, A). Rupture of a chorda tendinea leads to a flail mitral leaflet with chaotic valve motion and complete eversion of a tip of the leaflet into the left atrium in systole. With advancing disease the valve becomes progressively thickened, and left atrial and left ventricular enlargement are noted. With severe MR the left atrium enlarges disproportionately to the left ventricle. Left ventricular systolic function can be difficult to assess accurately in dogs with CVHD and severe MR (Bonagura and Schober, 2009). Fractional shortening is normal or increased in the early stages of the disease and increases with increasing regurgitant fraction. With the onset of myocardial failure fractional shortening can move from hyperdynamic to the normal range and may even become decreased. The latter two findings are more often noted in large-breed dogs. The left ventricular free wall often develops a relatively reduced excursion compared with the septum (the opposite of the situation in normal dogs). Although left atrial size is a better objective measure of severity of chronic MR, Doppler methods also can be used. The location and extent of the regurgitant jet can be mapped using color flow Doppler echocardiography as a crude indicator of disease severity (Figure 177-3, B). Additional Doppler methods such as semiquantitative assessment of the MR jet area in relation to the left atrial area or evaluation of the proximal isovelocity surface area may permit more accurate estimation of the regurgitant flow fraction using color Doppler methods. However, each of these methods is imperfect, especially when considered in isolation. Doppler studies of transmitral flow velocities and tissue Doppler imaging are used in the evaluation of systolic and diastolic function and prediction of left ventricular filling pressures; however, these are also confounded by the presence of volume overload. In general, a peak transmitral E-wave velocity of more than 1.2 m/sec in the setting of an enlarged left atrium is indicative of severe MR and considered a negative prognostic indicator (Borgarelli et al, 2008). Frequently there is concurrent evidence of tricuspid valve disease. This can include tricuspid prolapse, valvular thickening, and Doppler imaging evidence of TR. High-velocity TR is a marker for PHTN, which can become severe in some dogs with CVHD. Pericardial effusion related to right-sided CHF or left atrial tear is observed

CHAPTER  177  Chronic Valvular Heart Disease in Dogs

A

B

C Figure 177-2  A to C, Serial thoracic radiographs taken from a dog with mitral and tricuspid chronic valvular heart disease. Note the progressive increase in cardiac size, elevation of the trachea, and compression of the left main-stem bronchus. Perihilar infiltrates and a pleural fissure line can be visualized in C.

V 2

V

.98

LV 5

3

LA

10

4

A

B Figure 177-3  A, 2D echocardiogram from a dog with severe mitral valve prolapse secondary

to chronic valvular heart disease. The white arrow is pointing to the anterior mitral leaflet, which is bulging into the left atrium during systole. B, Color flow Doppler demonstrating a large jet of mitral insufficiency extending to the dorsal wall of the LA. LA, Left atrium; LV, left ventricle.

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occasionally on echocardiography (see the later section on left atrial tear or splitting).

Biomarkers Natriuretic peptides, including B-type natriuretic peptide (BNP) and atrial natriuretic peptide (ANP) and their N-terminal propeptide segments (NT-proBNP and NT-proANP), are released in response to ventricular and atrial stretch, and the levels of these peptides increase progressively with worsening disease severity and onset of CHF. Studies have documented that levels of these peptides are elevated in dogs with CVHD and CHF and increase progressively as the heart enlarges (Oyama et al, 2008). Natriuretic peptides hold great promise for early identification of patients at risk of developing CHF (e.g., NT-proBNP > 1500 pmol/L indicates higher risk of CHF in the next 6 to 12 months) and for confirmation of the diagnosis in those dogs with signs consistent with CHF. Natriuretic peptide levels also may offer some prognostic information as stand-alone tests or in conjunction with other clinical, imaging, or laboratory findings. It remains to be seen whether these hormones can be used to assist in treatment decisions or evaluate response to therapy. Commercial assays are currently available for canine BNP and NT-proBNP, and in-house (point-of-care) natriuretic peptide testing may become available in the near future.

Treatment of Chronic Valvular Heart Disease The therapy for dogs with CVHD includes consideration of the patient with preclinical disease and the dog coughing from bronchial compression, the need for both shortterm in-hospital and long-term at-home treatment plans for the dog with overt CHF, and the management of additional complications of this disorder. See Table 177-2 for ACVIM consensus recommendations on the treatment of CVHD at various stages of the disease.

Management of Asymptomatic Dogs Treatment of asymptomatic CVHD in the dog is controversial. Although angiotensin-converting enzyme (ACE) inhibitors are useful in the treatment of overt CHF, the Scandinavian Veterinary Enalapril Project (SVEP) trial evaluating the use of the ACE inhibitor enalapril in asymptomatic cavalier King Charles spaniels failed to show a significant preventive benefit in terms of delaying onset of CHF (Kvart et al, 2002). However, the recently reported Veterinary Enalapril Trial to Prove Reduction in Onset of Heart Failure in Dogs (VETPROOF) suggested a possible modest long-term survival benefit for enalapril therapy in dogs with advanced mitral disease treated before the onset of CHF (Atkins et al, 2007). Clearly, more studies are needed before definitive recommendations can be made. In view of the results of these studies most cardiologists do not initiate therapy in small-breed dogs with chronic MR in the absence of significant cardiomegaly. Some clinicians initiate ACE inhibitor therapy in animals with preclinical disease when there is moderate to severe heart enlargement or when marked progressive

cardiac enlargement is observed on serial examinations. However, this therapy still is considered empiric, and there is no unanimity about such treatment. Aside from the controversy noted previously, there may be some other reasons to consider ACE inhibition in CVHD. For example, in larger-breed dogs with MR, cardioprotective therapy with an ACE inhibitor with or without a β-blocker may be reasonable, especially when there is evidence of volume overload, because progressive left ventricular dilation and systolic dysfunction are more common in this patient group. A dog with left atrial enlargement that is coughing from presumed bronchial compression may benefit from ACE inhibitor therapy (or an ACE inhibitor and a low-dose diuretic, pimobendan, or cough suppressant). In dogs with CVHD and concurrent systemic hypertension the hypertension should be managed; ACE inhibitors generally are selected first in this particular setting, with amlodipine added for adjunctive antihypertensive therapy as needed for moderate to severe hypertension. β-Blockers are dangerous to initiate in dogs with uncontrolled CHF, but there may be a role for these drugs in dogs with compensated heart failure or asymptomatic disease. There certainly is some enthusiasm for the use of β-blockers in the preclinical phase of CVHD based on extrapolation of results of research studies in canine models of volume overload. However, clinical studies documenting a clear clinical benefit in dogs with spontaneous CVHD are still ongoing, and evidence of benefit in this disease is lacking at the current time, with a recent study of bisoprolol failing to demonstrate favorable effects. When a β-blocker is prescribed, most cardiologists use carvedilol, bisoprolol, or metoprolol (see Chapter 175). Again, large-breed dogs with significant CVHD may be the best candidates for such strategies to protect the myocardium. Severe dietary sodium restriction is not recommended in dogs with asymptomatic CVHD because of the potential for early activation of the renin-angiotensin-aldosterone system. However, client education on avoidance of highsodium diets, treats, and table foods is important. One study evaluating the use of a novel diet for management of dogs with asymptomatic CVHD identified a reduction in cardiac size during the 4-week dietary trial, which demonstrates the impact of dietary sodium on plasma volume and cardiac size (Freeman et al, 2006). Studies that document a clear clinical benefit such as a delay in the onset of CHF or improved survival are lacking; thus firm dietary recommendations cannot be made at this time.

Management of Dogs with Congestive Heart Failure Once CHF develops, many options are available for patient management (see Chapter 176 and Table 177-2). The patient with severe pulmonary edema requires aggressive diuresis. Oxygen administration and sedation (e.g., butorphanol 0.1 to 0.2 mg/kg IM as needed) are helpful supplements in treatment of hospitalized patients. Some clinicians use topical 2% nitroglycerin as a venodilator for dogs in the hospital setting, but efficacy data for this approach are lacking. Sodium nitroprusside is useful in

CHAPTER  177  Chronic Valvular Heart Disease in Dogs cases of life-threatening pulmonary edema caused by ruptured chordae tendineae (see the section on chordae tendineae rupture later in the chapter). Once in stable condition, most dogs are treated with a combination of oral drugs in the home setting to prevent recurrence of CHF, minimize clinical signs, and prolong life. Furosemide is the most commonly used diuretic, and the dose is titrated to effect (i.e., to control clinical  signs resulting from fluid accumulation). In patients  with severe pulmonary edema, intravenous boluses of 1 to 4 mg/kg of furosemide are indicated, and some clinicians transition from bolus dosing to a constant-rate infusion of furosemide at 0.5 to 2 mg/kg/hr for particularly severe or refractory cases. The dose of furosemide required to clear significant edema accumulations and cause the animal to be minimally symptomatic (the desired dose) is often close to that resulting in electrolyte disturbances, dehydration, and the development of prerenal azotemia. Dosages of furosemide can vary from 2 mg/kg/day in mild CHF to 4 to 6 mg/kg every 8 hours in advanced disease. Azotemia and electrolyte imbalance can result from the combined use of ACE inhibitors and diuretics; thus serial monitoring of the appropriate laboratory parameters is indicated. Baseline levels of blood urea nitrogen (BUN), creatinine, and serum electrolytes should be obtained, with rechecks of these values 3 to 7 days after starting these drugs and 3 to 7 days after any significant dosage adjustment, followed by routine evaluation every 3 to 6 months. ACE inhibitors combined with diuretics may not be well tolerated in some dogs with preexisting renal disease; thus careful monitoring of clinical signs (appetite and activity) and more frequent assessment of electrolyte, BUN, and creatinine levels are advisable in these patients. The development of acute renal failure with the initiation of ACE inhibitor therapy should prompt reconsideration of this treatment because some dogs simply cannot tolerate the usual dosages of these drugs, especially when undergoing diuresis. Some of these dogs respond favorably to discontinuation of the ACE inhibitor and judicious volume expansion with 0.45% NaCl solution. Once the animal is in stable condition, acceptable renal values can be maintained in some dogs by using low-dose ACE inhibition combined with standard medical therapy. Several clinical trials in dogs with CVHD and CHF have demonstrated the clinical benefits of ACE inhibitors in reducing clinical signs or delaying the time until clinical deterioration or death (Woodfield et al, 1995). Drugs such as enalapril, lisinopril, or benazepril can be initiated in the hospital or home setting. A full dosage of these drugs generally is considered to be 0.5 mg/kg every 12 hours PO, but many clinicians initiate therapy at one half that dosage and optimize to a full dosage at the time of first or subsequent follow-up. Measurement of blood pressure and renal function often is used to monitor treatment. Pimobendan (Vetmedin), a calcium sensitizer and phosphodiesterase inhibitor, is an effective drug for management of CHF, and this drug is associated with minimal adverse effects. The positive inotropic and mixed vasodilator properties of pimobendan result in improved control of CHF and clinical signs of heart failure. Pimobendan does not appear to have significant proarrhythmic

791

properties at commonly used clinical dosages. Several small clinical trials have documented that pimobendan combined with diuretic therapy is at least as effective as furosemide and ACE inhibitors and may have fewer adverse effects than many of the commonly used cardiovascular medications. The larger Quality of Life and Extension of Survival Time (QUEST) Trial demonstrated a distinct survival advantage to treatment with pimobendan and furosemide relative to treatment with benazepril and furosemide in dogs with CVHD (Haggstrom et al, 2008). However, no studies have evaluated the efficacy of combined therapy with pimobendan, furosemide, and an ACE inhibitor, the treatment approach advanced by the vast majority of cardiologists. Cardiologists hold some differing opinions on the role that pimobendan plays in the management of CHF in dogs with CVHD. Some believe that initial management of CHF should center on furosemide and pimobendan, whereas others opt for furosemide with an ACE inhibitor. In our practice, and in the ACVIM consensus statement, the initial treatment strategy for dogs with CVHD and well-defined  CHF includes combined triple therapy with furosemide, pimobendan, and an ACE inhibitor (with or without spironolactone). As cardiac disease progresses, additional medications will be required to control advancing CHF. This therapy may include a dose escalation of furosemide; administration of supplemental doses of furosemide by subcutaneous injection every 12 to 48 hours; addition of other diuretics to combat diuretic resistance; treatment with digoxin or antiarrhythmics as necessary; and various dietary manipulations. Diuretic resistance typically is defined as the need for dosages of furosemide in excess of 4 to 6 mg/kg/day to control congestive signs during long-term treatment of CHF (ACC/AHA stage D heart failure). In this situation the addition of spironolactone (1 to 2 mg/kg once or twice daily PO) or a combination of hydrochlorothiazide and spironolactone is recommended. If hydrochlorothiazide is prescribed, initial dosages should be conservative (0.5 to 1 mg/kg q12-24h PO) and renal function and electrolytes should be evaluated within 3 to 7 days. Another diuretic that may be added in severe CHF is the potent loop diuretic torsemide. Torsemide is approximately 10 times more potent than furosemide, has a longer half-life, and has ancillary aldosterone-antagonizing effects. The initial dose typically is one tenth of the furosemide dose that would be added. In addition to diuretic “stacking,” careful investigation to identify other causes of fluid retention, such as high-sodium diets or treats or glucocorticoid therapy, is indicated in patients with apparent diuretic resistance. Nonsteroidal antiinflammatory drugs also have been implicated in the development of diuretic resistance in people, but this has not been documented in dogs with CVHD. Digoxin still has some role in the management of CVHD, although it has largely been supplanted by newer drugs with fewer adverse effects. There is no consensus on the use of cardiac glycosides in dogs with CVHD; however, in cases of CHF with atrial fibrillation or CVHD with frequent or sustained supraventricular arrhythmias, digoxin should be considered. In addition, digoxin may

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be useful in the management of syncope in dogs with CVHD when no clear cause for collapse (e.g., arrhythmia or severe PHTN) can be established. Digoxin toxicosis leading to anorexia, depression, and gastrointestinal signs has the potential to contribute to a decision for euthanasia, and the narrow therapeutic window for digitalis glycosides predisposes to its occurrence. Serial monitoring of serum digoxin levels is advisable, with target serum concentrations 8 hours after dosing in the range of 0.8 to 1.2 mg/ml. The combination of digoxin and diltiazem has been shown to be more effective in controlling the ventricular response rate to atrial fibrillation than either agent used alone (see Chapter 171). Thus, for dogs with persistently rapid ventricular response rates, either extended-release diltiazem or a β-blocker may be required in addition to digoxin to reduce the heart rate to less than 160 beats/min during the recheck examination. Amiodarone also has been demonstrated to reduce the ventricular response rate to atrial fibrillation; however, in our practice this drug is not recommended as first-line therapy in this setting because of concerns about the potential for multiple organ toxicities and relative lack of efficacy for rate reduction or conversion to sinus rhythm. β-Blockade has gained favor as a therapeutic modality for treatment of CHF in human patients, and several studies have documented the benefits that accrue from long-term treatment, although these effects often are not seen for several months. Reported benefits include up-regulation of previously down-regulated β-receptors, improved cardiac performance (increased stroke volume), and improved survival. These clinical benefits appear to have a sound theoretic basis, but there is no consensus among cardiologists about the use of β-blockers in dogs with CVHD, and in the ACVIM survey (and two surveys of cardiologists) β-blockers are not considered standard therapy. Carvedilol is tolerated by many dogs with naturally occurring CHF caused by both cardiomyopathy and CVHD when started at a low dose that is then slowly increased. Since β-blockers are negative inotropes, their most demonstrable effect when used in dogs with active CHF is likely to be a worsening of CHF. The negative inotropic and chronotropic effects of β-blockers can be harmful to dogs with active heart failure and those at the edge of compensation. If used at all, β-blockers are best administered to patients that are minimally symptomatic with early or mild heart failure and those with later stages of CHF in which the disease already is well controlled by a stable cardiac drug regimen (see Chapter 175 for more details). Carvedilol, metoprolol, bisoprolol, and atenolol all have been used for cardioprotection in dogs with CVHD, but carvedilol may have some advantages because of its concurrent α-blockade (which lowers vascular resistance), potent antioxidant effects, and more convenient dosing formulations. If metoprolol is used, the extendedrelease formulation is recommended for twice-daily administration. Addition of any β-blocker in a dog with advanced cardiac disease or congestive heart failure must be undertaken cautiously. Our recommendation is that a cardiologist should be consulted before initiating this form of treatment. Moderate dietary sodium restriction also is important in the management of dogs with CVHD. The owners of

asymptomatic dogs with CVHD and cardiac enlargement should be counseled to avoid feeding diets high in sodium as well as to avoid giving treats or table food (or any foods used to administer medications) high in sodium. For  dogs with advanced disease but no signs of cardiac  failure, the selected diet should have a sodium content  of less than 100 mg/100 kcal of energy. Once CHF  develops, additional sodium restriction is recommended (75 mm Hg) and of dogs with moderate PHTN (estimated systolic pulmonary artery pressures between 50 and 75 mm Hg) and

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unresolved syncope or tachypnea following radiographic resolution of pulmonary edema. It is important to recall that concurrent sildenafil and nitrate therapy theoretically is contraindicated because of the potential for severe hypotension and cardiovascular collapse. Currently, the off-label use of these drugs is quite expensive in most countries.

Surgical Intervention in Chronic Valvular Disease Surgical procedures have been developed to repair or replace the mitral valve in dogs with CVHD. Cardiopulmonary bypass is required for these procedures. Successful cardiopulmonary bypass requires a dedicated team of surgeons, perfusionists, anesthesiologists, cardiologists, and intensive care specialists, and strong veterinary technician support. The cost associated with surgery can be prohibitive ($8000 to $15,000). Once these techniques are mastered and refined for veterinary medicine, it seems probable that surgery or emerging catheter-based interventions (or hybrid procedures) to limit MR will become the preferred treatment for those that can afford the procedure.

References and Suggested Reading Atkins CE et al: Results of the veterinary enalapril trial to prove reduction in onset of heart failure in dogs chronically treated with enalapril alone for compensated, naturally occurring mitral valve insufficiency, J Am Vet Med Assoc 231:1061, 2007. Bonagura JD, Schober KE: Can ventricular function be assessed by echocardiography in chronic canine mitral valve disease?   J Small Anim Pract 50:12, 2009. Borgarelli M et al: Survival characteristics and prognostic variables of dogs with mitral regurgitation attributable to myxomatous valve disease, J Vet Intern Med 22:120, 2008.

Falk T et al: Arteriosclerotic changes in the myocardium, lung and kidney of dogs with chronic congestive heart failure and myxomatous mitral valve disease, Cardiovasc Pathol 15:185, 2006. Freeman LM, Rush JE, Markwell PJ: Effects of dietary modification in dogs with early chronic valvular disease, J Vet Intern Med 20:1116, 2006. Griffins LG, Orton EC, Boon JA: Evaluation of techniques and outcomes of mitral valve repair in dogs, J Am Vet Med Assoc 224:1941, 2004. Haggstrom J et al: Effect of pimobendan or benazepril hydrochloride on survival times in dogs with congestive heart failure caused by naturally occurring myxomatous mitral valve disease: the QUEST study, J Vet Intern Med 22:1124, 2008. Kvart C et al: Efficacy of enalapril for prevention of congestive heart failure in dogs with myxomatous valve disease and symptomatic mitral regurgitation, J Vet Intern Med 16:80, 2002. Oyama MA et al: Clinical utility of serum N-terminal pro-B-type natriuretic peptide concentration for identifying cardiac disease in dogs and assessing disease severity, J Am Vet Med Assoc 232:1496, 2008. Oyama MA, Chittur SV: Genomic expression patterns of mitral valve tissues from dogs with degenerative mitral valve disease, Am J Vet Res 67:1307, 2006. Oyama MA, Levy RJ: Insights into serotonin signaling mechanisms associated with canine degenerative mitral valve disease, J Vet Intern Med 24:27, 2010. Rush JE et al: C-reactive protein concentration in dogs with chronic valvular disease, J Vet Intern Med 20:635, 2006. Serres R et al: Chordae tendineae rupture in dogs with degenerative mitral valve disease: prevalence, survival and prognostic factors (114 cases, 2001-2006), J Vet Intern Med 21:258, 2007. Woodfield JA et al: Acute and short-term hemodynamic, echocardiographic, and clinical effects of enalapril maleate in dogs with naturally acquired heart failure: results of the invasive multicenter PROspective Veterinary Evaluation of Enalapril study, J Vet Intern Med 9:234, 1995.

CHAPTER 

178 

Dilated Cardiomyopathy in Dogs AMARA H. ESTRADA, Gainesville, Florida HERBERT W. MAISENBACHER III, Gainesville, Florida

D

ilated cardiomyopathy (DCM) is a myocardial disease characterized by primary systolic dysfunction of the left ventricle with secondary eccentric hypertrophy and left atrial dilation. Left ventricular diastolic dysfunction is identified in some dogs. The right heart chambers are variably involved in this disease. DCM is the most common myocardial disease in dogs and the second or third most common cause of acquired canine heart disease in most surveys, after degenerative valvular disease and heartworm disease (where Dirofilaria immitis is endemic). Although DCM begins with an asymptomatic phase, also called a preclinical or occult phase, of variable duration, it is a progressive and usually fatal disease that leads to congestive heart failure (CHF), arrhythmias, and often sudden cardiac death.

Causes Most cases of DCM in dogs are considered idiopathic; however, it is recognized in both human and veterinary medicine that one or more factors can trigger the DCM phenotype of myocardial failure with cardiac chamber enlargement. Potential causes include genetic, infectious, immune-mediated, toxic, nutritional, and metabolic  processes. The term dilated cardiomyopathy usually is reserved for idiopathic or familial forms. When a specific cause is identified, the appropriate modifier should be used instead, as in taurine-deficiency cardiomyopathy or doxorubicin-induced cardiomyopathy. Several predisposed dog breeds exhibit a familial inheritance pattern of DCM, and a genetic basis is strongly suspected in these breeds. In humans, 20% to 50% of patients with idiopathic DCM are affected by a familial form, and mutations in more than 20 genes have been established as causes or risk factors (Hare, 2011). Based on known gene mutations in humans and molecular studies in affected dogs, a number of candidate genes have been evaluated in canine breeds affected with familial DCM. Until recently, no genetic markers for canine DCM had been identified. However, in 2010, Meurs and colleagues reported a mutation in Doberman pinschers in the gene that encodes pyruvate dehydrogenase kinase 4, a mitochondrial protein that regulates glucose metabolism. Undoubtedly, other genetic abnormalities will be discovered in the future, and these hold promise for identifying dogs at risk and for reducing the overall incidence of

DCM in the canine population by modifying breeding practices. Nutritional deficiencies have been associated with a DCM phenotype in dogs (see Chapter 168), but taurinedeficiency cardiomyopathy in dogs is very uncommon, and a response to L-carnitine supplementation is considered rare. Although viral and autoimmune factors have been postulated to be important causes of DCM in humans, there is little evidence to support an infectious (viral or other pathogenic) or immune-mediated cause of DCM in the majority of dogs. Toxic cardiomyopathies may be induced by anthracycline chemotherapeutic agents such as doxorubicin and may occur with newer tyrosine kinase inhibitors (TKIs), although this has not been reported with toceranib (Palladia), the only TKI labeled for veterinary use. It also is possible for persistent tachyarrhythmias to induce myocardial failure and ventricular dilation (tachycardia-induced cardiomyopathy). This is an important disorder to recognize because it is usually reversible with restoration of a sinus rhythm or adequate heart rate control.

Diagnosis Clinical Presentation DCM typically is an adult-onset disease of large- and giant-breed dogs, with the greatest prevalence in Doberman pinschers, Irish wolfhounds, Great Danes, and Newfoundlands. Other breeds that may be overrepresented include Scottish deerhounds, dalmatians, German shepherds, Saint Bernards, Airedales, standard poodles, and Old English sheepdogs. The disease generally is rare in small- and medium-breed dogs with the exception of American and English cocker spaniels, and juvenile forms are recognized in Portuguese water dogs and the toy Manchester terrier. Although historically boxers have been listed among the breeds predisposed to DCM, they most likely share a unique and familial disease process more accurately classified as arrhythmogenic right ventricular cardiomyopathy (see Chapter 179). Most studies have demonstrated an increased prevalence in male dogs compared with females. Most cases are diagnosed in dogs aged 4 to 9 years, and the incidence increases with age. However, it may be diagnosed in dogs as young as 2 years (and infrequently in even younger dogs). The specific 795

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juvenile form of DCM affecting Portuguese water dogs typically develops within the first 6 months of life. As noted earlier, DCM is characterized by a prolonged asymptomatic phase, referred to as preclinical or occult DCM, which may last for up to 2 to 4 years. Once clinical signs develop, the disease is referred to as overt DCM. Clinical manifestations are attributable to left ventricular dysfunction, heart rhythm disturbances, or both. Initial clinical signs can be subtle, such as exercise intolerance or weight loss, and may go unrecognized except in athletic or working dogs. Most commonly, DCM is recognized when clinical signs of CHF develop. Left-sided CHF signs usually predominate and include cough, tachypnea, and dyspnea; with right-sided or biventricular CHF, ascites and pleural effusion also may occur. Ventricular arrhythmias can cause syncope and even sudden death. These may precede any other signs, and sudden cardiac death is especially common in Doberman pinschers compared with other breeds. There is an interest in identifying and often treating DCM in the preclinical or occult phase, and a number of screening programs have been suggested, especially for breeding animals. Both ambulatory electrocardiographic (ECG), or Holter, monitoring and echocardiographic methods have been used to identify early disease in animals at risk. Some suggest that members of predisposed breeds should be screened annually beginning at 2 years of age. Early work suggests that the cardiac biomarker N-terminal prohormone B-type natriuretic peptide (NT-proBNP) may have some ability to detect preclinical disease, but further studies are needed to define the precise usefulness of this screening modality (Wess et al, 2011). In general, the adult onset of the disease makes genetic counseling to promote breeding of unaffected animals a significant challenge.

Physical Examination Cardiac auscultation may reveal a low-grade systolic  left apical murmur caused by mitral regurgitation, an S3 gallop caused by increased left ventricular filling pressure, or arrhythmias. Soft heart sounds sometimes are detected, related to impaired ventricular contractility even in the absence of overt effusions. Similarly, murmurs of mitral regurgitation often are softer than those encountered in primary degenerative valvular disease of dogs. Weak femoral pulses from reduced ventricular ejection or pulse deficits associated with arrhythmias may be palpated. With left-sided CHF, increased bronchovesicular sounds or pulmonary crackles may be auscultated, but the lack of these does not rule out the presence of pulmonary edema. Ascites, hepatomegaly, jugular venous distension or pulsation, and muffled lung sounds caused by pleural effusion may be present with right-sided or biventricular CHF.

Echocardiography Echocardiography is the test of choice for the diagnosis of DCM in both the occult and overt phases. The diagnosis is established by identifying primary left ventricular systolic dysfunction, often with evidence of cardiac

remodeling. Comprehensive echocardiography with Doppler examination offers a combined assessment of disease severity, ventricular and secondary valvular dysfunction, and estimated ventricular filling pressures (indicating risk of CHF). Although echocardiography also is used as the main screening test for DCM, distinguishing between early DCM and systolic function at the lower end of normal variation is a challenge. Frequently, divergent results for left ventricular systolic function are obtained when different echocardiographic indices are used, and in these cases, serial examinations can be important for identifying progressive trends. Additionally, a normal echocardiogram does not rule out the future development of DCM; thus annual screening of dogs of predisposed breeds is recommended. On two-dimensional or M-mode echocardiography, left ventricular, and sometimes right ventricular, chamber size is increased in both systole and diastole as assessed by left ventricular internal diameters at end systole and end diastole or by calculated end-systolic and enddiastolic left ventricular volumes. These measurements must be compared with established normal ranges based on body weight, for specific breeds when available, or indexed to body surface area. Recently, Wess and colleagues (2010) reported that in Doberman pinschers, an end-systolic and end-diastolic volume indexed to body surface area of more than 55 ml/m2 and 95 ml/m2, respectively, was superior to standard M-mode measurements for detection of occult DCM. Decreases in indices of left ventricular function, including fractional shortening and calculated ejection fraction, also are observed, but the diagnosis of DCM should not be based solely on a reduced fractional shortening or ejection fraction without assessment of the left ventricular chamber sizes in systole and diastole individually. Importantly, there is no single value for left ventricular shortening fraction that is both sensitive and specific for DCM in all breeds. Although the atria may be normal in size with occult DCM, the left atrium, and sometimes the right atrium, often is enlarged, and this is a consistent feature of overt DCM with CHF. Doppler echocardiography often demonstrates a central jet of mitral regurgitation, which occurs because of mitral annular dilation and papillary muscle displacement. The mitral coaptation point often is displaced apically from the annulus in DCM (increased valve tenting). So-called secondary mitral regurgitation due to DCM sometimes can be differentiated from primary mitral valve degeneration with systolic dysfunction by imaging findings: a degenerative valve is typically thickened; one or both leaflets are likely to prolapse into the left atrium; and the jet of regurgitation typically is eccentric. Many dogs with DCM also develop Doppler imaging evidence of diastolic dysfunction, which may be demonstrated on transmitral flow. Experienced examiners generally look for evidence of impaired relaxation, indicating left ventricular dysfunction, but a restrictive transmitral filling pattern is more often associated with CHF. The latter finding is an important negative prognostic indicator. Recently several indices of ventricular filling pressure derived from Doppler and tissue Doppler imaging also have been shown to correlate with the presence and resolution of CHF in dogs with DCM (Schober et al, 2010,

CHAPTER  178  Dilated Cardiomyopathy in Dogs 2011). Other tissue Doppler imaging–derived indices such as tissue velocity, strain, and strain rate may be useful in assessing left ventricular systolic and diastolic function with perhaps more sensitivity than M-mode and twodimensional indices, but there is not yet widespread acceptance of or data regarding these variables.

Electrocardiography Although many dogs with DCM have ECG abnormalities such as evidence of left ventricular enlargement, left atrial enlargement, or left bundle branch block, the standard resting ECG is neither sensitive nor specific for DCM. The most useful application of ECG in DCM is diagnosis of arrhythmias. DCM often is associated with atrial fibrillation (AF), and this appears to be more common in giantbreed dogs. Giant-breed dogs, especially Irish wolfhounds, also can develop lone AF without any evidence of underlying structural heart disease. In some dogs lone AF progresses to overt DCM; thus annual screening of these dogs is recommended. The onset of AF may precipitate CHF signs because AF causes an abrupt reduction in cardiac output. Ventricular arrhythmias, including ventricular premature complexes (VPCs or PVCs) and ventricular tachycardia (VT), also are common in dogs with DCM. Particularly malignant ventricular arrhythmias often are identified in Doberman pinschers, but dogs of other breeds also can demonstrate frequent or complicated ventricular ectopy. In dogs affected with syncope, VT is usually the cause, and degeneration of VT into ventricular fibrillation can lead to sudden death. Ventricular arrhythmias often precede the onset of echocardiographic changes in Doberman pinschers that develop DCM. Therefore 24-hour Holter monitoring is a good screening test in Doberman pinschers and is recommended annually with echocardiography. The occurrence of more than 50 to 100 VPCs in 24 hours or any couplets, triplets, or runs of VT are considered diagnostic for DCM in this breed. Although a recommendation for routine ambulatory ECG monitoring cannot be extended currently to all breeds as risk of DCM, it should be appreciated that breeds other than the Doberman pinscher (e.g., Great Danes) also may be at risk of malignant ventricular arrhythmias. Ventricular asystole also has been observed as a cause of syncope and sudden death in DCM.

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affected by idiopathic-familial DCM. Taurine deficiency has been described in dogs fed vegetarian or off-brand diets, and in these cases, blood taurine levels should be evaluated because supplementation may dramatically improve left ventricular function and prognosis. BNP is a hormone released from the ventricular myocardium in response to wall stress or hypertrophy, so that increased circulating levels are found in a multitude of heart diseases including overt and occult DCM. Commercial tests are now available for the prohormone of BNP (NT-proBNP) and for BNP in dogs. Special sample handling is required for these tests, and noncardiac diseases, including systemic hypertension and renal disease, can increase BNP concentrations in the blood. In mixed populations of dog breeds, especially in those with low risk of cardiac disease, concentrations of these biomarkers are not sufficiently sensitive or specific to be used as a screening test for asymptomatic cardiac disease. They are more useful for differentiating between cardiac and noncardiac disease (i.e., CHF or not) in dogs with respiratory signs. In a specific population of dogs at high risk of DCM, such as Doberman pinschers, NT-proBNP concentration may be useful as a screening test, but appropriate cutoffs must be established (Wess et al, 2011) and the test results should not be interpreted in isolation. A recent study suggests that BNP levels also may be useful to guide CHF therapy because levels decrease when pulmonary edema resolves, but more research is necessary to define this use (Schober et al, 2011). As a general point, therapy for DCM never should be based solely on the level of a circulating biomarker. As indicated earlier, many cases of DCM are familial, and it is likely that genetic testing will become a prominent method for evaluating dogs at risk of this disease. Currently a test for the pyruvate dehydrogenase 4 gene mutation in Doberman pinschers is available that uses either a blood sample or a cheek swab (contact the North Carolina State University Veterinary Cardiac Genetics Laboratory). Initial results demonstrated that all affected dogs were either homozygous or heterozygous for the mutation, but some genetically positive dogs did not show any evidence of DCM at the time of testing (Meurs et al, 2010). This could reflect the delayed onset of the disease or reduced penetrance.

Treatment

Thoracic radiographs may demonstrate cardiomegaly with left ventricular and left atrial enlargement, and these changes are invariable in overt DCM. Radiographs are imperative for the diagnosis of left-sided CHF with pulmonary edema and also are useful in the differential diagnosis of respiratory signs or distress. Right-sided chamber enlargement and pleural effusion may be observed with right-sided or biventricular CHF.

Ideal therapy for DCM would target the underlying cause, but this rarely is possible. Current treatments are designed to delay progression of disease, control clinical signs, improve quality of life, and prolong survival. There are differing opinions regarding the ideal therapy for dogs with DCM, and unfortunately, there is little high-grade scientific evidence to support most treatment decisions for this disease. The ideal therapy likely varies depending on breed, stage of disease, and clinical signs; therefore treatment should be tailored to the individual patient.

Other Diagnostic Tests

Occult (Preclinical) Dilated Cardiomyopathy

A DCM phenotype has been reported in some cocker spaniels and also in breeds that are atypical of those

Although there are no prospective studies evaluating  the efficacy of angiotensin-converting enzyme (ACE)

Thoracic Radiography

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inhibitors in dogs with occult DCM, there is considerable evidence that ACE inhibitors delay progression of the disease in humans (Hare, 2011). Activation of the reninangiotensin-aldosterone system has numerous deleterious effects on the failing heart, including vasoconstriction, fluid retention, increased sympathetic tone, and cardiac and vascular remodeling. Inhibiting the formation of angiotensin II with ACE inhibitors may block or attenuate these effects. A retrospective study in Doberman pinschers with occult DCM demonstrated that treatment with benazepril delayed the onset of overt DCM (O’Grady et al, 2009). It is likely that this benefit extends to all ACE inhibitors, and enalapril or benazepril (0.25 to 0.5 mg/kg q12h PO) is recommended for all dogs with occult DCM. One might argue in theory that the highest dose would be most likely to demonstrate beneficial results as a preventive treatment. It is known that persistent sympathetic stimulation of the heart leads to β-receptor down-regulation, cardiac remodeling and fibrosis, myocyte death, and tachyarrhythmias, all of which may contribute to progressive myocardial dysfunction and ventricular dilation in DCM. β-Blockers can prevent these effects and have been demonstrated to reduce morbidity and mortality as well as improve myocardial function in humans with DCM (Hare, 2011). To date, there have been no studies evaluating the effect of β-blockers in dogs with occult DCM, and there is no consensus on the use of β-blockers in canine DCM. However, if there is a beneficial effect, it is most likely to be demonstrated when these drugs are administered in the occult phase of the disease. Therefore it is reasonable to discuss the potential benefits and risks of β-blocker therapy with owners and to emphasize that treatment in dogs with occult DCM can be based only on comparative (human) and laboratory model evidence at this time. Carvedilol, a nonspecific β-blocker and α1-blocker, and metoprolol, a selective β1-blocker, demonstrate the most clearly defined benefits in humans and have been used in canine models of left ventricular dysfunction in laboratory settings. For DCM, β-blockers initially must be administered at very low dosages and gradually up-titrated over several months to a target or maximum tolerated dosage. It is emphasized that some patients cannot tolerate β-blockers even at low dosages, and administration can lead to decompensation and precipitate CHF. Carvedilol has been prescribed to dogs at a starting dosage of 0.05 to 0.1 mg/kg every 12 hours PO, with the dose gradually increased every 2 weeks to a maximum dosage of 0.5 to 1 mg/kg every 12 hours. During the up-titration phase, dogs must be monitored closely for the development of weakness, lethargy, or signs of CHF, and the dose must be reduced if any of these is noted. With regard to positive inotropic drugs, it should be mentioned that in humans with DCM treatment with positive inotropic drugs has not improved, and sometimes has reduced, survival. Accordingly one should not necessarily treat low fractional shortening with an inotropic drug like digoxin or pimobendan in a dog without heart failure. Very recently, however, a clinical trial of pimobendan (Vetmedin), a positive inotrope and balanced vasodilator,

has been completed in Doberman pinschers with occult DCM (Summerfield et al, 2012). The results indicated a statistically significant improvement in time to onset of CHF and survival in dogs receiving pimobendan versus those given placebo. Onset of CHF or sudden death was delayed by an average of 9 months and death due to any all-cause mortality was delayed by an average of 5 months. Although the study was small and focused on only one breed, these results suggest possible benefit of the drug in preclinical DCM. Risk of sudden death was no different in the two groups. Unresolved issues associated with this study include the generalizability of these results to other breeds (in addition to the Doberman pinscher), the cost of therapy for the approximately 2 years needed to identify these benefits, and the value, if any, of cotherapy. In this study pimobendan was compared with placebo but not with cardioprotectant drugs like ACE inhibitors or β-blockers. Drugs in the latter two classes often are prescribed by cardiologists (empirically) for occult DCM.

Congestive Heart Failure Since most clinical signs of DCM are due to CHF, most of the therapy for overt DCM is aimed at controlling CHF. For additional information on the treatment of CHF, including acute heart failure, see Chapter 176. The longterm management of CHF after initial stabilization has been accomplished is discussed here. Clinical signs due to the presence of pulmonary edema, ascites, or pleural effusion necessitate treatment with diuretics to control ongoing fluid retention. Furosemide typically is the first-line diuretic treatment in CHF therapy and has a wide dosage range (1 to 5 mg/kg q8-12h PO). It should be administered at the lowest effective dose that controls clinical signs to avoid dehydration, azotemia, and electrolyte loss. However, as DCM progresses and CHF recurs, it will be necessary to increase the furosemide dose. Spironolactone (1 to 2 mg/kg q12-24h PO) is a potassium-sparing but weak diuretic that often is administered in addition to furosemide as CHF worsens. In humans, addition of low-dose spironolactone to standard heart failure therapy has been shown to improve survival modestly due to antagonism of systemic aldosterone effects, but this has not been demonstrated conclusively in dogs. Most North American cardiologists include spironolactone in their long-term therapy regimens for CHF according to recent surveys. Thiazide diuretics typically are used in addition to furosemide and spironolactone in cases of refractory CHF. However, this regimen may result in severe dehydration, azotemia, and electrolyte depletion, so the authors initially recommend low-dose hydrochlorothiazide (1 to 2 mg/kg q48-72h PO) with careful monitoring of relevant parameters. The use of other diuretics, such as the loop diuretic torsemide, requires more study before general recommendations can be advanced. Blockade of the renin-angiotensin-aldosterone system is a cornerstone of CHF therapy, and there is good evidence from prospective, placebo-controlled trials of ACE inhibitors in dogs with DCM supporting an improvement in clinical signs and survival. These benefits are likely to occur with any ACE inhibitor, but experience in dogs is

CHAPTER  178  Dilated Cardiomyopathy in Dogs most extensive with enalapril and benazepril (0.25 to 0.5 mg/kg q12h PO). Especially when ACE inhibitors are administered in combination with diuretics, animals must be monitored for adverse effects of azotemia and hypotension. Since the primary cardiac abnormality in DCM is systolic dysfunction, it is logical that positive inotropes would be beneficial in treating the disease. Pimobendan is a calcium sensitizer and phosphodiesterase 3 inhibitor and as such is both a positive inotrope and balanced vasodilator. Prospective, placebo-controlled studies of dogs with DCM and CHF given pimobendan in addition to the standard therapy of furosemide and ACE inhibitors have demonstrated an improvement in quality of life, time to treatment failure, and survival (O’Grady et al, 2008). Therefore pimobendan (0.2 to 0.3 mg/kg q12h PO) should be administered to dogs with DCM and CHF. Digoxin is a weak positive inotrope with a narrow therapeutic range and has been largely supplanted by pimobendan, but it does have additional effects, including increasing vagal tone and improving baroreceptor function. There are no studies of the effectiveness of digoxin therapy in veterinary medicine, but human studies have shown beneficial effects and indicate that these effects may be observed with a lower incidence of toxicity when the drug is administered at lower dosages. The authors typically prescribe digoxin only when AF is present, but it may be considered as an additional treatment for CHF, especially in refractory disease. Of note, the two relative contraindications for digoxin are complex ventricular arrhythmias and azotemia, two conditions that are likely to occur in dogs with CHF. Because of the beneficial effects discussed earlier, β-blockers are considered to be standard-of-care therapy for CHF in humans, but the issue is unresolved in dogs. If the decision is made to prescribe a β-blocker, therapy should be administered only after CHF has been stabilized completely. The use of carvedilol has been studied in a small group of dogs with DCM and stabilized CHF; no significant positive or negative effects were demonstrated (Oyama et al, 2007). As indicated earlier, if there is a beneficial effect of β-blockers in dogs with DCM, it is possible that it will not be observed in the overt phase because survival with CHF is short, and the effects of β-blockade are time dependent. Currently the authors do not recommend β-blocker therapy in dogs with DCM and CHF.

Arrhythmias In dogs with DCM, AF further reduces cardiac output because of the reduction in ventricular filling from the loss of atrial contraction and the rapid ventricular rate. Therapeutic options include cardioversion to restore a sinus rhythm and the use of negative chronotropic drugs to slow the ventricular response rate. Techniques for  electrical and pharmacologic cardioversion have been described (see Web Chapter 60), but in most dogs with CHF, heart rate control is the goal. It should be noted that dogs with CHF and sinus rhythm have a higher resting heart rate than healthy dogs (by about 30 beats/min), so an acceptable target heart rate range for dogs with AF and

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CHF likely will be higher than that for a healthy dog. A practical target for rate control during clinical examination or in-hospital ECG is a rate of about 120 to 160 beats/ min. In this regard, 24-hour Holter monitoring may be useful in the assessment of overall response in terms of average heart rate and peak heart rates that develop with exercise. The drugs used for heart rate control include digoxin, the calcium channel blocker diltiazem, and β-blockers. Although digoxin is the only positive inotrope in this group, it usually is insufficient as a single agent. The authors administer digoxin at a low dosage (0.002 to 0.003 mg/kg q12h PO) and monitor trough serum levels, accepting a therapeutic range of 0.8 to 1.5 ng/ml. In addition to digoxin, or in place of digoxin in dogs that exhibit gastrointestinal signs or have considerable ventricular arrhythmias, the authors administer diltiazem (0.5 to 2 mg/kg q8h PO for the standard formulation or 2 to 6 mg/kg q12h PO for the sustained-release formulation). An argument can be made for administering β-blockers given the potential beneficial effects, but these drugs need to be increased very gradually to a therapeutic dosage, and most often dogs with DCM and AF also have  severe CHF. Ventricular arrhythmias are common in dogs with DCM, especially Doberman pinschers, and may cause weakness, lethargy, syncope, or sudden death. Indications for therapy include clinical signs caused by hemodynamic compromise, VT, and potentially other malignant characteristics such as fast couplets or triplets (two or three VPCs) as well as the R-on-T phenomenon (closely coupled VPC on the previous T wave). Because of a lack of data there is no consensus on when or how to treat serious ventricular ectopy. The goals of therapy may include the elimination of clinical signs, the control of VT or other malignant features, and the prevention of sudden death. The number of single VPCs does not serve as an indication for or a goal of treatment. Although often it is possible to control clinical signs, reduce the number or frequency of VPCs, and suppress runs of VT, there is no evidence that any antiarrhythmic therapy is protective against sudden death. Several drugs are recommended for the long-term management of ventricular arrhythmias, but none has proven effects in dogs with DCM. Sotalol (1 to 2 mg/kg q12h PO), a potassium channel blocker and nonspecific β-blocker, is prescribed most frequently, and the authors recommend an up-titration from one quarter to one half of the desired dose over 2 to 4 weeks to avoid decompensation due to β-blockade. Mexiletine (5 to 8 mg/kg q8h PO) is a sodium channel blocker similar to lidocaine and often is more effective when combined with β-blockers, including sotalol. Gastrointestinal adverse effects usually can be avoided by administering with food. Three-timesdaily administration is a problem for many clients. Amiodarone (10 mg/kg q12h for 2 weeks and then 5 mg/kg q24h PO) is a potent antiarrhythmic with effects in every antiarrhythmic class; however, its use often is limited by extensive adverse effects, including hepatotoxicity, neutropenia, and altered thyroid function, among others. Flecainide has not been studied sufficiently in this group of patients but has been used by some cardiologists.

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Other Therapies In addition to taurine supplementation for dogs found to be taurine deficient, several other nutritional recommendations, including moderate dietary sodium restriction and omega-3 fatty acid supplementation, may be advanced for dogs with DCM (see Chapter 168). Sufficient protein intake also is important because these dogs often exhibit cardiac cachexia. Gene and stem cell therapy have the potential to revolutionize the treatment of DCM by improving or even curing the underlying abnormalities that lead to DCM (Sleeper et al, 2011). There appears to be great promise in these therapies in light of data from experimental animal models of cardiac dysfunction and the discovery of gene mutations in dogs with DCM. Although several investigators currently are exploring the potential of gene and stem cell therapies, to date none of these has been proven to be beneficial in clinical canine DCM.

Prognosis Overall the long-term prognosis for dogs with DCM is guarded to poor; however, the prognosis is variable and depends on disease severity, breed, causes, concurrent diseases, and quality of veterinary and home-based management. Dogs with occult DCM may live for up to 2 to 4 years before developing any clinical signs. Once CHF develops, survival usually is limited to 6 to 12 months, although it has improved dramatically with the use of ACE inhibitors and pimobendan. Variables that have a negative impact on prognosis include young age at the onset of clinical signs, biventricular failure, AF, severely increased end-systolic volume index, and a restrictive transmitral flow pattern. Most of these predictors are logical and indicate that the heart is severely dilated, left ventricular function is severely impaired, and maladaptive neurohormonal responses are fully active. Most dogs

with DCM die of CHF or are euthanized because of severe clinical signs, declining quality of life, or poor prognosis. Clients should be warned that sudden death also is common.

References and Suggested Reading Hare JM: The dilated, restrictive, and infiltrative cardiomyopathies. In Bonow RO et al, editors: Heart disease, ed 9, Philadelphia, 2011, Saunders, p 1561. Meurs KM et al: A splice site mutation in a gene encoding for a mitochondrial protein is associated with the development of dilated cardiomyopathy in the Doberman pinscher, J Vet Intern Med 24:693, 2010 (abstract). O’Grady MR et al: Effect of pimobendan on case fatality rate in Doberman pinschers with congestive heart failure caused by dilated cardiomyopathy, J Vet Intern Med 22:897, 2008. O’Grady MR et al: Efficacy of benazepril hydrochloride to delay the progression of occult dilated cardiomyopathy in Doberman pinschers, J Vet Intern Med 23:977, 2009. Oyama MA et al: Carvedilol in dogs with dilated cardiomyopathy, J Vet Intern Med 21:1272, 2007. Schober KE et al: Detection of congestive heart failure in dogs by Doppler echocardiography, J Vet Intern Med 24:1358, 2010. Schober KE et al: Effects of treatment on respiratory rate, serum natriuretic peptide concentration, and Doppler echocardiographic indices of left ventricular filling pressure in dogs with congestive heart failure secondary to degenerative mitral valve disease and dilated cardiomyopathy, J Am Vet Med Assoc 239:468, 2011. Sleeper M et al: Status of therapeutic gene transfer to treat cardiovascular disease in dogs and cats, J Vet Cardiol 13:131, 2011. Summerfield NJ et al: Effect of pimobendan in the prevention of congestive heart failure or sudden death in Doberman pinschers with preclinical dilated cardiomyopathy (the PROTECT study), J Vet Intern Med 26:1337, 2012. Wess G et al: Use of Simpson’s method of disc to detect early echocardiographic changes in Doberman pinschers with dilated cardiomyopathy, J Vet Intern Med 24:1069, 2010. Wess G et al: Evaluation of N-terminal pro-B-type natriuretic peptide as a diagnostic marker of various stages of cardiomyopathy in Doberman pinschers, Am J Vet Res 72:642, 2011.

CHAPTER 

179 

Arrhythmogenic Right Ventricular Cardiomyopathy KATHRYN M. MEURS, Raleigh, North Carolina

T

he condition previously known as boxer cardiomyopathy is now more commonly referred to as arrhythmogenic right ventricular cardiomyopathy (ARVC). ARVC is a primary myocardial disease that typically presents in one of three forms: an asymptomatic form with ventricular premature complexes (VPCs); a symptomatic form with VPCs; and a form with ventricular dilation, myocardial dysfunction, and ventricular and supraventricular tachyarrhythmias. Affected dogs may live for years with the disease and remain asymptomatic, may experience sudden death, or may gradually progress to congestive heart failure. ARVC is an adult-onset familial disease that appears to be inherited in an autosomaldominant fashion. It has variable penetrance and expressivity; that is, not all boxers with the disease have cardiomyopathy to the same degree or develop it at the same age, although the frequency of disease, as well as disease severity, increases with age in affected dogs. A small percentage of boxers with myocardial disease brought for treatment for the first time have ventricular dilation and myocardial dysfunction without a history of ARVC. It is possible that these boxers have a separate myocardial disease that might be caused by an inherited carnitine deficiency, viral myocarditis, or some other myocardial insult that results in the development of a cardiomyopathic state.

Causes In human beings, ARVC is an inherited disease most commonly associated with a genetic mutation in a gene that encodes for one of many desmosomal proteins. In the boxer dog, a deletion mutation has been identified in the 3′ untranslated region of striatin, a gene that encodes for a desmosomal protein. This mutation has approximately 70% penetrance in dogs with the deletion, which means that about 70% of dogs with the mutation eventually show the disease (30% do not). It should be remembered that in human beings there are numerous genetic causes for the disease, and this may be the situation in the boxer dog as well.

Diagnosis Arrhythmogenic Right Ventricular Cardiomyopathy A single diagnostic test for boxer ARVC is unavailable, and the diagnosis is best based on a combination of

findings. Genetic evaluation for the deletion mutation can be performed. A test result that is positive for the mutation means that the dog is at increased risk of the disease and supports a diagnosis in dogs with clinical signs. However, a positive genetic test result does not mean that the dog absolutely will develop the disease since about 30% of dogs with the mutation show no signs of the disease (due to the variable penetrance described earlier). Similarly, if the test result is negative, it does not mean that the dog does not have ARVC since there may be more than one cause for the disease. Therefore genetic testing is a useful tool for screening dogs for a breeding program but is less helpful as a single diagnostic test. A family history of disease, the presence of a ventricular tachyarrhythmia, a history of syncope or exercise intolerance, and the exclusion of other systemic and cardiovascular diseases that could be responsible for the clinical presentation all are factors that support the diagnosis. Generally a thorough physical examination, electrocardiography (ECG), blood pressure measurement, and echocardiography should be performed when a diagnosis is suspected. In addition, ambulatory ECG (Holter) monitoring provides important information for both the initial treatment and long-term management of the case and should be performed whenever possible. Physical examination findings may include the auscultation of premature beats with post-extrasystolic pauses, a persistent or paroxysmal tachyarrhythmia, or no abnormalities at all. It should be emphasized that many affected dogs have very intermittent bouts of the arrhythmia, and the absence of a tachyarrhythmia during examination does not rule out the diagnosis. In addition, since this is primarily an electrical disease, the majority of affected boxers do not have a heart murmur, although a left apical systolic murmur of mitral regurgitation may be identified in dogs that also have myocardial dysfunction and many boxers have a left basilar ejection murmur of uncertain cause. The classic ECG findings of ARVC include the presence of upright VPCs with positive QRS complexes with a morphology resembling that of left bundle branch block on lead II (Harpster, 1991). However, in some affected dogs the morphology of the VPCs is different or, when the arrhythmia is intermittent, the ECG may not demonstrate any VPCs. It is important to note that normal ECG findings do not exclude a diagnosis of ARVC; if suspicion persists because of clinical signs (syncope, exercise intolerance), auscultation of an arrhythmia, or a family history of disease, 24-hour Holter monitoring and genetic testing 801

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SECTION  VIII  Cardiovascular Diseases

is strongly suggested. Even if occasional VPCs are identified on an in-house ECG, Holter monitoring is generally recommended to allow better assessment of the overall frequency and complexity of the arrhythmia. In addition, a pretreatment Holter ECG recording provides useful baseline information when one attempts to determine treatment efficacy as well as to assess for potential proarrhythmic effects of treatment once it has started. The results of Holter monitoring can be very useful in establishing a diagnosis of ARVC, particularly if the ECG findings are within normal limits. It is unusual for mature adult dogs to have ventricular ectopy. The median number of VPCs detected on the Holter readings from 600 mature asymptomatic boxers was 10 VPCs in 24 hours. Therefore the identification of frequent ventricular ectopy (>100 VPCs in 24 hours) in an adult boxer dog is strongly suggestive of a diagnosis of ARVC, particularly if there is significant complexity (couplets, triplets, bigeminy, or ventricular tachycardia) within the arrhythmia. However, in some cases a diagnosis of ARVC in a boxer is strongly suspected, based on the breed and a history of syncope, but the Holter monitor recording clearly does not show abnormalities. This may be explained by the significant day-to-day variability in the number of VPCs (up to 83%) in affected dogs. Alternatively, reflex-mediated syncope (e.g., vasovagal syncope, characterized by vasodilation and bradycardia) may be occurring. Reflex-mediated syncope has been observed in boxers and should be considered in a fainting boxer with no evidence of ventricular arrhythmias. In cases of uncertain cause, a second round of Holter monitoring or ambulatory ECG event monitoring may be performed to better determine the relationship of heart rhythm and syncope in a boxer dog. Blood pressure measurement, echocardiography, and in certain cases splenic ultrasonography are recommended in cases of suspected ARVC. Although in the majority of cases the blood pressure, cardiac chamber sizes, and systolic ventricular function are within normal limits, an echocardiogram can rule out other, less common causes of ventricular ectopy (e.g., neoplasia). Likewise, splenic masses are a known cause of ventricular arrhythmias in dogs and should be considered in the diagnostic workup of ventricular arrhythmias, particularly in older dogs. Blood pressure measurement may offer insight into additional systemic diseases capable of causing syncope. In addition, echocardiography is necessary to identify  the small percentage of dogs with ARVC that develop right and left ventricular enlargement and myocardial dysfunction.

Dilated Cardiomyopathy A small percentage of boxers have a clinical presentation consistent with dilated cardiomyopathy. Affected dogs may experience syncope or show signs of left-sided heart failure, including coughing and tachypnea, or signs of biventricular failure, such as coughing, tachypnea, and ascites. Thoracic radiographs may demonstrate left-sided or biventricular enlargement, pulmonary edema, and pulmonary venous congestion. The echocardiogram may demonstrate left or biventricular enlargement associated with systolic dysfunction. The cause in these cases is

unknown, although an association has been identified between homozygosity for the striatin deletion (two copies of the defective gene) and the development of the disease. Additionally, other causes of myocardial dysfunction, including L-carnitine deficiency and myocarditis (see Web Chapter 63), should be considered.

Screening Given the inheritable nature of ARVC, there is significant interest on the part of breeders and enthusiasts of the boxer breed in the development of a screening program. Genetic testing plays an important role in the development of a screening program because dogs with the mutation are at increased risk of developing clinical signs. Dogs that are found to be heterozygous for the related mutation should be evaluated annually for signs of disease. Adult dogs that do not show signs of disease may exhibit a reduced genetic expression and, if they demonstrate other positive breed attributes, might be bred to mutation-negative dogs. Puppies of this mating should be screened for the mutation, and over a few generations, mutation-negative puppies may be selected to replace the mutation-positive parent and gradually decrease the number of mutation-positive dogs in the population. Boxers homozygous for the mutation probably should not be used for breeding. They appear to be at higher risk of having significant clinical disease, and since both copies of their gene have the mutation, they certainly will pass on the mutation to future offspring. Dogs negative for the mutation still should undergo clinical screening for ARVC (e.g., Holter monitoring) since there may be more than one genetic cause for ARVC in boxers (as in people). Given this possibility of multiple genetic causes for ARVC, a dog that is negative for the striatin mutation still could develop clinical findings of disease. Multiple factors should be considered when making decisions about clinical screening results, including a family history of ARVC and results of repeated abnormal Holter monitor readings. Given the adult onset of the disease, many perform the first Holter monitoring at the age of 3 years and reevaluate on an annual basis. Holter monitor results should be evaluated for both the number of VPCs and the complexity of arrhythmia (e.g., singles, couplets, triplets, ventricular tachycardia). However, there still are many unanswered questions about ARVC and the relationship of the ventricular arrhythmia to the development of clinical signs. Some affected dogs can have thousands of VPCs and never develop clinical signs; others demonstrate severe clinical signs with a fairly low number of VPCs. We have not found the number of VPCs or the complexity of the arrhythmia to differ statistically in symptomatic (syncopal) dogs compared with asymptomatic affected dogs. In fact, the only factors that have been shown to correlate statistically with severe clinical signs (sudden death) are the presence of myocardial dysfunction (low fractional shortening) and the presence of homozygosity for the striatin mutation. Breeders should be encouraged strongly to screen for the disease but should be advised about the complexities of screening and counseled not to remove dogs completely from a

CHAPTER  179  Arrhythmogenic Right Ventricular Cardiomyopathy breeding program because of a single abnormal Holter reading. Annual Holter monitoring is recommended strongly, and an emphasis should be placed on the results of multiple evaluations in an asymptomatic animal. The results of 24-hour Holter monitoring in over 600 asymptomatic adult boxers yielded a median of 10 VPCs per 24 hours, with 25% and 75% confidence intervals of 2 and 110 VPCs, respectively. Based on this information we have developed the following initial classification system for screening asymptomatic dogs: Grade 1. 0 to 50 single VPCs per 24 hours: within normal limits Grade 2. 51 to 100 VPCs per 24 hours: indeterminate; suggest repeat testing in 6 to 12 months Grade 3. 100 to 300 single VPCs per 24 hours: suspicious; consider keeping the dog out of the breeding program for 1 year and repeating the Holter study Grade 4. 100 to 300 VPCs per 24 hours with increased complexity (frequent couplets, triplets, ventricular tachycardia) or 300 to 1000 single VPCs per 24 hours: the dog likely is affected Grade 5. More than 1000 VPCs per 24 hours: the dog is affected; may consider treatment as discussed in the following paragraphs These criteria are based on evaluation of the results of a single round of Holter monitoring in mature boxers with no history of syncope. Additional studies that evaluate long-term outcomes for boxers with arrhythmias of various grades are ongoing. This information is provided as a possible starting point for making screening recommendations. As indicated earlier, multiple criteria should be considered for each dog before any strict recommendations are advanced. The family history, evidence of any ongoing systemic disease that could be associated with ventricular arrhythmia, and results of repeated Holter studies are particularly important.

Treatment In affected boxers, antiarrhythmic therapy has been shown to decrease the number of VPCs, the complexity (grade) of the arrhythmia, and the frequency of syncope. However, the ability of antiarrhythmic therapy to decrease the risk of sudden death has been neither proven nor disproven. In addition, ventricular antiarrhythmic agents can demonstrate significant proarrhythmic effects in some patients. Therefore the risks and benefits always should be assessed when treatment is considered. For the asymptomatic dog the author generally recommends therapy to decrease the number and complexity of the arrhythmias if there are at least 1000 VPCs per 24 hours or if runs of ventricular tachycardia or evidence of the R-on-T phenomenon are identified. It should be remembered that some dogs with ARVC die suddenly without ever having any documented episodes of syncope. Thus the absence of a history of syncope does not imply a lack of risk, and a recent report has suggested that a history of syncope may not always increase the risk of sudden cardiac death. Ideally, boxers with syncope and

803

ventricular arrhythmias should be treated after results of 24-hour Holter monitoring are analyzed to quantify the pretreatment arrhythmia. If the syncope is frequent or if ventricular tachycardia is observed, a Holter monitoring evaluation may not be performed to avoid delay in initiating therapy. However, in these cases, the absence of pretreatment Holter monitoring recordings can make it difficult to assess fully the response to therapy. Therefore, whenever possible, a Holter monitoring evaluation should be performed first. If there is great concern about the risk of sudden death, the owner is advised to start therapy immediately after removing the monitoring electrodes (while awaiting the results). A few therapeutic protocols appear to be effective in reducing the number of VPCs and the degree of complexity of the arrhythmia in boxer dogs with ARVC. One is sotalol (1.5 to 2.5 mg/kg q12h PO); a second is mexiletine (5 to 6 mg/kg q8h PO). In some hard-to-control cases, both sotalol and mexiletine, at the dosages given, can be administered. This combination can be quite effective and typically is well tolerated by affected dogs. In management of most cases of boxer ARVC, sotalol as a monotherapy generally is chosen first because of the ease of dosing twice a day, the low level of adverse effects, and the demonstrated reduction in the number of VPCs in most dogs. However, in some cases, sotalol does not suppress the arrhythmia sufficiently and the addition of mexiletine may be useful. Occasionally, mexiletine causes a loss of appetite or mild gastrointestinal upset, which may improve if the drug is given with a small meal. Failure of the combination of sotalol and mexiletine to work should prompt referral to or consultation with a cardiologist. Despite their potential for beneficial antiarrhythmic effects, the aforementioned medications can exert proarrhythmic effects or may be insufficiently effective in some boxers with ARVC. Therefore a Holter ECG evaluation is recommended both before treatment and 2 to 3 weeks after treatment has been initiated. This evaluation can help determine the effect of treatment and confirm that the arrhythmia has not gotten worse. Significant day-to-day variability (up to an 83% change in daily VPC count) has been observed in affected boxers (Spier and Meurs, 2004). Therefore a positive therapeutic response is confirmed when at least an 80% reduction in VPC number along with a reduction in the complexity of the arrhythmia is observed on the posttreatment Holter recording. In contrast, an increase in symptoms after initiation of treatment or an increase of more than 80% in the number of VPCs per day may suggest a proarrhythmic effect.

References and Suggested Reading Basso C et al: Arrhythmogenic right ventricular cardiomyopathy causing sudden death in boxer dogs: a new animal model of human disease, Circulation 109:1180, 2004. Harpster N: Boxer cardiomyopathy, Vet Clin North Am Small Anim Pract 21:989, 1991. Keene B: l-Carnitine supplementation in the therapy of dilated cardiomyopathy, Vet Clin North Am Small Anim Pract 21:1005, 1991. Meurs KM et al: Familial ventricular arrhythmias in boxers, J Vet Intern Med 13:437, 1999.

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SECTION  VIII  Cardiovascular Diseases

Meurs KM et al: Comparison of in-hospital versus 24-hour ambulatory electrocardiography for detection of ventricular premature complexes in mature boxers, J Am Vet Med Assoc 218:222, 2001. Meurs KM et al: Comparison of the effects of four antiarrhythmic treatments for familial ventricular arrhythmias in boxers, J Am Vet Med Assoc 221:522, 2002.

CHAPTER 

Meurs KM et al: Genome-wide association identifies a mutation in the 3′ untranslated region of Striatin, a desmosomal gene, in a canine model of arrhythmogenic right ventricular cardiomyopathy, Hum Genet 128:315, 2010. Spier AW, Meurs KM: Spontaneous variability in the frequency of ventricular arrhythmias in boxers with arrhythmogenic cardiomyopathy, J Am Vet Med Assoc 224:538, 2004.

180 

Feline Myocardial Disease VIRGINIA LUIS FUENTES, Hatfield, Hertfordshire, United Kingdom KARSTEN ECKHARD SCHOBER, Columbus, Ohio

Definition of Myocardial Disease Myocardial disease in cats is a heterogeneous group of conditions, paralleling the spectrum of diseases that make up human cardiomyopathy. Feline cardiomyopathies originally were categorized according to morphology and function, in line with the contemporary human classification. The main categories were hypertrophic, dilated, restrictive, and unclassified cardiomyopathy, with the later addition of arrhythmogenic right ventricular cardiomyopathy (ARVC). Human cardiomyopathies now are divided into primary cardiomyopathies in which the myocardial changes are the major abnormality (e.g., hypertrophic cardiomyopathy, or HCM) and secondary cardiomyopathies in which a multiorgan systemic disease (e.g., hyperthyroidism) affects the myocardium (Maron et al, 2006). Primary cardiomyopathies are divided into those with a genetic basis, those with an acquired cause, and those involving a combination of genetic and acquired factors (mixed). Hypertrophic cardiomyopathy and ARVC are considered genetic in humans, whereas dilated cardiomyopathy (DCM) and restrictive cardiomyopathy (RCM) are classed as mixed. There is evidence that HCM can be genetic in cats: two separate mutations in the cardiac myosin-binding protein C gene have been identified in Maine coon and Ragdoll cats with HCM. A deficiency in dietary taurine can result in a feline DCM phenotype. Secondary cardiomyopathies found in cats include myocardial disease related to hyperthyroidism, systemic hypertension, and chronic anemia, which commonly affect cardiac chamber size and function. Despite this classification, there is considerable overlap among groups. Cats may progress from one phenotype to another. Myocardial infarction can complicate HCM, resulting in regional wall thinning and hypokinesis that resembles a DCM phenotype. An end-stage form of HCM

also has been described in human and feline patients, characterized by left ventricular hypertrophy with dilation and reduced systolic function. Left ventricular remodeling in HCM with interstitial fibrosis and loss of cardiac myocytes can result in a morphology that is closer to RCM than to classic HCM, and chronic myocarditis may mimic RCM or DCM. Even on a genetic level, some sarcomeric mutations are associated with both DCM and HCM phenotypes. In addition, abnormal mitral valve morphology can be associated with dynamic outflow tract obstruction and left ventricular hypertrophy, which blurs the boundaries between congenital heart disease and primary cardiomyopathy.

Diagnostic Approach In addition to the difficulties in trying to assign a particular label to the cardiomyopathy in individual cats, feline cardiac disease presents a number of other diagnostic challenges. Healthy cats may have innocent heart murmurs that are not associated with any structural cardiac abnormality. The prevalence of murmurs in the healthy cat population is high, but as many as half of all feline murmurs may be functional and not actually caused by structural heart disease (Wagner et al, 2010). These low- to moderateintensity systolic murmurs often are associated with conditions characterized by increased sympathetic tone and high cardiac output, such as stress, anemia, hyperthyroidism, and fever, with the murmur arising from the left  or the right ventricular outflow tract. Dynamic right  ventricular outflow tract obstruction can be normal in cats. The best way to differentiate cats with functional murmurs from those with heart disease is with echocardiography. Unfortunately, interpretation of echocardiograms in cats requires a high level of expertise, particularly

CHAPTER  180  Feline Myocardial Disease in distinguishing between normal cats and cats with mild structural cardiac changes. Thoracic radiography may be used to identify cardiomegaly in asymptomatic cats, but the sensitivity of this method is low, especially in cats with mild structural changes. Plasma biomarker assays such as those for N-terminal prohormone B-type natriuretic peptide (NT-proBNP) and high-sensitive cardiac troponin I are showing promise as screening tests for cardiomyopathy in this setting but always should be used in conjunction with other tests (Fox et al, 2011). It is relatively easy to screen for secondary cardiomyopathies by measuring blood pressure, thyroxine concentration, and hematologic parameters. Noncardiac disease can cause respiratory distress that must be distinguished from congestive heart failure (CHF). Auscultation of a gallop sound in a cat with tachypnea is highly suggestive of CHF. Radiography can be helpful if cardiomegaly or venous engorgement is detected. If the cardiac silhouette is obscured or interpreted as normal, radiography is less useful as a discriminatory test because the distribution of pulmonary infiltrates with cardiogenic pulmonary edema is very variable in cats, and the presence of a pleural effusion is nonspecific. The careful positioning necessary for diagnostic radiography also can jeopardize patient safety when the cat is tachypneic. Although plasma NT-proBNP concentration may discriminate well between cardiac and noncardiac causes of respiratory distress in cats, it is not yet available as a cage-side test, and the delay in receiving results limits its usefulness. Cats with myocardial disease may have no detectable abnormalities on physical examination. The extent of this problem is unclear, although a recent study evaluating 103 apparently normal cats found heart murmurs in only 5 of the 16 cats with echocardiographic evidence of cardiomyopathy (Paige et al, 2009). Additionally, it is common for cats brought for treatment of aortic thromboembolism (ATE) and advanced cardiomyopathy to have shown no signs of cardiac disease at previous examinations. Without preemptive screening, these at-risk cats likely will continue to be denied the opportunity for cardiac therapy.

Therapeutic Approach Clearly it is never appropriate to treat a cat for heart disease based solely on the presence of an auscultatory abnormality such as a murmur or even a gallop sound or click. Most cats with heart disease have cardiomyopathy, but those with secondary cardiomyopathies must be identified because their treatment should be directed at the underlying disease. It is more important to determine symptomatic status than to try to categorize the cardiomyopathy phenotype because cats with clinical signs are managed differently from those without. Treatment decisions ideally should be evidence based, but relevant data mostly are lacking in feline heart disease. In the absence of valid evidence, management should focus on targeting cats at risk of recognized complications of cardiomyopathy. The most common sequelae of cardiomyopathy are CHF and ATE, although the incidence of sudden death is probably underestimated. When specific hemodynamic

805

disturbances (e.g., systolic dysfunction) are identified, therapy should be tailored to the specific functional problem. Nevertheless, it is important to recognize that many cats with myocardial disease remain asymptomatic for long periods without any intervention (Payne et al, 2010), and any incremental benefit from therapy in these cats may not justify the additional expense, time, and stress. Management strategies are presented in the following sections according to risk stratification for stages of heart disease (Table 180-1).

Asymptomatic Cardiomyopathy (Low Risk) Cats with occult cardiomyopathy exhibit a spectrum of risks, from those cats that will survive to old age and never experience any clinical signs associated with their heart disease to those at imminent risk of CHF or ATE. Cats at the low-risk end of this spectrum are likely to have a normal-sized left atrium (Payne et al, 2010) and may be difficult to differentiate from healthy cats if ventricular changes are subtle. Echocardiography is the most effective test for evaluating left atrial size in cats, although radiography can provide an approximate assessment in cats with moderate or severe atrial enlargement. Alternatively, plasma NT-proBNP concentrations may be used to provide an initial risk assessment to guide further testing (Fox et al, 2011). It is difficult to justify therapy in cats with a normalsized left atrium as a means of improving survival because most cats in this category do well without treatment, including cats with dynamic left ventricular outflow tract obstruction (DLVOTO), which typically is associated with systolic anterior motion of the mitral valve apparatus and mitral-septal contact. It is not known whether cats with DLVOTO experience the chest pain that some human HCM patients experience. Moreover, whether the wellknown effect of moderate and severe DLVOTO on activity and exercise level in people also occurs in cats is largely undetermined. These are some potential reasons for treating feline DLVOTO in the absence of any demonstrated effect on survival (see the later section on DLVOTO). Note that although cats with mild occult disease are unlikely to require treatment and often remain in stable condition for long periods, the risk remains that CHF will develop in response to interventions such as intravenous fluid therapy, anesthesia, or depot corticosteroid administration, or to periods of prolonged tachycardia associated with stress. Worryingly, cats in this category also may be at risk of sudden death (Payne et al, 2011).

Asymptomatic Cardiomyopathy (at Risk) Cats at the high-risk end of the occult cardiomyopathy spectrum are likely to have left atrial enlargement. Such cats have an increased likelihood of developing CHF or ATE compared with those with no left atrial enlargement. Although results of a few short-term trials of therapy in asymptomatic cats have been published, no therapy has been reported to be unequivocally beneficial. However, enrollees frequently have included cats with normal-sized left atria, which minimizes the likely benefit of intervention over a short period.

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SECTION  VIII  Cardiovascular Diseases

TABLE 180-1  Treatment Recommendations for Feline Myocardial Disease STAGE B

STAGE C

Asymptomatic HCM (Normal LA)

Asymptomatic HCM (Normal LA) + DLVOTO

Asymptomatic Other Cardiomyopathy (LA Enlargement)

Atenolol

X

✓

Diltiazem

?✓

Furosemide

STAGE D

Symptomatic (CHF)

Symptomatic (Acute Low-Output Signs)

Refractory CHF

Specific Indications

X

X

X

X

DLVOTO with syncope

X

X

X

X

X

Atrial fibrillation, supraventricular tachycardia

X

X

X

✓

X

✓

ACE inhibitor

?✓

?✓

?✓

✓

X

✓

Pimobendan

X

X

X

?✓ (only if no DLVOTO)

✓

✓ (if no DLVOTO)

Spironolactone

X

X

X

X

X

✓

Aspirin ± clopidogrel

X

X

✓

✓

✓

✓

Sotalol

?✓ (if ventricular tachycardia)

?✓ (if ventricular tachycardia)

?✓ (if ventricular tachycardia)

X

X

X

Systolic dysfunction

Ventricular arrhythmias (if structural heart disease but normal systolic function)

See text for details. X, Not indicated; ✓, used by the authors; ?, greater degree of uncertainty; ACE, angiotensin-converting enzyme; CHF, congestive heart failure; DLVOTO, dynamic left ventricular outflow tract obstruction; HCM, hypertrophic cardiomyopathy; LA, left atrium. Stage B, Heart disease without clinical signs; Stage C, heart failure treated with “standard methods” and dosages; Stage D, advanced or refractory heart failure.

Without experimental evidence to provide guidance, therapeutic decisions are based on extrapolation from human treatment protocols or knowledge of pathophysiology. This is the patient group about which there is the most controversy in terms of treatment decisions for feline cardiomyopathy. The theoretical goals of therapy in cats at high risk of decompensation might include improvement of hemodynamic function, reduction  of left ventricular filling pressures, counteraction of  neurohormonal activation, and modulation of platelet function. Treatments suggested include β-adrenergic antagonists (atenolol), calcium channel blockers (diltiazem), angiotensin-converting enzyme (ACE) inhibitors, and antiplatelet drugs (aspirin and clopidogrel). β-Blockers reduce myocardial oxygen consumption, an effect that should reduce demand ischemia. This benefit, along with slowing of the heart rate and prolongation of diastolic filling, may have some overall benefit on diastolic function in HCM. Atenolol also reduces or eliminates dynamic outflow obstruction (see following paragraph). Anecdotal evidence suggests that relief of moderate and severe outflow tract obstruction may be associated with increased activity and exercise level in some cats that were previously classified as asymptomatic. Moreover, poor tolerance of tachycardia frequently

has been documented in people with HCM and has been proposed as a mechanism for the development of CHF in patients with occult HCM. Prevention of unwanted tachycardia therefore may be beneficial in some cats. The total daily dosage of atenolol is generally 1 to 4 mg/kg q12h PO. Liquid atenolol can be easier to dose than tablets in some cats, but in others the relatively small pill fractions can be hidden in food, treats, pill pockets, or gelatin capsules. Many clinicians dose atenolol to a heart rate effect (e.g., to achieve a rate of 120 to 160 beats/min during physical examination in a hospital setting). Doppler echocardiography can be used to confirm that the dose of atenolol is sufficient to control DLVOTO, and the associated murmur should decrease in intensity or disappear completely. Adverse effects of atenolol in asymptomatic cats can include excessive bradycardia and cardiac dilation. The calcium channel blocker diltiazem has been said to improve left ventricular relaxation, although definitive evidence of this effect in cats is lacking. Diltiazem also slows heart rate, although less consistently than atenolol. Standard-release diltiazem is dosed at 7.5 mg per cat q8h PO, which is impractical for most cat owners. Extendedrelease preparations of diltiazem such as Dilacor XR permit once- or twice-daily dosing at 15 to 30 mg per cat

CHAPTER  180  Feline Myocardial Disease q12-24h PO. These long-acting diltiazem compounds can achieve therapeutic plasma levels, but precise dosing guidelines for cats have not been reported. Adverse effects of diltiazem include salivation, anorexia, and weight loss. Although ACE inhibitors have theoretic benefits in cardiomyopathy, there are no data supporting their use in asymptomatic cats. Well-controlled studies in asymptomatic Maine coon cats failed to show a benefit of 12 months of treatment with ramipril at 0.5 mg/kg q24h PO (MacDonald et al, 2006). Another randomized, controlled study (Taillefer and Di Fruscia, 2006) comparing the effects of benazepril (0.5 mg/kg q24h PO) and diltiazem CD (10 mg/kg q24h PO) in 21 cats with preclinical HCM did not identify any relevant difference between groups after 6 months, although a control group was not studied. However, some cardiologists do consider an ACE inhibitor for treatment of asymptomatic cats demonstrating moderate and severe left atrial enlargement. Although severe left ventricular hypertrophy has been identified as an independent risk factor in people with HCM, and thus therapeutic targeting of left ventricular hypertrophy has been suggested, similar information is not available in feline HCM. Moreover, the mechanisms of hypertrophy may be so diverse in different forms of HCM that one common therapeutic strategy may not be capable of achieving the desired result. ACE inhibitors or angiotensin II receptor antagonists, spironolactone, diltiazem, and statins all have been used successfully in experimental HCM models. However, neither the ACE inhibitor regimen in the study cited previously nor 4 months of treatment with the aldosterone antagonist spironolactone (2  mg/kg q12h PO) showed any effect on estimates of left ventricular diastolic function or chamber dimensions in cats with preclinical HCM  (MacDonald et  al, 2006, 2008). In the spironolactone study, several cats developed skin lesions with chronic administration. The specific risk of ATE in asymptomatic cats with HCM has not been reported. Most clinicians view left atrial enlargement as a likely risk factor for this complication, and many consider antithrombotic therapy appropriate in cats with HCM with this echocardiographic finding. This treatment is discussed in the following paragraphs and in Chapter 181. Evaluation of size, content, and flow velocity in the left auricle may contribute to the decision on whether to use antithrombotic treatment (Schober and Maerz, 2006).

Hypertrophic Cardiomyopathy with Dynamic Left Ventricular Outflow Tract Obstruction In human HCM patients, DLVOTO is associated with increased risk of heart failure and death (Maron et al, 2003). Control of DLVOTO usually is initiated when patients become symptomatic (e.g., with syncope or exertional dyspnea), when DLVOTO is feared to be contributing to the development of left ventricular hypertrophy, or when DLVOTO is associated with more than mild mitral regurgitation, contributing to left atrial enlargement. In cats there is some controversy over the clinical significance of DLVOTO because several retrospective feline studies have shown an association between systolic

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anterior motion of the mitral valve and longer survival times (Fox et al, 1995; Payne et al, 2010; Rush et al, 2002). Often it is possible to control DLVOTO with β-blockers in cats, and anecdotal evidence suggests some clinical benefits on activity level following administration of β-blockers in cats with occult HCM. It is possible that symptomatic cats are more difficult to identify than symptomatic humans, particularly since human symptoms include signs such as chest pain and exercise intolerance. Cats with severe DLVOTO may be treated with atenolol and reexamined within the first month of treatment to confirm that DLVOTO has been controlled and that no adverse effects (e.g., bradycardia or an increase in left atrial size) have developed. Cats with CHF are less likely to demonstrate DLVOTO, but it is unclear whether any benefits of atenolol in this patient group are outweighed by its negative inotropic effects. β-Blockers should be used with great care (or not at all) in cats with DLVOTO and CHF.

Cardiomyopathy with Congestive Heart Failure Myocardial disease should be high on the differential list for cats with respiratory distress. Physical examination findings that might arouse suspicion of myocardial disease with CHF include combinations of a systolic murmur, gallop sounds, or arrhythmias with tachypnea, pulmonary crackles, and jugular vein distention. Crackles are a helpful finding for parenchymal disease but are not always evident. Muffled breath sounds ventrally may suggest pleural effusion or lung consolidation. Soft heart sounds with normal breath sounds have been identified in cats with ventricular dysfunction, especially DCM. Sometimes no auscultatory abnormalities are present, although respiration generally is labored in inspiration and often in expiration. The differential diagnosis of CHF in cats includes other causes of respiratory distress, pulmonary infiltration, pleural effusion, and airway obstruction. Acute pulmonary infiltration with labored breathing and tachypnea can be associated with thoracic trauma, excessive infusion of crystalloid, noncardiogenic pulmonary edema (see Chapter 9), severe pulmonary infections, vasculitis, lung parasitism (see Web Chapter 57), or spontaneous heartworm death (see Chapter 183). The two most common types of pleural effusion identified in cats with CHF are modified transudates (with small lymphocytes on cytologic examination) and chylothorax related to obstruction of systemic venous and lymphatic return. The differential diagnosis of pleural effusion is extensive and is considered in Chapter 164. Feline asthma can be associated with acute dyspnea but is readily distinguished from CHF by physical examination and radiography  (see Chapter 161). Uncommonly, cats with dyspnea are found to have major airway obstruction related to nasopharyngeal polyps (see Chapter 157), laryngeal paresis  or neoplasia (see Chapter 158), or tracheal obstruction. Tachypnea in cats with ATE may be related to severe pain rather than CHF. Imaging is critical to diagnosis. Radiography can be helpful for documenting pulmonary infiltrates or pleural effusion associated with CHF and excluding other causes

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of respiratory distress, although great care always should be taken when handling dyspneic cats. Sedation (butorphanol 0.1 mg/kg IM, repeated to a 0.3 mg/kg cumulative dose) may allow safer handling of stressed feline patients. These cats are very fragile, and thoracic ultrasonography with the cat in sternal recumbency may offer a safer option for identifying pleural effusions and perhaps the comet tail artifacts often related to pulmonary infiltration or edema. Echocardiography is the only practical way of identifying the underlying structural and functional abnormality of the heart, and demonstration of left atrial enlargement can be extremely useful as a means of supporting a  clinical suspicion of CHF and assessing the risk of thromboembolic complications. A full echocardiographic examination always can be delayed until the cat is in a more stable condition. Short-term goals of therapy in cats with CHF include relieving life-threatening hypoxemia, lowering left ventricular filling pressure, and improving cardiac function. Improving hemodynamic function is particularly difficult in cats with diastolic heart failure as occurs in HCM. Acute Congestive Heart Failure Severely dyspneic cats must be handled with care, and stress should be avoided at all costs. Most cats benefit from low doses of butorphanol (0.1 mg/kg IM, repeated as needed) as sedation. Oxygen supplementation, diuresis, and venodilation all are appropriate treatments for any cat with left-sided heart failure. Pleural effusion must be drained if it causes respiratory distress, and this can be achieved using a 23-gauge butterfly cannula with the cat in sternal recumbency. Furosemide is the mainstay of treatment for cats with acute pulmonary edema. Doses should be lower than those used in dogs, but some cats still require aggressive diuresis, and intravenous furosemide should be titrated to effect. Doses of 1 to 2 mg/kg should be repeated q30-60min until respiratory rate is near normal. Renal function, electrolyte levels, and blood pressure must be monitored. A constant-rate infusion of furosemide also can be considered (see Chapter 175). Reduction of respiratory rate is the most vital monitoring variable indicating successful diuretic therapy. Although ACE inhibitors may have some favorable venodilating effects, caution should be used in administering these drugs to cats with hypotension, and they are best avoided until systemic arterial pressures have reached at least 100 mm Hg. The severity of short-term clinical signs associated with CHF does not necessarily relate to prognosis. Cats that respond promptly to therapy may become asymptomatic and remain so for long periods. This is particularly true of cats in which CHF has been precipitated by some event, such as stress, intravenous fluid therapy, or general anesthesia. Low-Output Heart Failure Some cats have signs of low cardiac output, with or without CHF, which would be characterized by some as cardiogenic shock. These cats typically are hypothermic, bradycardic, and severely hypotensive (systolic blood pressure of 1.015). Cytologic findings are related to the originating condition. Infectious causes usually are related to plant awn migration, bite wounds, or extension of infection in nearby structures. Various aerobic and anaerobic bacterial infections, actinomycosis, coccidioidomycosis, disseminated tuberculosis, and rarely systemic protozoal infections have been identified. Sterile exudative effusions have occurred with leptospirosis, canine distemper, uremia, and idiopathic pericardial effusion in dogs and with feline infectious peritonitis and toxoplasmosis in cats.

Diagnostic Evaluation Blood Pressure Measurement Arterial blood pressure should be measured in all cases of suspected pericardial disease. Hypotension (arterial systolic blood pressure of 1 : 1024 • *Positive results on polymerase chain reaction assay of blood, body fluid, or tissue for Bartonella DNA Diagnosis Definite • Valve lesions • Two major criteria • One major and two minor criteria Possible • One major and one minor criterion • Three minor criteria Rejected • Firm alternative diagnosis • Resolution after 75% for amoxicillin, >90% for Clavamox, and >90% for the fluoroquinolones). Based on the resistance profiles of bacteria cultured from patients at the author’s hospital, many bacteria are resistant to ampicillin, and empiric use of ampicillin cannot be recommended without an MIC determination. The treatment of choice for Bartonella infections has not been defined in human or veterinary medicine. MICs are not indicative of the therapeutic efficacy of antibiotics against intracellular bacteria, including Bartonella, and minimum bactericidal concentration may be more appropriate. In an in vitro study only gentamicin and not ciprofloxacin, streptomycin, erythromycin, ampicillin, or doxycycline exerted bactericidal activity against Bartonella (Rolain et al, 2000). Treatment with aminoglycosides for at least 2 weeks has been shown to improve survival in humans with Bartonella IE (Raoult et al, 2003). Current treatment recommendations for humans include aminoglycosides and β-lactam antibiotics for 4 to 6 weeks (Baddour et al, 2005). Since there are no controlled efficacy studies for treatment of canine bartonellosis, no treatment of choice has been defined. In 24 dogs with various systemic manifestations secondary to bartonellosis, treatment with the following antibiotics resulted in clinical recovery and negative posttreatment titer results: doxycycline, azithromycin, enrofloxacin, and amoxicillin/ clavulanate (Breitschwerdt et al, 2004). There have been several experimental studies evaluating effects of various antibiotic therapies in cats experimentally infected with B. henselae, but extrapolating these results to dogs may not be valid. Treatment with enrofloxacin (5 to 7 mg/kg twice daily PO, although clinically the maximal dose that should be administered in cats is a 5 mg/kg/day limit) eliminated B. henselae in 4 of 6 cats and B. clarridgeiae in 5 of 7 cats, but treatment with doxycycline (4 to 12 mg/kg twice daily PO) eliminated bacteremia in only 1 of 6 cats treated for 14 days and 1 of 2 cats treated for 28 days (Kordick et al, 1997). Azithromycin achieves high intracellular concentrations, which is necessary for treatment of IE, and also possesses attractive antiinflammatory and immunomodulatory properties. Although it is recommended for treatment of bartonellosis in dogs and cats, no controlled long-term

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efficacy studies have been performed. A study comparing in vitro antimicrobial activity of enrofloxacin, azithromycin, and pradofloxacin (an expanded-spectrum fluoroquinolone) against B. henselae isolated from cats and a human found that azithromycin had the lowest antimicrobial activity and pradofloxacin had the greatest antimicrobial activity based on MIC (Biswas et al, 2010). Hepatic enzyme levels should be monitored carefully when azithromycin is administered long term since it may cause hepatotoxicity. Anticoagulant or antiplatelet therapy currently is not recommended since there has been a trend toward increased bleeding episodes and no benefit in vegetation resolution or reduction of embolic events in humans with IE treated with aspirin (Baddour et al, 2005). However, anticoagulant or antiplatelet therapy may be considered in patients with hypercoagulable states (e.g., protein-losing nephropathy, disseminated intravascular coagulation).

Treatment of Congestive Heart Failure Dogs with CHF should be treated with furosemide at the appropriate dosage, depending on the severity of pulmonary edema (for stable mild to moderate CHF, 1 to 4 mg/ kg two or three times daily PO; for acute fulminant CHF, 5 to 6 mg/kg q2-4h IV initially with dosage then reduced according to patient’s response). In dogs with significant aortic insufficiency secondary to aortic IE or massive mitral regurgitation, afterload reduction using amlodipine, hydralazine, or nitroprusside should be instituted provided the dog is not hypotensive at baseline. Aggressive afterload reduction in hypertensive patients is warranted in all cases. In normotensive animals the target reduction of blood pressure from baseline is 10 to 15 mm Hg. Adjunctive therapy for chronic CHF includes an angiotensinconverting enzyme inhibitor and possibly digoxin if there is myocardial failure (see Chapter 176). Pimobendan (0.25 mg/kg twice daily PO) is indicated for treatment of acute or chronic CHF caused by aortic or mitral valve IE as long as there is not significant subaortic stenosis. Antiarrhythmic treatment may be necessary, especially if there are high-grade ventricular arrhythmias (see Chapter 172).

Follow-up In patients with initially positive culture results (blood or urine), repeat culture is recommended 1 to 2 weeks after starting antibiotic therapy and 2 weeks following termination of antibiotic therapy. An echocardiogram should be obtained after 2 weeks of antibiotic treatment, in 4 to 6 weeks, and 2 weeks after termination of antibiotic therapy to assess the size of the vegetative lesion and the severity of valvular insufficiency. In patients infected with Bartonella, repeat serologic testing should be performed a month after initiation of treatment, and titers should be reduced. If titers are persistently elevated, a different antibiotic may be needed.

Prophylaxis In dogs with congenital heart disease, in particular subaortic stenosis, perioperative parenteral antibiotics such

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as a β-lactam or a cephalosporin should be given 1 hour before surgery or dentistry and 6 hours after the procedure. Clindamycin may be useful as a prophylactic antibiotic for dental procedures. The 2007 revision of the American Heart Association guidelines provide for more stringent use of antibiotic dental prophylaxis and call for prophylaxis only in patients with a prosthetic heart valve, a history of IE, certain forms of congenital heart disease, or valvulopathy after cardiac catheterization, and only before procedures that involve manipulation of gingival tissue or the periapical region of teeth, and not for routine dental cleaning (Wilson et al, 2007). Prophylactic administration of antibiotics to dogs with myxomatous valve degeneration that are undergoing a dental procedure is controversial since these dogs are not at increased risk of development of IE (Peddle and Sleeper, 2007).

Prognosis Dogs with aortic IE have a grave prognosis, and median survival in one study was only 3 days compared with a median survival of 476 days for dogs with mitral IE (MacDonald et  al, 2004). Dogs with Bartonella IE have short survival times since the aortic valve is affected almost exclusively. Similarly, in another case series 33% of dogs with aortic IE died within the first week, and 92% died within 5 months of diagnosis (Sisson and Thomas, 1984). Glucocorticoid administration before treatment of IE is associated with higher mortality in dogs with IE (Calvert, 1982). Death within a short time after diagnosis most often is caused by CHF or occurs suddenly. Likewise, in humans with IE the presence of CHF has the greatest negative impact on prognosis. Other causes of death in dogs with IE within the first week of treatment include renal failure, pulmonary hemorrhage, and severe neurologic disease. Other negative predictors of survival include thrombocytopenia, high serum creatinine concentration, and thromboembolic complications (Sykes et  al, 2006a).

References and Suggested Reading Baddour LM et al: Infective endocarditis: diagnosis, antimicrobial therapy, and management of complications, AHA scientific statement, Circulation 111:e394, 2005. Barker CW et al: Pharmacokinetics of imipenem in dogs, Am J Vet Res 64:694, 2003. Biswas S, Rolain JM: Bartonella infection: treatment and drug resistance, Future Microbiol 5(11):1719, 2010. Bonow RO et al: ACC/AHA 2006 guidelines for the management of patients with valvular heart disease: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (writing committee to revise the 1998 Guidelines for the Management of Patients with Valvular Heart Disease): developed in collaboration with the Society of Cardiovascular Anesthesiologists: endorsed by the Society for Cardiovascular Angiography and Interventions and the Society of Thoracic Surgeons, Circulation 114:e156, 2006. Breitschwerdt EB et al: Sequential evaluation of dogs naturally infected with Ehrlichia canis, Ehrlichia chaffeensis, Ehrlichia equi, Ehrlichia ewingii, or Bartonella vinsonii, J Clin Microbiol 36:2645, 1998. Breitschwerdt EP et al: Clinicopathological abnormalities and treatment response in 24 dogs seroreactive to Bartonella vinsonii (berkhoffii) antigens, J Am Anim Hosp Assoc 40:92, 2004.

Calvert CA: Valvular bacterial endocarditis in the dog, J Am Vet Med Assoc 180:1080, 1982. Chomel BB et al: Aortic valve endocarditis in a dog due to Bartonella clarridgeiae, J Clin Microbiol 39(10):3548, 2001. Cook LB et al: Vascular encephalopathy associated with bacterial endocarditis in four dogs, J Am Anim Hosp Assoc 41(4):252, 2005. Fournier PE et al: Value of microimmunofluorescence for diagnosis and follow-up of Bartonella endocarditis, Clin Diagn Lab Immunol 9:795, 2002. Fournier PE et al: Value of microimmunofluorescence for diagnosis and follow-up of Bartonella endocarditis, Clin Diagn Lab Immunol 9:795, 2002. Houpikian P, Raoult D: Blood culture-negative endocarditis in a reference center, etiologic diagnosis of 348 cases, Medicine 84:162, 2005. Kordick DL, Papich MG, Breitschwerdt EB: Efficacy of enrofloxacin or doxycycline for treatment of Bartonella henselae or Bartonella clarridgeiae infection in cats, Antimicrob Agents Chemother 41(11):2448, 1997. Macarie C et al: Echocardiographic predictors of embolic events in infective endocarditis, Kardiol Pol 60(6):535, 2004. MacDonald KA et al: A prospective study of canine infective endocarditis in northern California (1999-2001): emergence of Bartonella as a prevalent etiologic agent, J Vet Intern Med 18:56, 2004. Meurs KM et al: Comparison of polymerase chain reaction with bacterial 16s primers to blood culture to identify bacteremia in dogs with suspected bacterial endocarditis, J Vet Intern Med 25(4):959, 2011. Mügge A et al: Echocardiography in infective endocarditis: reassessment of prognostic implications of vegetation size determined by the transthoracic and the transesophageal approach, J Am Coll Cardiol 14(3):631, 1989. Ohad DG et al: Molecular detection of Bartonella henselae and Bartonella koehlerae from aortic valves of Boxer dogs with infective endocarditis, Vet Microbiol 141(1-2):182, 2010. Pappalardo BL et al: Immunopathology of Bartonella vinsonii (berkhoffii) in experimentally infected dogs, Vet Immunol Immunopathol 83:125, 2001. Peddle G, Sleeper MM: Canine bacterial endocarditis: a review, J Am Anim Hosp Assoc 43:258, 2007. Perez C et al: Molecular and serological diagnosis of Bartonella infection in 61 dogs from the United States, J Vet Intern Med 25:805, 2011. Pesavento PA et al: Pathology of Bartonella endocarditis in six dogs, Vet Pathol 42:370, 2005. Raoult D et al: Outcome and treatment of Bartonella endocarditis, Arch Intern Med 163:226, 2003. Reynolds HR et al: Sensitivity of transthoracic versus transesophageal echocardiography for the detection of native valve vegetations in the modern era, J Am Soc Echocardiogr 16:67, 2003. Rolain JM et al: Bactericidal effect of antibiotics on Bartonella and Brucella spp.: clinical implications, J Antimicrob Chemother 46:811, 2000. Sisson D, Thomas WP: Endocarditis of the aortic valve in the dog, J Am Vet Med Assoc 184:577, 1984. Sykes JE et al: Clinicopathologic findings and outcome in dogs with infective endocarditis: 71 cases (1992-2005), J Am Vet Assoc 228:1735, 2006a. Sykes JE et al: Evaluation of the relationship between causative organisms and clinical characteristics of infective endocarditis in dogs: 71 cases (1992-2005), J Am Vet Assoc 228:1723, 2006b. Timian J, Yoshimoto SK, Bruyette DS: Extraskeletal osteosarcoma of the heart presenting as infective endocarditis, J Am Anim Hosp Assoc 47(2):129, 2011 Wilson W et al: American Heart Association Rheumatic Fever, Endocarditis and Kawasaki Disease Committee, Council on

WEB CHAPTER  62  Mitral Valve Dysplasia Cardiovascular Disease in the Young; Council on Clinical Cardiology; Council on Cardiovascular Surgery and Anesthesia; Quality of Care and Outcomes Research Interdisciplinary Working Group; American Dental Association. Prevention of infective endocarditis: guidelines from the American Heart Association: a guideline from the American Heart Association Rheumatic Fever, Endocarditis and Kawasaki Disease

WEB CHAPTER 

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Committee, Council on Cardiovascular Disease in the Young, and the Council on Clinical Cardiology, Council on Cardiovascular Surgery and Anesthesia, and the Quality of Care and Outcomes Research Interdisciplinary Working Group, J Am Dent Assoc 138(6):739, 747, 2007. Zeaiter Z et al: Diagnosis of Bartonella endocarditis by a real-time nested PCR assay using serum, J Clin Microbiol 41:919, 2003.

62 

Mitral Valve Dysplasia BARRET J. BULMER, North Grafton, Massachusetts

A

ppropriate opening and closing of the mitral valve allows unimpeded left ventricular filling and prevents valvular regurgitation. These functions depend on the integrated activity of all anatomic components of the mitral valve apparatus. Disruption or malformation of any of these components, including the mitral leaflets, the chordae tendineae, the mitral annulus, the left atrial wall, the papillary muscles, or the left ventricular wall, may produce valve dysfunction. Although acquired degenerative valve disease is the most common cause of mitral valve dysfunction in dogs, it should be recognized that mitral valve dysplasia (MVD) is a common form of congenital heart disease in both dogs and cats. Currently MVD may have surpassed ventricular septal defect as the most common congenital anomaly in cats. Alterations in cases of MVD include annular enlargement; short, thick leaflets with an occasional cleft; short and stout or long and thin chordae tendineae; upward malposition of atrophic or hypertrophic papillary muscles; and insertion of one papillary muscle directly into one or both leaflets (Liu and Tilley, 1975). Animals that appear to be overrepresented include cats of all breeds, Great Danes, German shepherds, bull terriers, golden retrievers, Newfoundlands, dalmatians, and Mastiffs (Oyama et al, 2005). A recent study suggests that male cats as well as Siamese and Siamese-cross cats are more commonly affected with supravalvular mitral stenosis (Campbell and Thomas, 2012).

Pathophysiology The pathophysiologic consequences of MVD relate to (1) systolic regurgitation of blood from the left ventricle into the left atrium, (2) impaired left ventricular diastolic filling across a stenotic mitral valve, or (3) obstruction to left ventricular ejection in cases of inappropriate systolic displacement of the mitral valve into the left ventricular

outflow tract. More than one functional disturbance can occur in the same animal. Like acquired degenerative mitral valve disease, congenital insufficiency of the mitral valve produces volume overload of the left atrium and left ventricle. The two primary determinants of the volume of insufficiency are the regurgitant orifice area and the left ventricular–to–left atrial pressure gradient. Therefore animals with a large regurgitant orifice area and those that must generate greater left ventricular pressures (e.g., due to MVD complicated by subaortic stenosis) experience greater hemodynamic consequences than animals with small leaks and unimpeded left ventricular ejection. As the left atrial, pulmonary venous, and pulmonary capillary pressures rise secondary to the volume overload, left-sided heart failure develops with accumulation of fluid within the pulmonary interstitium and alveoli. If the valvular dysfunction is manifested primarily as stenosis, it produces a different range of pathophysiologic consequences. Lesions that restrict pulmonary venous return and left atrial emptying, including mitral stenosis, supravalvular mitral stenosis, and cor triatriatum sinister, are accompanied by elevated left atrial and pulmonary venous pressures. The severity of this pressure increase depends on the resistance of the stenotic valve and the volume of transmitral flow, which increases during exercise. In the initial stages of the disease the increased pressure maintains an adequate gradient for left ventricular filling. This elevated pressure gradient contributes to left atrial enlargement and hypertrophy, pulmonary venous congestion, and pulmonary edema because of increased pulmonary capillary hydrostatic pressure. The chronic hypoxia associated with lack of alveolar ventilation, and perhaps responses related to elevated left atrial pressures, may produce reactive pulmonary arterial vasoconstriction in an attempt to diminish ventilation-perfusion mismatch. Ultimately, right ventricular dysfunction and

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right-sided heart failure may develop from the pressure overload associated with long-standing pulmonary hypertension. The third alteration that may accompany MVD is systolic displacement of the anterior mitral valve leaflet, a chordae tendineae, or a papillary muscle into the left ventricular outflow tract. Although systolic anterior motion (SAM) or dynamic left ventricular outflow tract obstruction is most frequently associated with hypertrophic cardiomyopathy, it also may stem from mitral dysplasia independent of septal hypertrophy. Several mechanisms have been hypothesized for this association, including (1) a decrease in the ability of the papillary muscles to restrain the valve posteriorly, and (2) an interposition of the leaflets anteriorly into the outflow stream, which then propels them anteriorly into the outflow tract, and a geometry for mitral valve coaptation that favors SAM (Levine et al, 1995). Consequences of SAM include increases in systolic left ventricular pressure, wall tension, and myocardial work (promoting concentric hypertrophy); increased myocardial oxygen demand; reduced coronary perfusion pressure as aortic diastolic pressure falls and left ventricular diastolic pressure rises; and mitral regurgitation caused by incomplete valve closure (Sherrid, 1998).

Diagnosis History and Physical Examination As is true for many forms of congenital heart disease, animals with MVD commonly are identified before the development of clinical signs because of abnormal findings on cardiac auscultation during the initial veterinary examination. The absence of clinical signs often continues for a variable period of time until owners begin to recognize evidence of left-sided heart failure (e.g., coughing, tachypnea, restlessness, and exercise intolerance). Uncommonly, animals with mitral stenosis also may display evidence of right-sided heart failure (e.g., abdominal distention secondary to ascites formation and tachypnea resulting from pleural effusion). Severe mitral stenosis can be associated with recurrent bouts of flash pulmonary edema or hemoptysis. Less common historical complaints may include syncope, and on occasion animals may die suddenly without any history of clinical signs. The wide range of phenotypic expressions and pathophysiologic consequences of MVD produce a variety of abnormal physical examination findings. Regardless of whether the valve primarily is insufficient or stenotic or displays SAM, the most common auscultatory abnormality is a left apical systolic murmur of mitral valve regurgitation. Careful auscultation in animals with mitral stenosis may identify a left apical diastolic rumbling murmur of mitral valve stenosis, whereas patients with SAM often have a left-sided systolic murmur that varies in intensity directly with the heart rate (and sympathetic tone) and some exercise or other provocation may be required for the abnormality to be identified clearly. Additional abnormal cardiac auscultatory findings may include S3 or S4 gallops, a variety of supraventricular or ventricular

arrhythmias, and on very rare occasions an audible systolic click or opening snap. Animals with pulmonary edema may have increased bronchovesicular sounds or crackles, whereas those with pleural effusion may have muffled heart and lung sounds. Jugular venous distention or pulsation, hepatojugular reflux, ascites, and hepatomegaly may signify the presence of right-sided heart failure.

Electrocardiography Electrocardiographic alterations that may be identified in animals with MVD include chamber enlargement patterns, arrhythmias, and potentially ST-segment alterations. An increased R wave amplitude and prolonged QRS duration may accompany left ventricular enlargement, whereas a prolonged or widened P wave classically is associated with left atrial enlargement (although tall P waves also may be encountered). If significant right ventricular enlargement is present as a result of mitral stenosis and pulmonary hypertension, deep S waves (in leads I, II, aVF, and V2 to V4), and a right-axis shift in the mean electrical axis may be identified. Small-amplitude QRS complexes (30%) and high mortality rates (18% to 38%) following surgery. Complications included continued obstruction from edema at the surgical site, urine leakage, recurrent obstruction from stones remaining in the renal pelvis, and ureteral stricture formation. Nevertheless, the survival rates were dramatically higher for cats that underwent surgery and had ureteroliths removed than for those treated with medical management alone (Kyles et al, 2005). Lessinvasive, safer, and more effective alternatives certainly are desired, and interventional/endourologic options effectively have replaced open ureteral surgery in human medicine. The placement of a double-pigtail ureteral stent, nephrostomy tube, or ureteral bypass device could potentially circumvent the complications of surgery (e.g., leakage, stricture, and reobstruction), while quickly and efficiently stabilizing the patient, decreasing renal pelvic pressure, and stopping the cycle of pressure-induced nephron death. To date over 200 cats and 150 dogs have been treated in the authors’ practice for ureteral obstructions with the following interventional therapies. These techniques can be applied for all causes of ureteral obstructions including tumors, strictures, and stones.

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SECTION  IX  Urinary Diseases

A

B

C

D Figure 195-3  Placement of a percutaneous nephrostomy tube using the Seldinger technique

under fluoroscopic guidance. A, Renal access is obtained using an 18-gauge renal access needle (white arrow) under ultrasonographic and fluoroscopic guidance. B, A 0.035-inch angled guidewire (black arrows) is advanced through the needle and curled inside the renal pelvis. C, A locking-loop pigtail catheter is advanced over the guidewire (black arrow) until the entire loop is inside the renal pelvis (white arrows). D, The guidewire is removed and the locking string is pulled to lock the catheter (arrows) in place.

7.5%, and no cat died because of surgical complications or associated with their ureteral obstruction. The rate of short-term complications (occurring within 1 month of stent placement) was 8%. Complications include stent misplacement, ureteral tear during stent placement, and urine leakage at a ureterotomy site that was performed concurrently. Urine leakage resolved following closed abdominal suction in all cases without the need for  further intervention. The long-term com­plications (occurring after 1 month) were minor and included dysuria, stent migration, ureteral reaction to the stent, and occlusion around the stent (Berent et al, 2011). The most worrisome long-term complication of ureteral stenting is an occlusion of the stent. This is most commonly seen at the site of a stricture, which either was the primary obstructive lesion or developed after a ureterotomy was performed. This is most commonly seen 3 to 6 months after stent placement. The authors typically recommend placement of a SUB device (see next section) rather than a ureteral stent in cats with a known ureteral stricture. Overall, stenting is safe and effective in both dogs and cats, with very low perioperative complications; if a complication occurs

with the stent in the long term, it is usually minor, requiring an outpatient stent exchange or some medications to address dysuria. To date, the authors have placed stents successfully in over 250 dog or cat ureters for various clinical purposes, and outcomes have been excellent. Subcutaneous Ureteral Bypass (SUB) Device Placement Placement of a nephrostomy tube has been very useful in veterinary medicine when renal pelvic drainage is required (Figure 195-5). The biggest limitation of nephrostomy tubes is the external drainage apparatus, which requires hospitalization and intensive care management to prevent infection or dislodgement. The authors developed an indwelling nephrostomy device for veterinary patients using a combination locking-loop nephrostomy catheter and cystostomy catheter. This SUB device has a subcutaneous port that can be sampled and flushed as needed. In humans, a similar device has been shown to reduce the complications associated with externalized nephrostomy tubes and to improve patients’ quality of life. The successful use of a SUB device in 23 cats and 2 dogs has been described recently (Berent, Weisse, and Bagley,

CHAPTER  195  Interventional Strategies for Urinary Disease

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Urinary Bladder and Urethra Antegrade Urethral Catheterization

A

B Figure 195-4  Radiograph of a feline patient before (A) and

after (B) ureteral stent placement. Notice the numerous ureteroliths and nephroliths present (arrow). The double-pigtail ureteral stent goes from the renal pelvis to the urinary bladder (white arrows) with the shaft travelling down the entire length of the ureter (black arrows).

Figure 195-5  Lateral radiograph of a cat with a subcutaneous ureteral bypass device placed for a ureteral obstruction.

2011), and over 100 of these devices have been placed to date in our practice. Subcutaneous ureteral bypass is typically reserved for cases in which a ureteral stent cannot be placed or is contraindicated, such as those involving ureteral strictures or severe ureteritis. The perioperative, short-term, and long-term complication rate with the new commercially available product is very low (~5%). To prevent occlusion of the device regular flushing through the subcutaneous port is recommended (see Figure 1965). At this time, the authors are performing this routinely for feline ureteral obstructions, of any cause, due to the lower rate of dysuria and reocclusion compared with feline ureteral stents. In dogs ureteral stenting is still considered ideal, and a SUB device is considered a salvage procedure.

Transurethral catheterization is a simple and routine procedure and is used primarily to establish urinary drainage in patients with a urethral obstruction. Occasionally, standard retrograde catheterization can be difficult; for example, in very small female dogs or cats, females with obstructive tumors, or male cats with urethral tears or significant urethral trauma. With fluoroscopic guidance, percutaneous transvesicular catheterization can be performed in an antegrade manner. An 18-gauge catheter is advanced into the bladder to facilitate placement of a guidewire, which is passed through the urethra to the outside; then a small-diameter catheter is threaded over the guidewire. Minimally invasive antegrade catheterization can help to avoid the need for emergency surgical intervention in patients with obstruction and is especially valuable in managing urethral tears.

Urethral Stenting for Malignant Obstructions Malignant obstructions of the urethra can cause severe dysuria and life-threatening azotemia in dogs. Transitional cell carcinoma affecting the bladder trigone, urethra, or prostate is encountered most commonly. Chemotherapy has been successful in slowing tumor growth in many cases; however, more aggressive debulking or diversion has been necessary to prolong good-quality life when obstruction occurs. Cystostomy tube drainage, transurethral resection or ablation, and surgical diversion have been described but are invasive procedures and often have poor outcomes. Placement of a self-expanding metallic stent using fluoroscopic guidance is fast, reliable, and safe in establishing urethral patency in both male and female dogs with malignant obstruction. Using transurethral retrograde access, contrast cystourethrography is performed, and measurements of the normal urethral diameter and obstruction length are obtained (Figure 195-6). An appropriately sized selfexpanding metallic stent is chosen to cross the entire obstruction. The stent is deployed under fluoroscopic guidance, and repeat contrast cystourethrography is performed to document restored urethral patency. Stent placement typically is performed as outpatient procedure. The authors have found the procedure to be successful in 97% of attempts. The major adverse effect of urethral stent placement is moderate-to-severe urinary incontinence, which has been reported to occur in approximately 25% of both male and female dogs regardless of stent diameter or length. Overall, the median survival time after urethral stenting for carcinoma of the urinary tract was 78 days, but for dogs receiving adjunct chemotherapy it improved to 251 days (Blackburn et al, 2010). Urethral stenting also may be useful in patients with benign urethral strictures when traditional therapies have failed or when surgery is refused or not indicated. The authors have long-term experience with dogs and cats that underwent stenting for benign strictures, with some stents in place for over 5 years without complications. To

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5 mm

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B

C

Figure 195-6  Fluoroscopic images of a dog with urethral and prostatic carcinoma before and

after urethral stent placement (cranial is left and caudal is right). A, A urethrocystogram outlining the obstruction and tumor inside the urethra (arrows) and extravasation of contrast into the cystic prostate (white asterisk). The urethra is measured for appropriate stent placement (lines) using a colonic marker catheter to adjust for magnification. B, The self-expanding metallic stent (SEMS) (arrowhead) is advanced over the guidewire and situated across the obstructive lesion. C, The SEMS is deployed under fluoroscopic guidance to provide urethral patency. Some tumor is seen (asterisk) caudal to the stent and the obstruction is no longer present.

date over 150 urethral stents have been placed in the authors’ practice.

Intraarterial Chemotherapy for Lower Urinary Tract Neoplasia

Bladder and Urethral Stone Treatment

Transitional cell carcinoma is the most common tumor of the canine urinary tract. Unfortunately, this disease often is diagnosed at an advanced stage, and a majority of animals are euthanized because of failure to control the local disease within the urinary tract. Current treatments include chemotherapy, radiation therapy, and surgical debulking, but none consistently produces durable remissions. Research suggests that these tumors can respond more favorably to higher concentrations of chemotherapy drugs or nonsteroidal antiinflammatory medications; however, both classes of drugs have significant deleterious adverse effects, which limits the systemic doses that can be administered. Recent advancements in IR now enable the administration of therapeutic agents directly into the arteries feeding the actual tumors via femoral or carotid arterial access (Figure 195-7). High regional drug concentrations can be achieved within the tumor without amplification of the systemic adverse effects. Studies confirm both higher levels of chemotherapy agents within the targeted tissues and improved tumor remissions in laboratory animals. Intraarterial delivery of carboplatin and meloxicam, as well as other agents, has been performed safely in dogs with carcinoma of the urinary tract. Investigation into intraarterial delivery of other chemotherapeutic agents currently is under way.

Numerous minimally invasive stone-retrieval techniques currently are available in veterinary medicine, including voiding urohydropropulsion, cystoscopic stone basketing, cystourethroscopically guided laser lithotripsy, and percutaneous cystolithotomy. Other chapters in this text discuss a majority of these in more detail. Stone Basketing Basket retrieval of bladder and urethral stones is performed routinely in both male and female dogs and female cats. This procedure is accomplished by transurethral cystourethroscopy. Stones of less than 5 mm in female dogs and 3 mm in male dogs and female cats routinely can be retrieved. This procedure typically is done on an outpatient basis. Percutaneous Cystolithotomy The newer minimally invasive technique termed percutaneous cystolithotomy (PCCL) (Runge et al, 2011) combines cystic and urethral stone retrieval for animals of any size, sex, or species, and stones of any size or number. This procedure is very easy to perform in both cats and dogs. An approximately 1-cm incision is made over the apex of the bladder appreciated during digital palpation. Then three stay sutures are placed to secure the bladder up to the incision so that a port can be placed at the apex. Antegrade cystoscopy (both rigid and flexible) then is performed, and a stone-retrieval basket is used for calculi removal. PCCL also allows for excellent visualization of the bladder, urethra, and ureterovesicular junction and assists in various interventions (upper and lower tract) when needed. PCCL currently is the procedure of choice in the authors’ practice for the retrieval of cystic or urethral calculi in cases that do not fit the criteria for other minimally invasive techniques. A similar technique is described in more detail in Chapter 199.

Cystoscopic-Guided Laser Ablation of Ectopic Ureters (CLA-EU) Pharmacologic and endoscopic treatments for urethral sphincter mechanism incompetence are discussed in other chapters of this text and the accompanying electronic resources. Less commonly, incontinence is caused by congenital ectopic ureters, in which the ureteral orifice is positioned distal to the bladder trigone within the ureter, vagina, vestibule, or uterus. Over 95% of ectopic ureters traverse intramurally and exit into the urethra and are candidates for a minimally invasive IE procedure.

CHAPTER  195  Interventional Strategies for Urinary Disease

Figure 195-7  Fluoroscopic image of a dog with prostatic carcinoma during intraarterial chemotherapy delivery. Digital subtraction angiography is being used to view the caudal pudendal and prostatic arteries, which are feeding the caudal vesicle and urethral arteries. This patient also has a urethral stent in place.

Endoscopic repair of ectopic ureters has been performed over the past 5 to 7 years in male and female dogs and cats using fluoroscopy, cystoscopy, and a diode or holmium:YAG laser. The laser is applied to transect the medial side or the membrane of the ectopic ureter to separate the ureter from the normal trigone and urethra. The procedure can be performed on an outpatient basis at the same time as cystoscopic diagnosis of ectopic ureter(s) is made, which avoids the need for more than one anesthetic procedure for fixation. During the CLA-EU procedure various vaginal anomalies can be treated simultaneously as well (dual vagina, vaginal septum, persistent paramesonephric remnants). However, many affected dogs have concurrent urethral incompetence and require additional medication or procedures. A prospective study of CLA-EU in 30 female dogs was reported recently and showed an overall urinary continence rate of 77% after CLA-EU with the addition of medical management, collagen injections, or placement of a hydraulic occluder (Berent et al, 2012a). The success rate of the CLA-EU procedure alone in female and male dogs is 56%. The addition of a hydraulic occluder may increase the continence rate to nearly 90% (Figure 195-8).

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A

B

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D Figure 195-8  Endoscopic images of a female dog in dorsal recumbency during cystoscopically

guided laser ablation of intramural ectopic ureters. A, The urethroscopic image shows the urethral lumen (asterisk) and the ectopic ureteral opening. B, A ureteral catheter (black arrow) is advanced into the ureteral lumen, and the urethral lumen is seen just ventral (asterisk). C, A laser (short arrow) is used to ablate the common wall between the urethra (asterisk) and the ureter (long arrow) inside the urethral lumen. D, Once the laser ablation is complete the ureteral opening is successfully advanced to the level of the urinary bladder (asterisk). A guidewire sits inside the ureteral lumen, and it is seen here to exit at the new ureteral orifice. Notice that there is no bleeding associated with this procedure.

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References and Suggested Reading Berent A: Ureteral obstructions in dogs and cats: a review of traditional and new interventional diagnostic and therapeutic options, J Vet Emerg Crit Care 21(2):86, 2011. Berent A et al: Ureteral stenting for feline ureteral obstructions: 79 ureters with ureterolithiasis, 21st European College of Veterinary Internal Medicine—Companion Animals Congress, Sevilla, Spain. J Vet Intern Med 25(6):1506, 2011 (abstract). Berent A et al: Prospective evaluation of cystoscopic guided laser ablation of intramural ectopic ureters in female dogs: 30 cases (2006-2009), J Am Vet Med Assoc 240:716, 2012a. Berent A et al: Use of locking-loop pigtail nephrostomy catheters in dogs and cats: 20 cases (2004-2009), J Am Vet Med Assoc 241:348, 2012b. Berent A, Weisse C, Bagley D: The use of a subcutaneous ureteral bypass device for ureteral obstructions in dogs and cats. American College of Veterinary Internal Medicine Forum, Denver, Colorado, J Vet Intern Med 25(3):632, 2011 (abstract). Berent A, Weisse C, Beal M: Use of indwelling, double pigtail ureteral stents for the treatment of malignant ureteral

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obstructions in dogs: 12 cases (2006-2009), J Am Vet Med Assoc 238(8):1017, 2011. Blackburn A, Berent A, Weisse C: The use of self expanding urethral stents for the treatment of urothelial carcinoma: 42 dogs, American College of Veterinary Internal Medicine Forum, 2010, Anaheim, California, J Vet Intern Med 24(6):1577, 2010 (abstract). Gookin JL et al: Unilateral nephrectomy in dogs with renal disease: 30 cases (1985-1994), J Am Vet Med Assoc 208:2020, 1996. King MD et al: Effect of nephrotomy on renal function and morphology in normal cats, Vet Surg 35:749, 2006. Kyles A et al: Management and outcome of cats with ureteral calculi: 153 cases (1984-2002), J Am Vet Med Assoc 226(6):937, 2005. Runge J et al: Transvesicular percutaneous cystolithotomy for the removal of cystic calculi in dogs, J Am Vet Med Assoc 239:344, 2011. Weisse C et al: Potential applications of interventional radiology in veterinary medicine, J Am Vet Med Assoc 233(10):1564, 2008.

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Medical Management of Nephroliths and Ureteroliths JESSICA E. MARKOVICH, North Grafton, Massachusetts MARY ANNA LABATO, North Grafton, Massachusetts

Prevalence and Predisposition Upper urinary tract uroliths currently represent approximately 3% of all uroliths submitted to the Minnesota Urolith Center (Albasan et al, 2009). Any of the uroliths typically identified in the lower urinary tract also can be found in the upper urinary tract; however, the prevalence of stone types does differ slightly. In cats, 70% to 98% of analyzed uroliths are calcium oxalate in composition, whereas the remaining 2% to 30% are calcium phosphate, magnesium ammonium phosphate (struvite), and dried solidified blood calculi (Osborne et al, 2009; Westropp et al, 2006). In dogs, there is nearly an equal distribution of calcium oxalate and struvite uroliths in submitted upper tract stones (Ling et al, 1998; Snyder et al, 2005). Female dogs are more likely to form nephroliths than male dogs. Canine breeds at increased risk include the miniature schnauzer, Lhasa apso, Shih Tzu, and Yorkshire terrier. As with uroliths in the lower urinary tract, male dalmatians are more predisposed than females to the development of urate nephroliths. Cats differ from dogs

in that there is no gender predisposition to the development of renal calculi or ureteroliths, and domestic shorthairs and longhairs are the most commonly affected breeds. Both cats and dogs tend to be middle-aged or older at the time of initial presentation (mean age, 8 years) (Kyles et al, 2005a; Ling et al, 1998).

Diagnosis Clinical signs associated with nephrolithiasis and ureterolithiasis may be completely absent or may include nonspecific signs such as vomiting, anorexia, weight loss, and lethargy. Abnormalities noted on physical examination may include pyrexia, pain on abdominal palpation, and enlarged or asymmetric kidneys (i.e., big kidney, little kidney). Clinicopathologic abnormalities may include hyperkalemia, hypercalcemia, hyperphosphatemia, azotemia, anemia, and a neutrophilic leukocytosis. Hematuria, pyuria, proteinuria, crystalluria, and bacteriuria all may be noted on routine urinalysis. Urine culture is an essential component of the diagnostic workup, and an

CHAPTER  196  Medical Management of Nephroliths and Ureteroliths estimated one third of cats and two thirds of dogs with ureterolithiasis have been found to have a concurrent bacterial infection.

Imaging Radiography Although a clinical suspicion may be present based on physical examination findings, definitive diagnosis is obtained via imaging. Abdominal radiography generally is the first-line diagnostic imaging modality used to evaluate the urinary tract for radiopaque uroliths. With radiography, the exact location and number of uroliths often can be determined, whereas these sometimes can be difficult to distinguish with other forms of imaging. On the other hand, radiography has the distinct limitation of being able to identify only radiopaque uroliths, and thus dried solidified blood calculi, mucus plugs, and radiolucent uroliths potentially can be missed. Furthermore, overlapping visceral organs occasionally can make diagnosis difficult; abdominal preparation with enemas is necessary if fecal material obscures the ureteral paths. The sensitivity of abdominal radiography for the diagnosis of ureteroliths was 81% in one feline study and 88% in one canine study (Kyles et al, 2005a; Snyder et al, 2005). Ultrasonography Parenchymal hyperechogenicity, perirenal effusion, and ureteral wall thickening may be observed on ultrasonographic examination. Although dried solidified blood calculi, mucus plugs, and radiolucent uroliths can be challenging to visualize via ultrasonography, renal pelvic and ureteral dilation would support a diagnosis of ureteral obstruction. Marked hydronephrosis or hydroureter may be noted with prolonged or complete obstruction. The sensitivity of abdominal ultrasonography was 77% for the detection of feline ureteroliths in one retrospective series, whereas in one canine study, sensitivity reached 100% (Kyles et al, 2005a; Snyder et al, 2005). Abdominal ultrasonography and radiography are best used as complementary imaging modalities. When ultrasonography and radiography were evaluated in tandem, sensitivity for detection of uroliths was 90% in cats with ureteral obstruction (Kyles et al, 2005a). In dogs, ureteroliths and nephroliths were identified during ultrasonographic examination that were missed on abdominal radiographs (Snyder et al, 2005). Other Modalities When the location and degree of ureteral obstruction are difficult to document definitively, advanced techniques occasionally must be used to aid diagnosis and planning. One such technique is antegrade pyelography, in which a contrast agent is injected directly into the renal pelvis with ultrasonographic guidance, which minimizes systemic absorption. Fluoroscopy or serial radiography follows the flow toward the urinary bladder. Antegrade pyelography has a high specificity for ureteral obstruction; in a retrospective study of 11 cats with 18 obstructed kidneys, antegrade pyelography allowed correct identification of the anatomic location of the ureteral obstruction in 13 (72%) of the ureters (Adin et al, 2003). However,

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leakage of contrast material developed in 8 of 18 kidneys (44%) and prevented diagnostic interpretation in 5 of 18 studies (28%). Although highly useful, antegrade pyelography requires general anesthesia and a skilled sonographer. Hemorrhage also is a possible complication of the technique.

Treatment Medical Management Conservative Management of Nephroliths Most nephroliths initially are managed conservatively and never require further intervention. The majority of nephroliths in dogs are asymptomatic. Nephroliths have not been associated with an increase in disease progression or poorer outcome in cats with concurrent kidney disease and nephrolithiasis compared with cats with chronic kidney disease alone (Ross et al, 2007). Nephroliths can become damaging to renal function and patient comfort, however, when they contribute to recurrent urinary tract infection or obstruction. In 2006, Dalby and colleagues described seven cases of spontaneous retrograde movement of ureteroliths in two dogs and five cats. Based on this observational study, the authors theorized that some mobile nephroliths may contribute to continued kidney injury by intermittent obstruction of the ureter. The location of the nephrolith may influence the risk of obstruction; nephroliths that are located within the renal interstitium certainly pose less threat of intermittent obstruction than nephroliths located within the renal pelvis. Indications and options for intervention in cases of problematic nephroliths are discussed further in Chapter 195. Management of Concurrent Urinary Tract Infection In two studies of dogs with upper urinary tract urolithiasis, 65% to 70% of dogs had a concurrent urinary tract infection (Ling et al, 1998; Snyder et al, 2005). The most commonly observed bacteria were Staphylococcus intermedius, Escherichia coli, Proteus mirabilis, and Streptococcus spp, and infection was recognized more commonly in female than in male dogs. Cats with urolithiasis less commonly have an associated concurrent infection than do dogs, although approximately one third of cats have a bacterial infection (Ling et al, 1998). Antibiotic therapy should be guided by urine or urolith culture results and should be continued for a minimum of 4 to 6 weeks, with repeat urine cultures performed 1 to 2 weeks after the initiation of antibiotic therapy and 1 week after the completion of therapy (Weese et al, 2011). If the patient has concurrent azotemia, then the possibility of pyelonephritis should be considered and the duration of antibiotic therapy should be 6 to 8 weeks, with cultures performed every 2 weeks during therapy and 1 to 2 weeks after  the termination of treatment. In dogs, in which 50%  of nephroliths are struvite (infection-induced) uroliths, antibiotics may need to be administered for as long as  2 to 3 months before there is complete dissolution.  Some dogs have had documented negative results on cultures of lower urinary tract specimens, but positive results on cultures of samples from the upper urinary

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tract, particularly when the infection is associated with urolithiasis or antibiotics were administered before culture (Snyder et al, 2005). Diuresis to Promote Ureterolith Passage The ideal outcome of medical management of ureterolithiasis is that the urolith passes into the urinary bladder to be voided or removed. Medical dissolution of ureteroliths is not likely because ureteroliths are not bathed continuously in urine and most ureteroliths are composed of calcium oxalate and are not amendable to dissolution. The optimal time to allow for passage of ureteroliths by medical management is unknown, but the authors typically attempt medical management for a period of 2 to 3 days depending on the patient’s clinical status and the owner’s wishes. In one study of 52 cats with ureterolithiasis that underwent medical management, 7 cats (13.5%) responded with a significant decrease in serum creatinine concentration (Kyles et al, 2005b). Aggressive intravenous fluid therapy is recommended in an attempt to push the urolith along the ureter. Typically, the authors administer 80 to 120 ml/kg/day of crystalloids depending on the patient’s cardiovascular status. Continued administration of fluids to patients with poor urine output can lead to overhydration, as can overzealous diuresis in an attempt to flush out stones. Careful monitoring of body weight, hydration status, and urine production are key in the management of obstructive ureteroliths. Pharmacologic Agents Pharmaceutical options to promote the movement of nephroliths and ureteroliths are limited, with few studies to validate their use in veterinary medicine. In human medicine, α2-antagonists are considered the standard of care for ureteral dilation. Consequently, a number of α2antagonists have been investigated experimentally in dogs to evaluate their ureteral dilatory effects. The α2antagonists vary greatly in their selectivity, particularly in regard to ureteral dilatory effects. Phenoxybenzamine is a nonselective, noncompetitive antagonist, whereas the newer α2-antagonists such as prazosin and tamsulosin all are variably selective. Possible adverse effects of all of the α2-antagonists include hypotension, sedation, and occasionally urinary incontinence. The authors typically administer prazosin at a dosage of 0.25 to 0.50 mg q12-24h PO in cats and 1 mg/15 kg q12h PO in dogs. Blood pressure should be monitored, particularly in the first few days after initiation of therapy, because profound hypotension can occur in some animals. A tricyclic antidepressant, amitriptyline, may be of assistance both by modulating the pain associated with the ureteral obstruction and by acting as a ureteral relaxant by causing the opening of voltage-gated potassium channels in smooth muscle. One report described the use of amitriptyline in cats with obstructed urethras and demonstrated in vitro relaxant effects on the porcine and human ureter (Achar et al, 2003). Recommended dosages of amitriptyline vary (1 to 2 mg/kg q24h PO); in cats, a starting dose of one 10-mg tablet per cat is recommended because of the extremely bitter taste of the medication when split or compounded into a liquid.

Glucagon is a hormone that is produced naturally by the pancreas and is known to have a variety of physiologic effects, including ureteral dilation and relief of pain associated with ureteral obstruction in people. One prospective study evaluating the intravenous administration of glucagon to cats with ureteral obstruction found that glucagon may promote urination in some cats; however, no long-term benefits were noted (Forman et al, 2004). Possible adverse effects of glucagon include significant functional gastrointestinal ileus with resultant diarrhea or vomiting, and respiratory effects such as tachypnea or dyspnea. Described intravenous dosages vary greatly and range from 0.05 to 0.1 mg per cat q6-24h. This medication should be administered with caution, and blood glucose and potassium levels should be monitored regularly with usage. In addition to fluid diuresis, administration of diuretic agents, particularly osmotic diuretics such as mannitol, has been advocated but has not been evaluated prospectively or retrospectively in feline or canine patients with ureteral obstruction. The theory behind the use of diuretics is to increase the glomerular filtration rate and raise the intraureteral luminal pressure to push the ureterolith into the urinary bladder. These medications should be used concurrently with intravenous fluids so that the patient does not become systemically dehydrated or experience further kidney injury. At the authors’ hospital, furosemide is used most frequently at a dosage of 0.5 to 1 mg/kg/hr after a 1- to 2-mg/kg initial bolus. Kidney function values and electrolyte levels should be monitored every 6 to 12 hours during the continuous administration of diuretics for ureteral obstruction. Pain Management Ureteral obstruction can be very painful, and use of opioid pain medications is recommended until the obstruction is resolved. Morphine specifically is not recommended, however, because in one in vitro canine ureteral study morphine was found to have spasmogenic effects that were not reversed by the administration of naloxone (Lennon et al, 1993). Meperidine, on the other hand, initially did cause ureteral spasms transiently, followed by complete inhibition of activity. The effects of meperidine also were not affected by naloxone (Lennon et al, 1993). The effects of other opioids on ureteral contraction have not been evaluated thus far in the canine or feline patient. Nonsteroidal antiinflammatory medications (NSAIDs) are not recommended at this time because of the potential for worsening kidney injury; however, NSAIDs currently are considered one of the first-line therapies in the  treatment of renal colic in people (Yilmaz et al, 2009). Certain nonsteroidal agents—namely, diclofenac and indomethacin—were shown in one in vitro canine study to have spasmolytic effects on the canine ureter (Lennon et al, 1993). Further studies are indicated as to the role of NSAIDs in canine and feline ureterolithiasis. The canine ureter has been shown to contain histamine receptors, both histamine-1 (H1) and H2 (Dodel et al, 1996). Interestingly, the two histamine receptors appear to demonstrate opposite but uneven clinical effects on the canine ureter in in vitro studies. The H1 receptors demonstrate a contractile response, whereas the

CHAPTER  196  Medical Management of Nephroliths and Ureteroliths H2 receptors show a relaxant response and generally are activated after the stimulation of the H1 response (Dodel et al, 1996). Chlorpheniramine, an H1 receptor antagonist, has demonstrated spasmolytic effects and has been shown to directly inhibit the ureteral spasmogenic effects induced by morphine in an in vitro canine model (Lennon et al, 1993). In another in vitro canine study, the H2 receptor antagonist cimetidine was found to significantly attenuate the relaxation effect of histamine in precontracted canine ureters (Dodel et al, 1996). These effects certainly are important considerations because it is not uncommon to administer an H2-receptor antagonist to a patient with kidney disease, and this in fact may result in the inability of the body to provide relaxation of the ureter naturally. It appears wise to avoid administration of H2-receptor antagonists in dogs with ureteral obstruction until further studies are performed to specifically elucidate the role of each H2-receptor antagonist on the canine ureter. At this time, there are no similar studies analyzing the role of histamine in the feline ureter. Other pharmacologic agents may help preserve kidney function during and immediately following ureteral obstruction. In experimental studies in dogs, angiotensinconverting enzyme (ACE) inhibitors have been shown to assist in the preservation of kidney function in animals with partial unilateral ureteral obstruction and to assist in recovery of renal function after the obstruction is eliminated (Soliman et al, 2009b). Similarly, the angiotensin receptor blocker losartan exhibited promising effects on the recovery of kidney function in dogs with experimentally induced unilateral partial chronic ureteral obstruction, presumably because of vasodilation and increased renal blood flow. Further studies of losartan have been performed in rats with complete ureteral obstruction,  and losartan significantly decreased renal fibrosis, oxidative stress, and apoptosis (Soliman et al, 2009a). No studies have investigated the use of ACE inhibitors or angiotensin receptor blockers in cats with obstructive ureterolithiasis.

Advanced Supportive Modalities Dialysis The goals of hemodialysis or peritoneal dialysis in managing ureteral obstruction are multifactorial: (1) to reduce the degree of azotemia, hydration, or electrolyte derangements before induction of anesthesia for procedures or definitive treatment, (2) to provide time to treat infection, sepsis, or other concurrent abnormalities, and (3) to allow time to determine whether the ureteral calculus will pass on its own with medical management. Many of these patients have profound fluid overload, which renal replacement therapy also will normalize. Perioperative dialytic management is particularly beneficial in the patient in which kidney transplantation, ureteral surgery, or ureteral stent placement is planned. Nephrostomy Tubes Preoperative nephrostomy tube placement has goals similar to those of hemodialysis in terms of improving the stability of the patient’s condition before surgery. A benefit of nephrostomy tubes over hemodialysis is the

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immediate decompression of the renal pelvis, which decreases the compressive damage to the renal parenchyma (see Chapter 195). Nephrostomy tubes can be lifesaving and can prevent further renal damage; however, in one study approximately half of cats in which nephrostomy tubes were placed experienced complications, which included urine leakage into the peritoneal cavity, poor drainage, and tube dislodgement (Kyles et al, 2005b). Unfortunately, decompression also may reduce the antegrade pressure on the obstructing material, minimizing other efforts to promote spontaneous passage. Surgical and Interventional Therapies If medical management has failed, the patient has many ureteroliths, or several levels of the urinary tract are affected, then a surgical or interventional procedure may be recommended. The type of surgery performed depends on the location of the ureterolith within the ureter, as well as the viability of the ureter and the preference of the surgeon. A ureteral stent may be placed during surgery after stone removal or, in dogs, occasionally may be placed with a cystoscope. Interventional stenting is discussed more extensively in Chapter 195. Renal Transplantation Renal transplantation has been considered a salvage procedure for cats with renal dysfunction due to urolithiasis. In one review of feline renal transplantation over a period of 8 years, approximately one fourth of all transplants were required because of confirmed or suspected calcium oxalate urolithiasis (Aronson et al, 2006). Furthermore, 60% of these cats continued to develop uroliths despite appropriate urolith prevention therapy. However, the recurrence of kidney and ureteral calculi did not cause these cats to have a lower mean survival time than cats that did not experience urolith recurrence.

Prevention Dietary Therapy Prevention and monitoring are essential in the long-term management of this dynamic disease. Except in cases of infection-induced struvite nephroliths, stone recurrence or growth is likely in all patients with nephroliths or ureteroliths. The saturation of stone-inducing minerals can be reduced with the use of therapeutic diets. As in all urinary diseases, diets that are high in water content are most beneficial for decreasing the recurrence of urolith formation. Canned diets allow the greatest percentage of water to be added to the diet; however, adding water to a dry diet also is possible. Urolith analysis is recommended to permit the most accurate recommendations to be made for dietary composition; however, a diet can be prescribed based on the most likely urolith type. Additionally, several feline diets currently are composed and marketed for the prevention of both magnesium ammonium phosphate and calcium oxalate urolithiasis and can be prescribed if the stone type is undetermined (see Chapter 197). Finally, underlying kidney disease is common in patients with nephroliths and ureteroliths (especially cats). In cats affected with both disorders,

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dietary management for renal disease often trumps the dietary considerations for urolithiasis. Patients with International Renal Interest Society stage 2 kidney disease or higher should be started on a diet that is restricted in protein, phosphorus, and sodium (see Chapter 189).

Monitoring and Recurrence In one study, a second episode of ureterolithiasis was documented in 14 of 35 cats (40%) in which serial abdominal imaging was performed after medical or surgical management (Kyles et al, 2005b). In 12 of these 14 cats, nephroliths had been noted at the time of initial examination and had not been removed. Recurrence rates in dogs have not been reported. Serum creatinine and electrolyte levels should be monitored at a frequency determined by the degree of azotemia and clinical progress of the patient. Monitoring including abdominal radiography or ultrasonography, urinalysis, urine culture, and blood chemistry studies should be repeated every 3 months for the first year and every 6 months thereafter, or sooner in the event that any changes in behavior or clinical signs are noted at home. Therapeutic targets include a urine specific gravity of less than 1.030 for cats and less than 1.020 for dogs, minimal crystalluria, stable or decreasing azotemia, stable or improving upper tract dilation, and lack of progression in urolith size and number.

References and Suggested Reading Achar E et al: Amitriptyline eliminates calculi through urinary tract smooth muscle relaxation, Kidney Int 64:1356, 2003. Adin CA et al: Antegrade pyelography for suspected ureteral obstruction in cats: 11 cases (1995-2001), J Am Vet Med Assoc 222:1576, 2003. Albasan H et al: Rate and frequency of recurrence of uroliths after an initial ammonium urate, calcium oxalate, or struvite urolith in cats, J Am Vet Med Assoc 235(12):1450, 2009. Aronson LR et al: Renal transplantation in cats with calcium oxalate urolithiasis: 19 cases (1997-2004), J Am Vet Med Assoc 228(5):743, 2006. Dalby AM et al: Spontaneous retrograde movement of ureteroliths in two dogs and five cats, J Am Vet Med Assoc 229:1118, 2006.

Dodel RC, Hafner D, Borchard U: Characterization of histamine receptors in the ureter of the dog, Eur J Pharmacol 318(23):395, 1996. Forman MA et al: Use of glucagon in the management of acute ureteral obstruction in 25 cats. In Proceedings of the 22nd Annual ACVIM Forum, 2004. Kyles AE et al: Clinical, clinicopathologic, radiographic, and ultrasonographic abnormalities in cats with ureteral calculi: 163 cases (1984-2002), J Am Vet Med Assoc 226(6):932, 2005a. Kyles AE et al: Management and outcome of cats with ureteral calculi: 153 cases (1984-2002), J Am Vet Med Assoc 226(6):937, 2005b. Lennon GM et al: Pharmacological options for the treatment of acute ureteral colic: an in vitro experimental study, Br J Urol 71:401, 1993. Ling GV et al: Renal calculi in dogs and cats: prevalence, mineral type, breed, age, and gender interrelationships (1981-1993), J Vet Int Med 12:11, 1998. Osborne CA et al: Analysis of 451,891 canine uroliths, feline uroliths, and feline urethral plugs from 1981 to 2007: perspectives from the Minnesota Urolith Center, Vet Clin North Am 39(1):183, 2009. Ross SJ, et al: A case-control study of the effects of nephrolithiasis in cats with chronic kidney disease, J Am Vet Med Assoc 230(12):1854, 2007. Snyder DM et al: Diagnosis and surgical management of  ureteral calculi in dogs: 16 cases (1990-2003), N Z Vet J 53(1):19, 2005. Soliman SA et al: Recoverability of renal function after relief of chronic partial unilateral ureteral obstruction: study of the effect of angiotensin receptor blocker (losartan), J Urol 75:848, 2009a. Soliman SA et al: Study of the effect of angiotensin converting enzyme inhibitor (enalapril) on renal function during and after relief of partial unilateral ureteral obstruction: a controlled canine study, J Urol 181(4 Suppl):662, 2009b (abstract). Weese JS et al: Antimicrobial use guidelines for treatment of urinary tract disease in dogs and cats: Antimicrobial Guidelines Working Group of the International Society for Companion Animal Infectious Diseases, Vet Med Int 2011:263768, 2011. Westropp JL et al: Dried solidified blood calculi in the urinary tract of cats, J Vet Intern Med 20:828, 2006. Yilmaz E et al: Histamine 1 receptor antagonist in symptomatic treatment of renal colic accompanied by nausea: two birds with one stone? Urology 73(1):32, 2009.

CHAPTER 

197 

Calcium Oxalate Urolithiasis BENJAMIN G. NOLAN, Madison, Wisconsin MARY ANNA LABATO, North Grafton, Massachusetts

C

alcium oxalate (CaOx) urolithiasis is a condition affecting dogs and cats that has become more common over the last several decades (Cannon et al, 2007; Low et al, 2010). A recent study examined the composition of uroliths submitted to the Minnesota Urolith Center between the years 1981 and 2007 (Osborne et al, 2008). During this time the percentage of CaOx stones in total submissions increased from 5% to 41% in dogs, whereas that in cats increased from 2% to 41%. Concurrently, the incidence of struvite uroliths decreased from 78% to 40% in dogs and from 78% to 49% in cats. It is thought that the primary factor causing this trend was dietary modifications made to address struvite urolithiasis. Overall, the pathophysiology of CaOx urolithiasis is complex, and much still remains to be understood. This chapter outlines what we know about CaOx urolithiasis and how this knowledge can be applied to design effective therapies for this disease.

Epidemiology Dogs and cats affected with CaOx urolithiasis typically are middle-aged to older, male, and neutered. As in humans, obesity has been associated with a higher risk in dogs, but this has not yet been shown to be true for cats. Breeds of dogs most recently identified as having an increased risk of forming CaOx uroliths are the bichon frise, miniature schnauzer, Shih Tzu, Lhasa apso, Pomeranian, Cairn terrier, Yorkshire terrier, Maltese, and Keeshond. Cat breeds at higher risk include the Persian and Himalayan.

Pathophysiology The physical chemistry governing crystal formation in urine is complex, and many variables must be considered. The two major factors that affect this process are supersaturation of urine with calculogenic materials (calcium and oxalate) and the balance between substances that promote and those that inhibit CaOx formation. When urine is supersaturated with calcium and oxalate, crystal formation is more likely to occur; one measure that reflects this state is the relative supersaturation of urine (RSS). This measure is used widely to assess the risk of CaOx formation in people and is finding use in veterinary medicine as well. In one study, the CaOx RSS of stoneforming dogs was found to be significantly higher than that of control dogs (Stevenson, Robertson et al, 2003). To assess supersaturation of the urine with calculogenic materials, the relative importance of urinary water

content, calcium concentration, and oxalate concentration have been examined. Water content is perhaps the single most important variable affecting CaOx formation. Increased water dilutes the urine and increases urine volume, thereby reducing CaOx RSS. Hyperoxaluria also plays a role. Urinary excretion of oxalate depends on dietary intake, intestinal absorption, renal tubular secretion, and the rate of endogenous synthesis. Intestinal absorption is influenced by factors that determine the amount of free oxalate in the gut lumen. Calcium and magnesium both can bind oxalate, creating complexes that are excreted instead of absorbed. Intestinal flora such as Oxalobacter formigenes and lactic acid bacteria can degrade oxalate and may play a role in the pathophysiology of this disease. Hyperoxaluria due to endogenous overproduction has been found to be a primary genetic condition in people caused by metabolic defects and exists in two forms (type I and type II). A few cases of primary hyperoxaluria also have been reported in cats and appear to be most similar to the type II variant in people (DeLorenzi et al, 2005). Like oxalate excretion, urinary calcium excretion depends on dietary intake, intestinal absorption, and renal tubular excretion. Intestinal absorption of calcium is similar to that of oxalate in that calcium is poorly absorbed when it exists as a complex but is absorbed more readily when unbound. The appropriate level of calcium intake to minimize urinary CaOx RSS is thus intertwined with the amount of oxalate present, as well as the amount of other substances with which it may form complexes (e.g., phosphate). Hypercalciuria also can result from hypercalcemia, impaired tubular reabsorption of calcium (renal leak), and administration of certain drugs such as glucocorticoids or loop diuretics (e.g., furosemide). Several substances have been identified as promoting or inhibiting CaOx formation in urine. Inhibitors include magnesium, citrate, and pyrophosphate, which form soluble complexes with calcium in the urine and prevent crystal formation with oxalate. Citrate also may lower the risk of CaOx formation by alkalinizing the urine. Proteins such as nephrocalcin and Tamm-Horsfall glycoprotein interfere with CaOx crystal formation and may play an additional role. There most likely are many promoters of CaOx formation, but two that have been identified are uric acid and foreign material. Uric acid can block certain CaOx inhibitors, and a group of CaOx-forming miniature schnauzers was found to excrete significantly higher levels of uric acid than healthy controls (Lulich et al, 1991). The presence of foreign material such as intraluminal suture  897

898

SECTION  IX  Urinary Diseases

in the urinary tract can act as a nidus for crystal nucleation. The urinary pH also has been evaluated for its role in CaOx formation, and there is controversy over its importance. The absolute solubility of CaOx in urine is affected marginally over a broad pH range, but there are several reasons why a low pH may promote CaOx formation: persistent aciduria is associated with low-grade metabolic acidosis, which induces calcium resorption from bone and can increase urinary calcium excretion; acidic urine may diminish the ability of citrate and pyrophosphate to act as CaOx inhibitors; and increased reabsorption of calcium from the distal tubule occurs when the urine is alkaline. Furthermore, feeding an acidifying diet has been identified as a risk factor for CaOx formation in cats and dogs. In dogs the risk was three times higher overall (Lekcharoensuk et al, 2002), whereas in cats the risk was three times higher when diets were fed producing a urinary pH of 5.99 to 6.15 compared with diets producing a pH of 6.5 to 6.9 (Lekcharoensuk et al, 2001). Studies also have evaluated the effect of pH specifically on CaOx RSS, but results so far have been conflicting.

Diagnostic Approach The initial evaluation of a dog or cat with CaOx urolithiasis should include a thorough investigation for any underlying cause. A complete blood count, chemistry panel, urinalysis, and urine culture are considered a minimum database. If the total calcium concentration is elevated, the ionized calcium level should be measured, and if hypercalcemia is confirmed, measurement of parathyroid hormone, parathyroid hormone–related protein, and possibly serum vitamin D levels is recommended. Imaging should include both abdominal radiography and ultrasonography because in some cases stones may be missed when only one modality is used. This is especially the case for ureteroliths, which can cause severe illness. Ultrasonographic imaging also may reveal more detailed information about the urinary tract (e.g., ureteral obstruction, cystitis).

Treatment Surgical and Interventional Management There is no known protocol to dissolve CaOx uroliths at this time, and in many cases the only effective treatment is removal. Urolith removal can be achieved surgically, and less invasive methods are becoming increasingly available (see Chapters 195 and 199). Depending on the location of the urolith various techniques may be employed, such as lithotripsy (extracorporeal and intracorporeal), cystoscopic removal, or urohydropulsion. An obstructive stone also can be addressed by the placement of a stent, subcutaneous ureteral bypass device, or other interventional procedures.

Medical Management Once CaOx urolithiasis is identified, preventive medical management of this problem still is of utmost importance

because this is a chronic disease. Dietary options and medications can be used to minimize the chance of stone recurrence or further growth. Additionally, regular monitoring of the patient is needed to evaluate response to therapy and to identify new stones that may form. In the case of a stone in the upper urinary tract (ureterolith, nephrolith), medical strategies are often instituted before surgery or other procedures (see also Chapter 196). Diet Perhaps the most important dietary modification that can be made is to increase water intake and urinary volume while decreasing urine specific gravity. Retrospective studies of cats (Lekcharoensuk et al, 2001) and dogs (Lekcharoensuk et al, 2002) with CaOx urolithiasis found a significantly lower risk of CaOx formation with higher dietary moisture content. Feeding a canned diet is the best way to increase water intake, but some dogs and cats will not eat canned food. In these cases, water or broth can be added to dry food, or broth can be added to the water supply. Water fountains also may be helpful to increase water intake in cats. Appropriate targets for specific gravity are less than 1.025 in cats and less than 1.020 in dogs; achieving dilute urine can be very difficult  in cats. Supplementation of sodium chloride has been investigated as a means of increasing water consumption but has been a point of controversy. Increased sodium consumption increases urinary calcium excretion and may increase the risk of CaOx urolithiasis. However, prospective studies have shown that increasing dietary sodium content significantly decreased the CaOx RSS in healthy and CaOx stone–forming dogs (Lulich et al, 2005; Stevenson, Hynds et al, 2003) as well as in healthy cats. The total daily urinary calcium excretion increased in these studies, but apparently the effect on CaOx RSS is offset by the increase in water intake and urine volume. These findings suggest a benefit to NaCl supplementation, but long-term studies still are needed. Sodium supplementation can be considered if there is an inadequate response to dietary therapy and the urine is not dilute, but patient selection must be done carefully. Short-term studies in cats have shown no adverse effects on kidney function or blood pressure, but caution is required when considering adding salt to the diets of dogs or cats with kidney disease  or hypertension until longer-term studies are done.  Additionally, high-sodium diets are contraindicated for animals with heart disease. Higher dietary protein historically has been associated with an elevated risk of CaOx formation because it can promote acidosis and hypercalciuria. However, retrospective studies in dogs and cats have found a lower risk of CaOx formation with higher dietary protein (Lekcharoensuk et al, 2001, 2002). Overall, the exact amount and type of protein that is ideal has yet to be determined, but most diets designed to reduce CaOx urolithiasis have reduced protein levels. The importance of the calcium and oxalate content of food was demonstrated by a study in healthy dogs (Stevenson, Hynds et al, 2003). In these dogs, urinary oxalate excretion and CaOx RSS increased when oxalate intake was increased, but only when the intake of calcium was

CHAPTER  197  Calcium Oxalate Urolithiasis low. The lowest CaOx RSS was found in dogs fed a diet that was lowest in both calcium and oxalate. If only calcium or only oxalate was decreased, the CaOx RSS increased. This emphasizes the need for a balanced amount of calcium and oxalate in the diet, but in all cases high calcium or oxalate content should be avoided. Examples of high-oxalate foods are leafy green vegetables and nuts. For a more complete list of foods with high oxalate content, see the Oxalosis and Hyperoxaluria Foundation website (www.ohf.org/diet.html). Vitamin intake also can be important: hypercalciuria can result from excessive vitamin D intake because of enhanced intestinal absorption, and excessive vitamin C may promote hyperoxaluria, although this has yet to be proven in dogs and cats. A deficiency in vitamin B6 (pyridoxine) also may play a role in urinary oxalate excretion. A study in healthy kittens showed that urinary oxalate excretion was higher in those fed a diet deficient in pyridoxine than in those fed a normal amount (Bai et al, 1989). Supplementation with vitamin B6 (2 mg/kg q24-48h PO) thus can be considered as adjunct medical treatment. Three studies have prospectively evaluated the effect of commercially available urinary diets on dogs and cats with CaOx urolithiasis. The diets evaluated were canned Royal Canin Canine SO Lower Urinary Tract Support, canned Hill’s Prescription Diet Feline c/d-oxl, and canned Hill’s Prescription Diet u/d. A fourth diet is available for cats (Purina Veterinary Diets UR Urinary St/Ox Feline Formula). Unpublished work indicates that feeding this diet to normal cats yielded urine that was metastable for CaOx, which suggests that it would be an appropriate option for cats with CaOx urolithiasis. However, published studies still are needed for a more complete evaluation. In dogs fed canned Canine SO, the CaOx RSS was reduced significantly by 63% compared to that in dogs fed a maintenance diet (Stevenson et al, 2004). This group of dogs was followed for 12 months, during which time no recurrence of CaOx stones was noted. In cats fed Prescription Diet Feline c/d-oxl, the activity product ratio (measure of CaOx supersaturation) was reduced significantly by 59% compared with that in the same group of cats fed a variety of dry maintenance diets (Lulich et al, 2004b). This diet is no longer available, but Hill’s Prescription Diet c/d Multicare Feline has similar efficacy according to the manufacturer. A third study evaluated the effect of feeding canned Prescription Diet u/d to dogs with CaOx urolithiasis (Lulich et al, 2001). Compared with dogs fed a maintenance diet, dogs fed Prescription Diet u/d had significantly lower urinary concentrations of both calcium and oxalate. Protein malnutrition is rare but possible during long-term feeding of Prescription Diet u/d; dogs fed this diet had a significantly lower serum albumin level than controls, although values remained in the normal range. The low protein levels make this diet contraindicated in dogs with dilated cardiomyopathy or in breeds that are predisposed to this disease. In recent years Hill’s has supplemented Prescription Diet u/d with taurine and carnitine, but concerns still remain. In general, veterinary nutritionists recommend against using Prescription Diet

899

TABLE 197-1  Target pH Values for Urinary Diets Food

Target pH

Hill’s Prescription Diet c/d Multicare Feline

6.2-6.4

Hill’s Prescription Diet u/d Canine

7.1-7.7

Royal Canin Veterinary Diet Urinary SO Canine

5.5-6.0

Royal Canin Veterinary Diet Urinary SO Feline

6.0-6.3

u/d as a maintenance diet. Furthermore, this diet tends to be higher in fat and may not be the best choice for dogs with a history of pancreatitis or hyperlipidemia. As mentioned earlier, acidifying diets have been associated with a higher risk of CaOx formation in both dogs and cats, but further studies have yielded conflicting results regarding the importance of daily urinary pH in CaOx prevention. Overall, it can be said that pH generally appears to be less important in controlling CaOx stone formation than in controlling formation of other stones such as struvite. Given the available information it seems prudent to avoid significant acidification of the urine. An appropriate initial target urine pH is approximately 7.0; however, with this in mind, the target urinary pH values achieved by feeding almost all of the diets listed in Table 197-1 are acidic. The only diet designed to produce a urinary pH of more than 7.0 is Hill’s Prescription Diet u/d, with the others aiming for an acidic pH. This is because the goal of the Royal Canin Urinary SO formulation and Hill’s Prescription Diet c/d Multicare is to prevent both CaOx and struvite uroliths. Since urine pH control is more important for dissolution and prevention in treating struvite stones than in treating CaOx stones, these diets target a lower pH as part of the strategy to prevent struvites. Despite causing a mildly acidic urine, all the listed diets are effective in producing urine with a low CaOx RSS. This apparent paradox exemplifies the complex nature of CaOx urolithiasis and the many factors must be considered in designing an appropriate diet. Of course, if CaOx uroliths continue to be a problem despite feeding an appropriate diet, alkalinization of the urine can be considered (see later) to potentially improve control. Another important aspect of dietary treatment of CaOx urolithiasis is to control the types of treats, table food, and supplements given to dogs or cats. Owners often do not consider these things when dietary modifications are made, which can affect the efficacy of a diet adversely. Aside from being high in oxalate or calcium (see the previously referenced website for more details), certain treats or supplements can change the composition of urine by other mechanisms. Any discussion with owners concerning dietary recommendations thus should include a focus on this subject. Medications Pharmacologic agents can be added to the management plan for CaOx urolithiasis if dietary therapy alone is  not effective in preventing stone growth or regrowth.

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SECTION  IX  Urinary Diseases

Potassium citrate has been used effectively in people as a urinary alkalinization agent, and it also may help due to the inhibitory action of citrate on CaOx formation. However, no study to date has shown a clear benefit to the use of citrate in dogs or cats. Furthermore, there is no evidence for hypocitraturia as a risk factor for CaOx formation in dogs or cats. One prospective study in healthy adult dogs was designed to evaluate the effect of supplemental potassium citrate on urinary parameters compared with controls (Stevenson et al, 2000). Overall, there was no significant difference in urinary pH, urinary citrate excretion, or CaOx RSS. However, when only the three miniature schnauzers in this group of dogs were considered, a significant decrease in CaOx RSS was observed. The dosage of potassium citrate used in this study was 75 mg/kg q12h PO, which is the currently recommended starting dose of this medication. Potassium citrate supplementation thus may be helpful in miniature schnauzers, but further studies are needed to confirm this and to determine if higher dosages would be more effective. If potassium citrate is used clinically for alkalinization, the starting dosage mentioned previously can be used and the dosage increased until a pH of approximately 7.0 is achieved. Serum potassium level should be monitored when this drug is used to avoid hyperkalemia. Thiazide diuretics provide another medical option to reduce CaOx saturation. These drugs inhibit the sodiumchloride cotransporter in the distal tubule and by doing so stimulate calcium reabsorption and decrease urinary calcium excretion. The use of hydrochlorothiazide was evaluated in a group of dogs with a history of CaOx urolithiasis (Lulich et al, 2001). Urinary calcium excretion was significantly lower in dogs treated with the diuretic at a dosage of 2 mg/kg q12h PO. In a study of healthy cats treated with hydrochlorothiazide at a dosage of 1 mg/kg q12h PO, a significant decrease in urinary CaOx RSS was found (Hezel et al, 2007). Studies of the safety and effectiveness of long-term administration are lacking.

Monitoring The probability of CaOx urolith recurrence varies among studies but in general is not uncommon. Two studies in cats have found differing results: resubmissions of uroliths were recorded from 7.1% of over 2000 affected cats within a 5-year period (mean resubmission time, 25 months) (Albasan et al, 2009), whereas 40% of a group of cats with ureteroliths exhibited recurrence within about a year (Kyles et al, 2005). Neither study group reflects the total population at risk. Two studies in dogs found CaOx stone recurrence rates of 57% at 2 years (Lulich et al, 2004a) and 36%, 42%, 48%, and 52% after years 1, 2, 3, and 6, respectively (Lulich et al, 1992). If new stones are identified before they become large, less invasive therapies such as voiding urohydropulsion may be used. The size of stone that can be expelled varies depending on breed and size, but in general bladder stones smaller than 5 mm in female cats, 1 mm in male cats, 10 to 15 mm in female dogs, and 1 to 3 mm in male dogs are amenable to urohydropulsion. Removal of larger uroliths requires a more invasive method. Radiography or ultrasonography

is recommended immediately following a removal procedure to verify that no stones remain, 4 weeks after the initial procedure, then at 3 and 6 months, and every 6 months thereafter. Changes in diet or medical therapy designed to control CaOx formation also necessitate monitoring of urinalysis and blood work. Initially this testing is recommended 4 weeks after an intervention; it should then be repeated at 3 and 6 months, then every 6 months thereafter. The urine should be monitored for pH, specific gravity, and crystalluria. The timing of urine collection can affect interpretation. Urinary pH is not a constant and fluctuates during a 24-hour period. Various factors contribute, but in general pH is lowest through the night and highest during the day. In people, the greatest risk of CaOx crystallization was determined to be during the overnight period, and the same is thought to be true in dogs and cats. Thus it may be best to collect a urine sample in the morning before feeding. The urine specific gravity also is likely to be highest at this time, so two risk factors can be evaluated using the morning sample. If potassium citrate is being administered, the urinary pH also can be measured after a meal to determine if it is having an alkalinizing effect. Measurement of pH can be done using a colorimetric reagent strip or a pH meter. However, pH values obtained using a colorimetric strip can vary by as much as 0.5 units on either side of the observed value. A pH meter is more accurate, and these are available in a benchtop model and a less expensive portable handheld meter. The pH values obtained by a handheld meter appear to correlate well with those obtained using the benchtop device. If a nephrolith or ureterolith is present, urine culture is recommended every 4 to 6 months. When either potassium citrate or thiazide diuretics are administered, serum or plasma electrolyte levels should be monitored at each re-evaluation. If a change in dosage is required, electrolyte levels should be checked again 2 weeks after the adjustment is made. For patients with concurrent conditions such as hypercalcemic disorders, hyperadrenocorticism, or urinary tract infection, additional parameters are monitored as well.

References and Suggested Reading Albasan H, Osborne CA, Lulich JP: Rate and frequency of recurrence of uroliths after an initial ammonium urate, calcium oxalate, or struvite urolith in cats, J Am Vet Med Assoc 235:1450, 2009. Bai SC et al: Vitamin B-6 requirement of growing kittens, J Nutr 19:1020, 1989. Cannon AB et al: Evaluation of trends in urolith composition in cats: 5230 cases (1985-2004), J Am Vet Med Assoc 231:570, 2007. DeLorenzi D, Bernardini M, Pumarola M: Primary hyperoxaluria (L-glyceric aciduria) in a cat, J Feline Med Surg 7:357, 2005. Hezel A et al: Influence of hydrochlorothiazide on urinary calcium oxalate relative supersaturation in healthy young adult female domestic shorthaired cats, Vet Ther 8:247, 2007. Kyles AE, Hardie EM, Wooden BG: Management and outcome of cats with ureteral calculi: 153 cases (1984-2002), J Am Vet Med Assoc 226:937, 2005. Lekcharoensuk C et al: Association between dietary factors and calcium oxalate and magnesium ammonium phosphate urolithiasis in cats, J Am Vet Med Assoc 219:1228, 2001.

CHAPTER  198  Canine Urate Urolithiasis Lekcharoensuk C et al: Associations between dry dietary factors and canine calcium oxalate uroliths, Am J Vet Res 63:330, 2002. Low WW et al: Evaluation of trends in urolith composition and characteristics of dogs with urolithiasis: 25,499 cases (19852006), J Am Vet Med Assoc 236:193, 2010. Luckschander N et al: Dietary NaCl does not affect blood pressure in healthy cats, J Vet Intern Med 18:463, 2004. Lulich JP et al: Evaluation of urine and serum metabolites in miniature schnauzers with calcium oxalate urolithiasis, Am J Vet Res 52:1583, 1991. Lulich JP et al: Postsurgical recurrence of calcium oxalate uroliths in dogs. In Proceedings of the 10th Annual ACVIM Forum, 1992, p 802 (abstract). Lulich JP et al: Effects of hydrochlorothiazide and diet in dogs with calcium oxalate urolithiasis, J Am Vet Med Assoc 218:1583, 2001. Lulich JP et al: Biological behavior of calcium oxalate uroliths in Bichon Frise dogs. In Proceedings of the 22nd Annual ACVIM Forum, 2004a, p 861 (abstract) Lulich JP et al: Effect of diet on urine composition of cats with calcium oxalate urolithiasis, J Am Anim Hosp Assoc 40:185, 2004b.

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Lulich JP, Osborne CA, Sanderson SL: Effects of dietary supplementation with sodium chloride on urinary relative supersaturation with calcium oxalate in healthy dogs, Am J Vet Res 66:319, 2005. Osborne CA et al: Analysis of 451,891 canine uroliths, feline uroliths, and feline urethral plugs from 1981-2007: perspectives from the Minnesota Urolith Center, Vet Clin North Am Small Animal Pract 39:183, 2008. Stevenson AE et al: Effects of dietary potassium citrate supplementation on urine pH and urinary relative supersaturation of calcium oxalate and struvite in healthy dogs, Am J Vet Res 61:430, 2000. Stevenson AE et al: Nutrient intake and urine composition in calcium oxalate stone-forming dogs: comparison with healthy dogs and impact of dietary modification, Vet Ther 5:218, 2004. Stevenson AE, Hynds WK, Markwell PJ: The relative effects of supplemental dietary calcium and oxalate on urine composition and calcium oxalate relative supersaturation in healthy adult dogs, Res Vet Sci 75:33, 2003. Stevenson AE, Robertson WG, Markwell P: Risk factor analysis and relative supersaturation as tools for identifying calcium oxalate stone-forming dogs, J Small Anim Pract 44:491, 2003.

198 

Canine Urate Urolithiasis JODY P. LULICH, St. Paul, Minnesota CARL A. OSBORNE, St. Paul, Minnesota HASAN ALBASAN, St. Paul, Minnesota

B

etween January 1, 2009, and December 31, 2010, the Minnesota Urolith Center received uroliths from 99,598 dogs. Purines made up 5.1% of uroliths submitted; of these, 84.5% were ammonium urate, 11.3% were other salts of urate, 2.5% were uric acid, and 1.7% were xanthine. Although purine uroliths were diagnosed in 111 breeds, dalmatians were the most common purine stone formers on every continent. Uric acid is one of several biodegradation products of purine nucleotide biosynthesis and degradation. Purines are made up of three groups of compounds: (1) oxypurines (hypoxanthine, xanthine, uric acid, and allantoin), (2) aminopurines (adenine, guanine), and (3) methylpurines (caffeine, theophylline, and theobromine). In people, excess nucleotides are converted to xanthine and then uric acid via xanthine oxidase. In most dogs, excess uric acid is metabolized further to allantoin via the hepatic enzyme uricase. Allantoin is highly soluble in urine, whereas uric acid and xanthine are not. Risk factors associated with urate lithogenesis in dogs include the following:

1. Increased renal excretion and urine concentration of uric acid 2. Increased renal excretion or renal production of ammonium ions 3. Increased microbial production of ammonium ions 4. Aciduria 5. Formation of highly concentrated urine 6. Presence of promoters or absence of inhibitors of urate urolith formation Genetic factors also may be important. Hyperuricuria and urate urolithiasis have been linked to a mutation in a urate transporter that was identified recently in dalmatians, English bulldogs, and Black Russian terriers and sporadically in other breeds (Karmi et al, 2010). To promote dissolution and prevention of urate uroliths, appropriate diets are prescribed to minimize the risk factors listed previously. In studies of normal dogs, consumption of high-protein foods was associated with greater urine uric acid excretion and increased urine saturation with uric acid, sodium urate, and ammonium

902

SECTION  IX  Urinary Diseases

urate, compared with consumption of low-protein foods. The same association was found in dalmatian dogs. The following sections provide answers to questions essential for effective urate urolith management in dogs.

How Effective Is Medical Dissolution of Urate Uroliths? Efficacy of medical dissolution depends on several key factors: the location of the uroliths, the treatments selected, owner compliance with the treatment regimen, any underlying disease(s), and disease severity. In an uncontrolled clinical trial, 25 dogs with naturally occurring urate urocystoliths (without hepatic portovascular anomalies) were prescribed canned Hill’s Prescription Diet u/d and allopurinol (15 mg/kg q12h). Of these dogs, 36% experienced complete dissolution (median dissolution time, 3.5 months), 32% experienced partial dissolution, and 32% experienced no dissolution (Osborne et al, 2009). Aside from sporadic anecdotal reports, we are 

not aware of the efficacy of other potentially litholytic diets (e.g., vegetarian diets, Royal Canin Veterinary Diet Urinary UC Low Purine, and other lower-protein diets formulated for dogs with renal failure, liver disease, or dermatologic disorders). The role of a new selective xanthine oxidase inhibitor, febuxostat (Uloric), in safely promoting effective urolith dissolution also is unknown. Unlike allopurinol, febuxostat does not need to undergo hepatic transformation to more active metabolites. Therefore febuxostat would appear more suitable for dogs with portovascular shunts and urate urolithiasis; however, abnormal liver function test results were a frequent adverse event in humans taking the medication. Additional clinical studies are needed to evaluate the efficacy of contemporary diets and newer medications. Until such studies are completed, we recommend initially considering evidence-based medical dissolution therapies for dogs with asymptomatic or mildly symptomatic urate urocystoliths and nephroliths (Figure 198-1). More rapid urolith removal (surgery,  Contrast urethrocystography

No urethral obstruction

Uroliths smaller than urethral lumen

Voiding urohydropropulsion

Urethral obstruction

Uroliths larger than urethral lumen

Medical dissolution

or

or

Diet (purine restricted, urine alkalinizing, urine diluting) Allopurinol 15 mg/kg q12h PO

Figure 198-1  Managing urate uroliths in dogs.

Retrograde urohydropropulsion

Urolith removal (e.g., laser lithotripsy, cystoscopic cystotomy, laparoscopic cystotomy, traditional cystotomy)

1-Month recheck UA, urine sediment, double-contrast cystography Decreased urolith size & number. Continue therapy until complete dissolution

No change or increase in urolith size

Catheter retrieval of small uroliths or urine sediment for quantitative mineral analysis Confirm urate uroliths Ensure consumption of a low-protein, urine-alkalinizing, urine-diluting diet and increase allopurinol dose by 10%

Confirm allopurinolinduced xanthine uroliths To promote or xanthine dissolution, stop allopurinol & ensure consumption of a low-protein, urine-alkalinizing, urine-diluting diet. After 1-2 months reinstitute allopurinol at 10 mg/kg q12h and continue diet.

CHAPTER  198  Canine Urate Urolithiasis lithotripsy, cystoscopically assisted cystotomy, or laparoscopic cystotomy) should be considered for dogs with urethroliths and clinically active disease (e.g., moderate to severe clinical signs or urinary obstruction).

How Should Medical Dissolution Be Monitored? Frequent evaluations (monthly) are necessary to permit timely adjustments to therapy to improve dissolution and minimize adverse events. In addition to a defined history and physical examination, we use three tests to guide our assessment of progress.

Large Urine Sample The night before the veterinary appointment, dog owners collect sufficient urine (200 to 500 ml by voiding midstream sampling) to allow quantitative evaluation of urine sediment. The urine can be refrigerated overnight and submitted to the clinic during the appointment. Absence of any visible sediment in a cooled urine sample is a good indication that therapy is balanced appropriately. For samples with visible sediment, the clinician should proceed as follows: 1. Decant the supernatant. 2. Place 10 ml of the remaining mixture in a 10- to 15-ml cone-tipped centrifuge tube. Centrifuge the sample to separate the sediment from the solution (alternatively, the sample can sit undisturbed to allow for separation by gravity). 3. Decant the supernatant again. 4. Repeat this process by adding additional urine to the centrifuge tube until sufficient sediment (i.e., 0.5- to 1-cm depth) is reclaimed. 5. Allow the sediment to air-dry for several days   before submitting it for quantitative mineral   analysis. Unprocessed urine should not be submitted for quantitative mineral analysis.

Urinalysis of a Freshly Obtained and Rapidly Analyzed Urine Sample Owners should be encouraged not to let their dog urinate 2 to 3 hours before the veterinary appointment so that a fresh sample can be collected and analyzed within 30 minutes. Ideally, urine specific gravity should be below 1.020 (the lower the better), pH should be above 7, and there should be no visible crystals. If crystals are observed, quantitative mineral analysis will be necessary to differentiate urate from xanthine precipitation in dogs receiving allopurinol. Urate crystalluria is an indication of insufficient dietary purine (protein) reduction, insufficient urine alkalization, insufficient urine dilution, insufficient allopurinol administration, or both. Xanthine crystalluria is an indication of excessive allopurinol administration in relation to insufficient dietary purine (protein) reduction, insufficient urine alkalization, or insufficient urine dilution.

903

Medical Imaging It is difficult to monitor changes in urolith size and number by survey radiography because urate uroliths are marginally radiopaque. Therefore double-contrast cystography and ultrasonography often are used. Doublecontrast cystography is superior to ultrasonography because (1) virtually all uroliths can be visualized, (2) urolith size, shape, and number can be assessed accurately, and (3) small uroliths often can be retrieved through the infusion catheter and can be submitted  for quantitative mineral analysis. General anesthesia  is not required to perform double-contrast cystography (however, local anesthesia and sedation improve patient comfort). Ultrasonography has the advantage of being noninvasive but is not a sensitive method of determining urolith size or number. In addition, urethroliths usually are missed by ultrasonography. When uroliths recur, the size and position of all uroliths should be assessed to determine if patients are candidates for voiding urohydropropulsion, basket retrieval, or retrograde urohydropropulsion. Therefore treatment planning should not be based on ultrasonography alone. Survey radiography and contrast urethrocystography are essential to ensure that the extent of disease is not underestimated. Because the median urolith dissolution time is 3.5 months, medical imaging can be omitted during the first monthly evaluation but should be performed at all successive evaluations.

Is Urethral Surgery an Option for Urethroliths? Because the surface of most urate uroliths is smooth, successful expulsion of urethroliths using retrograde urohydropropulsion should be anticipated in every patient  after administration of sufficient anesthesia to relax the urethra properly. We recognize that for some patients, urethrotomy and urethrostomy may be required to avert the life-threatening consequences of complete urethral obstruction. However, urethrotomy is a common cause of urethral strictures, and urethrostomy is a common cause of recurrent urinary tract infections in male dogs. Avoidance of urethral surgery ensures that the integrity and function of the urinary tract will be preserved. Contemporary nonsurgical methods for removing urethroliths (e.g., retrograde urohydropropulsion and laser lithotripsy) are very successful and are becoming readily available at referral centers. Since surgery has no positive benefit for urolith prevention and can lead to urethral stricture, we recommend that urethral surgery be considered only as a salvage procedure when other approaches have been exhausted.

What Is the Appropriate Dosage of Allopurinol? The dosage of allopurinol required to prevent urate urolith recurrence sufficiently without promoting xanthine urolith formation varies and is influenced by the severity of disease, the quantity of protein (i.e., purines) in the diet, urine pH, and urine volume. In a case series

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of 10 dogs with previous urate urolithiasis, allopurinol administration in excess of 9 to 38 mg/kg/day was associated with xanthine urolith formation (Ling, 1991). Xanthines form because allopurinol inhibits the breakdown of xanthine to uric acid and because xanthine is less soluble in urine than uric acid. Based on these observations, we recommend a dosage of 5 to 7 mg/kg/day to prevent urate uroliths safely. Because the dosage of allopurinol associated with urolith dissolution (10 to 15 mg/ kg twice a day) is much higher, it is important to achieve decreased intake of dietary purine (i.e., protein), increased urine dilution, and increased urine pH before allopurinol is administered. Since allopurinol has a short half-life (2.5 hours) and requires hepatic transformation to its more effective, longer-lasting metabolite oxypurinol, an effective yet safe dosage has not been established for dogs with portovascular shunts (Ling et al, 1997).

Should Medical Treatment Be Considered to Manage Urate Crystalluria in Dogs without Uroliths? Urate crystalluria in a fresh urine sample from an otherwise clinically healthy dog is an indication to look for an underlying cause (e.g., portovascular shunt, mutation in the SLC2A9 urate transporter, myeloproliferative cancers, tumor lysis syndrome). Medical imaging of the urinary tract should be performed in breeds at risk of urate urolithiasis (e.g., dalmatian, English bulldog, Russian terrier). In the absence of uroliths or a history of uroliths, therapy to prevent crystalluria usually is not warranted based on the following observations. There is no scientific evidence that urate crystalluria causes clinical signs. Although all dalmatians are assumed to be hyperuricosuric, few (less than 10%) form clinically recognizable urate uroliths. Clinical urolithiasis is primarily a disease of young adult (1- to 6-year-old) male dogs. Of the urate uroliths from almost 20,000 dalmatians that have been submitted to the Minnesota Urolith Center for quantitative analysis, fewer than 3% were from females and fewer than 20% were from dogs 8 years of age or older. Therefore these groups are not likely to form urate uroliths. In 2009 and 2010, urate uroliths from 457 Yorkshire terriers with presumed portovascular anomalies were analyzed; only 19% were from female dogs. Although the need for urolith prevention appears to be greater in males, we recommend that in all cases risk factors associated with urate urolith formation (e.g., high-protein/purine diets, urine acidification, aspirin therapy, water restriction) be eliminated, if possible.

How Quickly Will Urate Uroliths Recur? Prospective studies addressing the issue of how quickly urate uroliths recur are limited. In one prospective crossover study, two diets (a canned maintenance food and a canned urolith-prevention food) were evaluated in six client-owned, male, urolith-forming dalmatians (age range, 2 to 5 years) (Lulich et al, 1997). Each diet was  fed for 6 months. Dogs were randomly assigned as to which diet was fed first. To accurately assess urolith recurrence, dogs were evaluated monthly by double-contrast

cystography. Uroliths that formed during the study were removed by voiding urohydropropulsion and submitted for quantitative analysis. When dogs were fed the canned maintenance diet (dry-matter protein content of 25%, chicken as the primary protein source), 87% of dalmatians developed recurrent urate uroliths within the 6-month period. Recurrent uroliths were small (4 to 6

CaOx MAP UA, Cy, Si

Difficult (consider alternative procedure or surgical back up)

Male Female Male

≥7 ≥7 ≥7

Bladder Bladder Bladder

>1 >1 >0.5

>1 ≥3 ≥3

CaOx MAP UA, Cy, Si

CaOx, Calcium oxalate; Cy, cysteine; MAP, magnesium ammonium phosphate; NI, not important; Si, silica; UA, urine acid. *Dog weight is used as a surrogate marker for urethral diameter. In some smaller dogs, urethral diameter may be larger than predicted, easily accommodating cystoscopy passage, and in some larger dogs urethral diameter may be smaller than predicted and not facilitate cystoscopy insertion. †Small stones ≤3 mm are not considered in urolith count because they may be removed easily without laser fragmentation.

WEB CHAPTER  70  Laser Lithotripsy for Uroliths

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(Adams et al, 2008; Grant, Were, Gevedon, 2008; Lulich et al, 2009). In all three studies, complete urolith removal was achieved in 100% of dogs with urethroliths. In dogs with urocystoliths, complete urolith removal rate was higher in females (83% to 96%) than in males (68% to 81%). In cases of incomplete urolith removal, dogs were allowed to void spontaneously small (103° F), dehydration and anorexia, depression, disinterest in offspring, agalactia, and malodorous sanguineous vaginal discharge. Abdominal palpation may reveal a doughy, enlarged, and painful uterus. Vaginal cytology reveals large numbers of degenerative neutrophils, bacteria, and debris. Clinical pathology often shows elevated total solids (secondary to dehydration) with immature leukocytosis; however, leukopenia can occur in severely ill patients. Ultrasonography or hysteroscopy may aid in identifying an underlying cause. Evaluation of the uterine lumen postpartum for retained placentas or mummified fetuses is accomplished best with ultrasound. Although not diagnostic for metritis, guarded cranial vaginal cultures with sensitivity may be helpful in determining appropriate antibiotic therapy. Removal of offspring from the dam and administration of intravenous fluids and broad-spectrum antibiotics are necessary for treatment of septicemia. Amikacin (5 to 10 mg/kg q12h IV) with cephalothin (22 mg/kg q8h IV) is recommended; however, antibiotics alone may be ineffective in treating postpartum metritis. Uterine evacuation using prostaglandin F2α tromethamine (Lutalyse) at a dosage of 25 to 50 µg/kg q4-6h SC results in a clinical cure with minimal side effects (e.g., emesis, hypersalivation, diarrhea, purring [queens]). If the patient is no longer needed for breeding, ovariohysterectomy is recommended when the patient is stable for general anesthesia. Bitches and queens recovering from acute postpartum metritis have retained their fertility and have demonstrated this by normal subsequent whelpings without future postpartum complications.

CHAPTER  209  Postpartum Disorders in Companion Animals

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Agalactia Agalactia can present as either complete failure of mammary gland development (primary) or failure of  milk to let down (secondary). Debilitating maternal illness, dehydration, malnutrition, and endocrine imbalances are predisposing factors. In addition, extremely stressed dams may have elevated epinephrine concentrations, leading to decreased pituitary release of oxytocin. Acepromazine (0.5 to 2 mg/kg SC) promotes prolactin secretion, which may increase pituitary oxytocin release. Oxytocin administered either parenterally (0.1 to 0.2 units/kg, not to exceed 10 units q2-3h SC) or intranasally using a nebulizing spray (Syntocinon) into one nostril (q2-3h) results in milk letdown within 2 minutes. In addition, efforts should be made to correct the underlying maternal condition. Neonates should be offered supplemental feedings or reared as orphans if the condition persists.

Figure 209-1  Acute septic mastitis. Cursors indicate a hypoechoic fluid accumulation suggesting abscessation. (Reprinted with permission from Davidson AP, Baker TW: Reproductive ultrasound of the bitch and queen, Top Companion Anim Med 24:55, 2009.)

Septic Mastitis Acute septic mastitis, an ascending bacterial infection involving one or more of the mammary glands, can occur secondary to unsanitary housing or galactostasis. Clinical signs include rectal temperature higher than 39.5° C (>103° F); dehydration and anorexia; depression; disinterest in offspring and agalactia; and painful, firm, and reddened mammary glands. Expressed mammary secretions tend to be sticky, chunky, and discolored (either purulent or blood tinged). Clinical pathology reveals a leukocytosis with marked immature neutrophilia. Cytologic examination of the mammary secretions may reveal bacteria, white blood cells, and erythrocytes. A Gram stain performed on mammary secretions improves antibiotic selection. Bacterial culture of mammary secretions typically yields Staphylococcus spp., Streptococcus spp., and E. coli as causal organisms. Milk white blood cell counts have been recommended in the past for diagnosing mastitis, but this test has not been reliable because cell counts tend to differ between individual animals as well as within glands from the same animal. Until culture and sensitivity results are obtained, cefadroxil (22 mg/kg q12h PO) is recommended because it has broad-spectrum antibacterial activity and has not been observed to affect nursing offspring. Neonates should be allowed to nurse because nursing may speed resolution of the disease. However, if many glands are affected or the mother is severely ill, the offspring should be hand raised. If the neonates are weaned, cabergoline (Dostinex) (5 µg/kg q24h PO for 5 days) should be used to stop lactation and prevent further bacterial extension. Warm compresses can be applied two to three times a day along with milking out the affected glands. Ultrasound of a mastitic mammary gland can be helpful in identifying fluid pocket development (abscessation) that warrants surgical intervention and in monitoring response to therapy (Figure 209-1). In cases of abscessation or gangrenous mastitis (Figure 209-2), surgical drainage and removal of the affected mammary gland may be necessary. In these cases a clear line of demarcation separates the healthy tissue from the gangrenous tissue.

Figure 209-2  This 5-year-old yellow Labrador retriever bitch

was 2 weeks postpartum when the owner first noticed swelling in her left hind leg (note presence of dermatitis in the medial thigh). When examined in left lateral recumbency, both pairs of mammary glands (caudal abdominal and inguinal) are swollen and erythematous. In addition, the overlying skin is necrotic in multiple areas with evidence of abscessation.

Puerperal Tetany Puerperal tetany, also known as postpartum hypocalcemia or eclampsia, generally develops less than 28 days after delivery but can occur during late pregnancy or during parturition. In the dog, puerperal tetany occurs most commonly in small-breed bitches, less frequently in medium-sized bitches, and rarely in large-breed bitches. Puerperal tetany has been reported in queens (pre- and postpartum) but occurs at a much lower incidence than in bitches. Other than breed, predisposing factors in dogs include young age, large litter size in relation to body weight, and diet during pregnancy. Diets high in calcium, animal protein (egg or meat), or containing cereals with phytates (a compound that binds ionized calcium making it biologically unavailable), may predispose to puerperal tetany. Puerperal tetany occurs with an acute decrease in ionized calcium concentration. A reduction in calcium

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concentrations increases membrane permeability in nerve cells to sodium ions, causing increased frequency of spontaneous nervous activity noticeable as muscle fasciculations. Clinical signs are related not only to the absolute decrease in ionized calcium concentrations but also to the rate and progression of its decline. The onset of clinical signs is usually rapid, and the progression of signs is predictable. Early clinical signs include restlessness, whining, panting, salivation, anorexia, vomiting, and behavioral changes. As the signs progress, muscle fasciculations, stiffness, ataxia, tonic-clonic muscle spasms, hyperthermia, tachycardia, seizures, and death may ensue. Ionized serum calcium concentrations less than 0.6 to 0.8 mmol/L are definitive for diagnosing puerperal tetany. If ionized calcium quantification is not available, total serum calcium measurements can be used, with concentrations less than 1.625 mmol/L highly indicative of puerperal tetany. Ionized calcium concentrations are typically 30% to 50% of total calcium concentrations; however, alkalosis resulting from hypersalivation may increase the protein-bound calcium fraction, resulting in a lower net decrease in ionized calcium levels. In addition to measuring calcium levels, a full serum chemistry evaluation is necessary because hypoglycemia and other electrolyte disturbances may develop concurrently with puerperal tetany. Treatment for puerperal tetany is aimed at returning ionized calcium concentrations to normal values. This is achieved by slow intravenous administration of 10% calcium gluconate (0.22 to 0.44 ml/kg) in combination with careful cardiac auscultation or electrocardiography. The development of bradycardia and other arrhythmias during intravenous calcium administration is indicative of too rapid replacement. Full recovery or clinical cure occurs within minutes of the intravenous treatment. Judicious administration of intravenous fluids and anticonvulsants (diazepam 1 to 5 mg once IV) is indicated for treatment of hyperthermia and seizures. The offspring

should be removed from the dam and hand fed a milk supplement for at least 12 to 24 hours to prevent a relapse. If the litter is older than 4 weeks old, they can be weaned. Lactation can be terminated using cabergoline (Dostinex) (5 µg/kg q24h for 5 days PO). Oral supplementation with calcium carbonate (100 mg/kg q24h) and vitamin D (10,000 to 25,000 units q24h) also is recommended to prevent a relapse. Bitches and queens may suffer from a puerperal tetany at the next parturition. However, dams should not be supplemented with calcium during pregnancy because this increases the likelihood of developing puerperal tetany rather than preventing its recurrence.

References and Suggested Reading Biddle D, Macintire DK: Obstetrical emergencies, Clin Tech Small Anim Pract 15:88, 2000. Burstyn U: Management of mastitis and abscessation of mammary glands secondary to fibroadenomatous hyperplasia in a primiparturient cat, J Am Vet Med Assoc 236:326, 2010. Davidson AP, Baker TW: Reproductive ultrasound of the bitch and queen, Top Companion Anim Med 24:55, 2009. Dickie MB, Arbeiter K: Diagnosis and therapy of the subinvolution of placental sites in the bitch, J Reprod Fertil Suppl 47:471, 1993. Drobatz KJ, Casey KK: Eclampsia in dogs: 31 cases (1995-1998), J Am Vet Med Assoc 217:216, 2000. Grundy SA, Davidson AP: Acute metritis secondary to retained fetal membranes and a retained nonviable fetus, J Am Vet Med Assoc 224:844, 2004. Sontas HB et al: Full recovery of subinvolution of placental sites in an American Staffordshire terrier bitch, J Small Anim Pract 52:42, 2011. Vaughan L, McGuckin S: Uterine prolapse in a cat, Vet Rec 132:568, 1993. Ververidis HN et al: Experimental staphylococcal mastitis in bitches: clinical, bacteriological, cytological, haematological and pathological features, Vet Microbiol 124:95, 2007. Wiebe VJ, Howard JP: Pharmacologic advances in canine and feline reproduction, Top Companion Anim Med 24:71, 2009.

CHAPTER 

210 

Nutrition in the Bitch and Queen During Pregnancy   and Lactation DAVID A. DZANIS, Santa Clarita, California

G

estation and lactation place some of the most rigorous nutritional demands on the dam, especially when compared with the adult, nonreproducing animal. A dietary deficiency or excess in one or more nutrients during this life stage can have profound effects on the ability of the dam to conceive, deliver, and raise a healthy litter. Successful nutritional management of the dam during pregnancy and lactation takes more than just recommending a particular brand of pet food. Instead, considering the nutrient needs of the individual animal, assessing the qualities of the ration in meeting those needs, and feeding the ration in an appropriate manner are critical elements. The American College of Veterinary Nutrition (ACVN) has developed a graphic representation to help demonstrate these basic principles (Figure 210-1).

Determining Nutrient Requirements Energy The nutrient of greatest increased demand during pregnancy and especially lactation is energy. Because daily caloric need of a given individual also is influenced greatly by body size, breed, age, activity, and environmental conditions, perhaps the best means of expressing energy needs for pregnancy and lactation is as a proportion of the normal energy requirements of the same animal at maintenance. However, to do that requires knowledge of the dam’s energy needs at maintenance. A number of equations are used to determine maintenance energy requirements of the dog, but perhaps the most widely accepted equation provided by the National Research Council (NRC, 2006) is for metabolizable energy (ME) in kilocalories per day: ME ( kcal/day ) = 130 × Body weight ( kg )0.75 Although some equations do not rely on an exponent and thus are easier to calculate, determination of metabolic body weight by this method best accounts for the great diversity in adult body size in dogs. The constant  in the formula (130) was determined in dogs under laboratory conditions; thus it assumes the dog to be at a moderate activity level and in environmentally favorable

conditions during most of the day. Actual maintenance requirements of a given individual may vary up to 30% either way. A mostly indoor, sedentary house pet requires less to maintain body weight than an outdoor, kenneled dog. Breed and body size are also factors. For example, the equation coefficient may vary from 94 for a large pet dog to 175 for a highly active pet Border collie. For cats, the equations recommended by NRC (2006) for estimating maintenance energy requirements are similar in format to the dog equation. Cats have less of a range of adult body sizes and are less apt to be highly active or exposed to extreme environmental conditions compared with dogs. Therefore variability in caloric requirements between individuals may be narrower. However, differences in requirements are seen with increasing body condition score (BCS); overweight cats require fewer calories per kilogram (kg) to maintain body weight. To account for this difference, ME can be calculated by two equations, one for “lean” (BCS ≤5 on a scale of 1 to 9) and one for “overweight” (BCS >5): Lean cats: ME ( kcal/day ) = 100 × Body weight ( kg )0.67 Overweight cats: ME ( kcal/day ) = 130 × Body weight ( kg )0.4 Because of the potentially large variation in caloric requirements, especially in dogs, perhaps a more practical means of determining needs of an individual is simply to monitor the amount of a given food (and number of calories that amount of food delivers) required to keep the animal in optimum body condition during prebreeding. During gestation and lactation the amount of the same food then can be adjusted by the appropriate proportion. If a more calorie-dense food is fed during these periods, the proportional increase would be modified relative to the calorie content of the old and new diets. In the bitch the energy requirements for early and midgestation are approximately the same as those for maintenance (Figure 210-2). Although the fetuses are developing rapidly, they remain relatively small. Only in the last few weeks of gestation are additional calories needed for growth of the fetuses and maternal tissues. Depending on the number of fetuses, total weight gain by the time of parturition should be around 15% to 25%. At this time the bitch likely is consuming approximately 961

SECTION  X  Reproductive Diseases

150% of her normal maintenance needs. Expressed  differently, the increase in energy requirements above maintenance from the fourth week after mating until parturition is approximately 26 kcal of ME per kilogram of body weight per day. Unlike in the bitch, increase in body weight and therefore caloric requirements of the gestating queen between mating and parturition are linear; that is, weight gain  is steady and consistent throughout gestation. The  weight gain in the queen during early pregnancy is not

Figure 210-1  The American College of Veterinary Nutrition

Energy requirement (% of maintenance)

Iterative Process of Nutritional Assessment requires consideration of the animal, the ration, and the feeding management. (Courtesy American College of Veterinary Nutrition.)

associated with fetal growth but apparently serves as an energy reserve to support later demands for lactation. Depending on the number of kittens, the mean body weight gain at the end of gestation is usually around 40% over premating body weight. In the bitch, dramatic increases in energy needs are seen after the first week of lactation, even though the dam may be approaching or even falling below her prebreeding body weight after delivery. This effect is tempered somewhat in queens; she remains above prebreeding weight at parturition but then uses the fat stored during early pregnancy for lactation. Still, increased energy is needed in bitches and queens to meet the monumental nutritional demands of milk production for the evergrowing offspring. For both species, the calorie requirement of a given individual depends on the amount of milk production, which in turn is correlated with the number of offspring. In bitches with litters of one to four neonates, milk production can be estimated at 1% of the bitch’s body weight per pup, which increases the bitch’s energy requirement by 24 kcal of ME per kilogram of body weight per day for each puppy in the litter. For litters larger than four, milk production and caloric needs per additional pup are approximately half of these values, and the increase in milk yield as litters exceed eight pups is negligible. Put more simply, in a bitch during peak lactation (4 weeks after parturition) with a moderate-tolarge litter, energy needs could be three or even up to four times the normal maintenance requirements. As the offspring are weaned and milk production declines, the calorie needs for lactation drop, and more energy can be directed toward reestablishing normal body weight. The increase in caloric requirements for the queen may not be as dramatic as in the bitch, because the queen still is using energy she stored during early gestation and continues to lose weight during lactation. In the lactating queen, NRC (2006) recommends energy requirements in

350

30

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5

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G1 G2 G3 G4 G5 G6 G7 G8 G9 L1 L2 L3 L4 Week of gestation (G) or lactation (L)

L5

L6

L7

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% change in body weight

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Energy req. Body weight

5

Figure 210-2  Energy needs and expected body weight changes of the bitch during gestation

and lactation. (Modified from Case LP et al: Canine and feline nutrition, ed 3, St Louis, 2010, Mosby.)

CHAPTER  210  Nutrition in the Bitch and Queen During Pregnancy and Lactation kilocalories (kcal) per day above maintenance by the following equation: ME ( kcal/day ) = maintenance + [ K × L × Body weight ( kg )] Where K = 18, if number of kittens in litter less than 3, K = 60, if number of kittens in litter 3 or 4, and K = 70, if number of kittens in litter greater than 4, And where L = 0.9 at first or second weeks of lactation, L = 1.2 at third and fourth weeks of lactation, L = 1.1 at fifth week of lactation, L = 1.0 at sixth week of lactation, and L = 0.8 at seventh week of lactation For example, a 4-kg queen with three kittens in peak lactation (fourth week) would require 288 kcal per day above the 253 kcal/day required for maintenance. As a rule of thumb, an energy need 2 to 2.5 times the maintenance requirement is expected during lactation.

Other Essential Nutrients In addition to calories, the needs for most other essential nutrients (e.g., amino acids, minerals, vitamins) increase during this life stage. For example, more protein, calcium, and phosphorus are needed for proper growth and bone development of the puppies and kittens. The Association of American Feed Control Officials (AAFCO) Dog and Cat Food Nutrient Profiles indicate for which nutrients are increased dietary needs above maintenance of the reproducing bitch or queen. For example, increased intake of dietary salt above maintenance needs is indicated to support normal milk production in the bitch, whereas the dietary levels of vitamins A and D are higher for reproducing queens versus cats at adult maintenance. Although many of the nutrient requirements in the AAFCO profiles appear the same for all life stages, absence of an established difference in the profiles between growth and reproduction versus maintenance reflects the lack of data showing a decreased need in the adult at maintenance (especially for many of the trace minerals and vitamins). Furthermore, although the amount in the diet may appear to remain the same, the actual daily intake of a given nutrient is higher in the gestating/lactating bitch or queen because of increased food intake.

Fatty Acids One recommendation by the NRC not incorporated into the AAFCO Dog or Cat Food Nutrient Profiles is for dietary omega-3 fatty acids, specifically of α-linolenic acid (ALA) and eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) in combination. Although no apparent developmental abnormalities caused by omega-3 fatty acid deficiencies have been reported for any commercial pet food, DHA, and to a lesser extent its precursors ALA and

963

EPA, appear to be important in normal nervous tissue development of puppies and kittens. Notwithstanding inclusion of fish oil or other sources of DHA in foods intended for postweaned puppies to improve “trainability,” only recently has there been evidence of effect on brain development or learning by this stage in either the puppy’s or the kitten’s life (Zicker et al, 2012). However, improvement in retinal function in young dogs was seen when the dams were fed omega-3 fatty acids during gestation and lactation, perhaps by transfer in utero but more likely via the milk during the early neonatal period (Bauer et al, 2006). Regardless, inclusion of omega-3 fatty acids in the diet of the gestating/lactating bitch and queen is prudent. The NRC recommended allowance for foods for dogs in gestation and lactation for ALA is 0.08% dry matter or 0.2 g/1000 kcal ME and for EPA and DHA in combination is 0.05% dry matter or 0.13 g/1000 kcal ME. The NRC also recommends these fatty acids for gestating/ lactating queens but at lower amounts (ALA = 0.02% dry matter, 0.05 g/1000 kcal ME; EPA/DHA = 0.01% dry matter or 0.025 g/1000 kcal ME). Revisions to the AAFCO Dog and Cat Food Nutrient Profiles are expected by 2014, including anticipated similar minimum requirements for these fatty acids in foods intended for growth and reproduction.

Nutritional Disorders During Pregnancy and Lactation Eclampsia The presence of eclampsia, a condition characterized by periparturient hypocalcemia in both species (more commonly in the bitch, especially during early lactation), may be thought to imply that dietary calcium requirements of late gestation have not been met and that further supplementation is indicated. Although definitive studies on the prevention of this condition in companion animals are lacking, a lesson may be drawn from what is known about milk fever, a similar condition in dairy cows. Contrary to intuition, the calcium needs of the growing fetus are relatively low, and a high dietary calcium intake during gestation initiates responses to suppress calcium intestinal absorption and bone and kidney resorption in the mother. Then, when lactation ensues, the dramatic loss of calcium into the milk cannot be countered by normal metabolic responses, and the animal cannot maintain normocalcemia regardless of dietary intake of calcium at that stage. On the other hand, a low calcium intake in cattle helps ensure that bone calcium remains relatively mobile and responsive to the sudden demands of lactation. The syndromes in companion animals and cows are different. Data are lacking to indicate that a lowcalcium diet in late gestation is an effective preventive in dogs and cats. However, calcium supplementation beyond that already provided in a balanced diet (which is already increased compared with diets intended for maintenance) may be imprudent at best.

Hypoglycemia Although infrequent in the dog and not well documented in the cat, periparturient hypoglycemia can occur, usually

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in the last weeks of gestation. Although carbohydrates are not recognized as essential nutrients in either species,  the diet of the gestating/lactating dam should provide  at least 20% of its energy content from carbohydrates  to mitigate the risk of periparturient hypoglycemia, to ensure ample glucose for the developing fetuses, and to help maintain lactose levels in the milk. Historically, most pet foods (and all dry or semi-moist foods) contained an ample source of carbohydrates, with the exception of some exclusive canned and frozen pet food products (e.g., “all beef”). However, considering the increased popularity for feeding pets “low-carb” diets in recent years, the clinician should assess the food for adequate carbohydrate content regardless of form.

Dehydration Finally, adequate water intake should not be overlooked, especially during periods of heavy demand such as at peak lactation. Lack of adequate intake could hurt the dam and the offspring from decreased milk production. Although data are lacking on the minimum water requirement of gestating/lactating bitches and queens, it is  presumed to be proportional to energy intake (1 ml  water per 1 kcal ME consumed for dogs, 0.6 ml water per 1 kcal ME consumed for cats). Clean, fresh water should be made available at all times, and dams must be monitored for signs of dehydration and/or decreased milk production.

Choosing the Appropriate Food An abundance of high-quality, nutritionally “complete and balanced” commercial foods are available for feeding bitches and queens in gestation and lactation. The flavor, form (dry vs. canned), and presence or absence of a particular ingredient are not as important as the product’s substantiation of nutritional adequacy. To ensure that  the product is suitable to be fed as the sole source of  nutrition, the information panel on the label should  bear either of the following: “(Product Name) is formulated to meet the nutritional levels established by the AAFCO Dog (or Cat) Food Nutrient Profiles,” or “Animal  feeding tests following AAFCO procedures substantiate that (Product Name) provides complete and balanced nutrition.” If it bears the statement that it is intended “for intermittent or supplemental feeding only,” includes reference to AAFCO in a manner other than either of the previous statements, refers to an organization other than AAFCO, or contains no reference to nutritional adequacy, the product should not be presumed to be nutritionally sufficient. The first AAFCO nutritional substantiation method requires that the product contain adequate but not excessive quantities of all recognized essential nutrients compared with the AAFCO Profiles, such as amino acids, calcium, and vitamin A. These levels were established using the results of scientific studies demonstrating adequacy of a given nutrient and then adding adjustment factors to allow for differences in bioavailability of nutrients in commonly used ingredients. For the feeding trial method, a specified number of bitches or queens must be

fed the product as the sole source of nutrition (except water) from breeding through peak lactation (4 and 6 weeks after parturition, for dogs and cats, respectively). Performance is judged on acceptable maintenance of body weight compared with prebreeding, normal hematologic and serum biochemical values, and lack of any other clinical or pathologic sign of nutritional deficiency or excess. In addition, litter size, survivability, and weight of the puppies or kittens at the end of the trial must compare favorably to animals fed a ration previously shown to be complete and balanced nutritionally. The profile method and the feeding trial method have their advantages and disadvantages, and neither is perfect. Overall the feeding trial method is the preferred choice  of substantiation. However, under current AAFCO Model Pet Food Regulations for a “product family,” a pet food deemed to be “nutritionally similar” to a tested product can bear a statement suggesting completion of animal feeding tests, even though the food actually never underwent the feeding trial. This is particularly troublesome because products substantiated under the product family criteria share the disadvantages of the profile and the feeding trial methods and therefore offer the least assurance of nutritional adequacy. Some product family member labels may bear a statement that accurately reflects the fact that the product is “nutritionally similar” to a tested product, but because of a provision in the  regulations most circumvent this statement. Instead, most product family members bear the same statement  allowed on the tested “lead member” products. Thus  the veterinarian or pet owner may not know whether  the particular food was tested solely on the basis of labeling. The good news is that the majority of products bearing the “animal feeding tests” label statements also are formulated to meet the AAFCO Profiles but simply do not allude to that fact on the label. On the other hand, a product bearing the AAFCO Profile statement most probably has not been subject to a feeding trial. Because each method has its pros and cons the best assurance of nutritional adequacy is if the product meets both criteria. The manufacturer’s representative for any specific product should be able to attest to and document its product family status and whether the feeding-tested product also meets the AAFCO Profiles. Another component of the nutritional adequacy statement is the food’s suitability for the intended life stage. Few if any labels bear reference to nutritional adequacy for female reproduction. Instead, most cite suitability  for “all life stages,” which includes the rigorous demands of gestation and lactation. Not all intended uses of the product may be evident from the front panel designation. Many of the higher-end “adult” foods may in fact be suitable for all life stages, as would be indicated on the information panel. This is meant to distinguish the product from the manufacturer’s “puppy” or “kitten” product, which is generally a bit higher in nutrient density than the adult formula. Regardless, both have been held up to the same nutritional criteria, and, although relatively more of the adult formula may have to be fed compared with the growth formula, both should perform as expected. In some cases the all-life stage, “adult” formula

CHAPTER  210  Nutrition in the Bitch and Queen During Pregnancy and Lactation may be more appropriate for the dam with a propensity for excessive weight gain. Clients who prefer to offer a raw or other homeformulated food rather than a commercial food should realize that a given recipe from books, Internet websites, or elsewhere is not obligated to meet regulatory requirements to be “complete and balanced.” Although testimonials or other assurances of the suitability of a given home formulation may abound, clients should seek the advice of a board-certified veterinary nutritionist or other professional sufficiently trained to evaluate scientifically the nutritional content of the proposed diet. Furthermore, recipes in which ingredients are not cooked may present an increased risk of harboring potentially pathogenic organisms. To mitigate the possible risk to animal and human health, appropriate handling and sanitary measures must be followed.

Feeding Management Feeding management of the reproducing bitch or queen should begin well before breeding. Difficulties in conception, parturition, and successful rearing of healthy offspring may occur in a dam that is either underconditioned or overweight. Strategies to bring the dam to optimum weight should begin many months before expected breeding. By the time of mating, the bitch or queen should be at a stable, if not ascending, plane of nutrition. By no means should success be assumed if the animal is on a weight loss regimen at the time of breeding. Under AAFCO Model Pet Food Regulations, feeding directions are required on all “complete and balanced” product labels, although the ranges of recommended feeding amounts are often too broad to be useful. Also, foods meeting the “all life stage” nutritional criteria but designated just for adult use generally do not have directions for the pregnant or lactating dam. A preferred method to determine amounts to be fed is to calculate the energy needs of the animal as described previously and then compare them to the calorie content of the diet. Voluntary calorie content label statements are allowed; however, except as required for “lite” or “less calories” products intended for weight loss, these statements rarely appear on the label. If stated, the energy content must be expressed in terms of kilocalories per kilogram of food as fed. More consumer-friendly units (e.g., kilocalories per cup or can) also may be given. If the latter information is not provided, measuring the number of cups in a known weight of food such as a 20-pound bag usually gives a more accurate estimate than trying to weigh precisely a single cup of product. In 2005 the ACVN proposed an amendment to the AAFCO regulations to require calorie content statements on all dog and cat food labels and to require these statements in terms of kilocalories of ME per kilogram and kilocalories of ME per cup or can. The amendment was adopted by AAFCO in January 2013, and the revised regulations will appear in the 2014 Official Publication. However, there will be a grace period for enforcement. Although the length of time to allow for complete compliance has yet to be decided, it is possible that some products may not bear the required calorie content

965

statement until 2017. Until that time, alternative methods of determining calorie content may be necessary. If the label calorie content information is absent or incomplete, the manufacturer’s representative may be able to provide that information. Alternatively, calorie content can be estimated from the guaranteed analysis values using the following formula: ME ( kcal/kg as fed ) = [(3.5 × CP ) + (8.5 × CF) + (3.5 × NFE )] × 10 where CP = percentage of crude protein, CF = percentage of crude fat, and NFE = percentage of nitrogen-free extract (carbohydrate), which is 100 minus the sum of percentages for crude protein, crude fat, crude fiber, moisture, and ash (AAFCO, 2013). This formula tends to overestimate the true calorie content of high-fiber or poor-quality foods and underestimate that of very digestible products. However, the equation tends to be more predictive of true caloric content for cat foods than for dog foods, not because of a species difference but probably because of less variability in crude fiber and NFE content between cat foods. A reportedly more accurate, albeit more complicated, calculation of ME for dog foods has been suggested by the NRC (2006): Gross energy (GE ) = (5.7 × CP ) + (9.4 × CF) + [ 4.1 × ( NFE + % crude fiber )] Percentage energy digestibility (PED) = 91.2 − [1.43 × (% Crude fiber/ proportion dry matter)] Digestible energy (DE ) = GE × PED/100 ME = [ DE − (1.04 × CP )] × 10 A similar equation also exists for cat foods but with different values used to estimate energy digestibility and energy loss from metabolism. An example of estimation of ME for a dog food using both methods on the same guaranteed analysis values is found in Figure 210-3. The NRC method does yield a higher estimate for this relatively higher-fat, lower-fiber example. As an alternative to using the NRC method, substitution of the coefficients for CP, CF, and NFE with the values 4, 9, and 4, respectively, in the previous AAFCO formula may yield more accurate results when estimating the calorie content of a higher-quality or homemade diet for either a cat or dog. Regardless, the AAFCO formula is still a good means of comparing energy content among products. Because this formula calculates energy on an as-fed basis, further conversion to dry matter (i.e., the derived value divided by the proportion of the nonmoisture component of the diet) is necessary to compare among products of different moisture contents such as a dry versus a canned or semi-moist product. Regardless of feeding directions or previous estimates of energy needs, an individual animal may vary greatly in its true requirements. Therefore careful monitoring of body weight and body condition score, with adjustment

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Guaranteed analysis: Crude protein 28% Crude fat 16% Crude fiber 3% Moisture 10% Ash 5% 62% Nitrogen-free extract (NFE)  100%  62%  38% Proportion dry matter  (100%  10%)/100%  0.9 AAFCO Method 28  3.5  98 16  8.5  136 38  3.5  133 Total 367 Calorie content  367  10  3670 kcal ME/kg as fed  3670/0.9  4078 kcal ME/kg dry matter NRC Method 28  5.7  159.6 16  9.4  150.4 41  4.1  168.1 Total 478.1 91.2  (1.43  3/0.9)  86.4 478.1  86.4/100  413 413  (1.04  28)  384 Calorie content  384  10  3840 kcal ME/kg as fed  3840/0.9  4267 kcal ME/kg dry matter

Figure 210-3  Example of estimating calorie content in a dog

food from label guaranteed analysis values using Association of American Feed Control Officials and National Research Council formulas.

in intake as needed to maintain optimum condition, is warranted. In the bitch, no change in food, feeding amount, or frequency usually is indicated the first two thirds of gestation. A temporary drop in voluntary food consumption may be observed during estrus and again in midgestation, but this is normal and does not indicate a need for adjusting the feeding management as long as body weight and condition are acceptable. Beginning about 3 weeks before expected whelping, a gradual increase in nutrient intake should be initiated. This can be done simply by increasing the amount of food offered or by switching to a more calorie-dense food. The frequency of feeding may have to be increased to accommodate the increased intake. By time of parturition, a calorie intake approximately 50% above prebreeding needs should be anticipated.

In the queen, an increase in feeding amounts should begin immediately after mating. At this stage, free-choice feeding usually is indicated if not already the norm. If the recommended energy allowance of 25% to 50% above maintenance needs is not met by increased consumption, a change to a more calorie-dense food is prudent. As with the bitch, some fluctuation in appetite during gestation may be observed but generally does not indicate a problem as long as body weight continues to increase. As the dam enters peak lactation, caloric requirements may double or more for queens and triple or more for bitches. If not already switched during gestation, switching the diet to a more energy-dense product generally is indicated. Offering food free choice may be necessary for the bitch to be able to consume adequate quantities throughout the day. Some degree of weight loss compared with prebreeding may be anticipated; however, if body weight drops more than a few percent below weight at maintenance, a more calorie-dense food should be offered. As the offspring are weaned and the dam regains any lost weight, the amounts offered can be cut back slowly so that she is near normal food intake and body weight by the time milk production has ceased. Assuming that the appropriate food is selected as discussed previously, no dietary supplementation should be necessary. At best supplements may do no harm, but injudicious use may create nutrient excesses. The example of calcium is given earlier. However, even something  as simple as added fat to increase total caloric intake  may be detrimental if it suppresses intake of the mainstay diet because it decreases intake of all other essential nutrients.

References and Suggested Reading Association of American Feed Control Officials: Official publication, Oxford, Ind, 2013, AAFCO. Bauer JE et al: Retinal functions of young dogs are improved and maternal plasma phospholipids are altered with diets containing long-chain n-3 polyunsaturated fatty acids during gestation, lactation, and after weaning, J Nutr 136(suppl):1991S, 2006. Case LP et al: Canine and feline nutrition, ed 3, St Louis, 2010, Mosby. Debraekeleer J, Gross KL, Zicker SC: Feeding reproducing dogs. In Hand MS, editor: Small animal clinical nutrition, ed 5, Topeka, Kan, 2010, Mark Morris Institute, p 281. Dzanis DA: Ensuring nutritional adequacy. In Kvamme JL, Phillips TD, editors: Petfood technology, Mt. Morris, Ill, 2003, Watt Publishing, p 62. National Research Council: Nutrient requirements of dogs and cats, Washington, DC, 2006, National Academies Press. Zicker SC et al: Evaluation of cognitive learning, memory, psychomotor, immunologic, and retinal functions in healthy puppies fed foods fortified with docosahexaenoic acid–rich fish oil from 8 to 52 weeks of age, J Am Vet Med Assoc 241:583, 2012.

CHAPTER 

211 

Pyometra FRANCES O. SMITH, Burnsville, Minnesota

P

yometra is a disease of the uterus, literally meaning pus in the uterus. Similar clinical entities include mucometra and hydrometra. Pyometra typically occurs in the estrogen-primed uterus during the period of progesterone dominance (diestrus) or thereafter (anestrus). It most commonly is diagnosed in an intact bitch from 4 weeks to 4 months after an estrous cycle. Pyometra is not as common in the queen as in the bitch because the queen is an induced ovulatory and thus does not experience repetitive estrogen and progesterone influences on the uterus. Many studies highlight an increased incidence of pyometra in nulliparous bitches and in bitches over 4 years of age. The queen has an increased incidence of pyometra with increasing age. In addition, African lions have been shown to have an increased risk of developing pyometra. Pregnancy has a sparing effect on the uterus. In one study of multiple breeds, previous pregnancy had a protective effect on the incidence of pyometra in the rottweiler, collie, and Labrador retriever but was not protective for the golden retriever. Thus protective factors and risk factor may vary between breeds. There is no correlation between clinical signs of false pregnancy and pyometra in the bitch.

Pathogenesis In one colony of beagles the incidence of pyometra was 15.2% of bitches older than 4 years of age, with the average age of onset 9.36 ± 0.35 years (Fukuda, 2001). In a population of insured dogs in Sweden in which routine ovariohysterectomy is disallowed, the crude 12-month incidence of pyometra over the 2-year period from 1995 through 1996 was approximately 2% in bitches under 10 years of age (Egenvall et al, 2001). A recent publication involving Swedish bitches lists the incidence of pyometra of bitches under 10 years of age at 25% (Hagman et al, 2011). The pathogenesis of pyometra in the bitch involves estrogen stimulation followed by prolonged periods of progesterone dominance. Progesterone results in endometrial proliferation, glandular secretions, and decreased myometrial contractions. Leukocyte inhibition in the progesterone-primed uterus tends to support bacterial growth. These effects are cumulative with each estrous cycle, exacerbating the uterine pathology. Cystic endometrial hyperplasia (CEH) pyometra has four stages.  Stage one is uncomplicated CEH. Stage two is CEH with

endometrial infiltration of plasma cells. Stage three is CEH with acute endometritis. Finally, Stage four is CEH with chronic endometritis. Estrogen therapy is associated with an increased risk of pyometra in bitches from 1 to 4 years of age. Use of estrogens (estradiol cypionate) for mismating in diestrous bitches is particularly dangerous and has resulted in approximately a 25% occurrence rate of pyometra. Furthermore, use of estrogens in the bitch has a potential for idiosyncratic, non–dose-related bone marrow suppression. The one (and only) time this author used estradiol cypionate for mismating in an 18-month-old golden retriever resulted in an open cervix pyometra. In queens, the administration of medroxyprogesterone acetate for estrus suppression increases the risk for development of pyometra. Risk for pyometra is increased in several breeds, including the golden retriever, miniature schnauzer, Irish terrier, Saint Bernard, Airedale terrier, cavalier King Charles spaniel, rough collie, rottweiler, and Bernese mountain dog.

Clinical Findings The medical history of a female dog with pyometra can be nonspecific. The queen may have nonspecific illness and a vaginal discharge. In older bitches the client may not recognize an estrous cycle and assume that the bitch has experienced “menopause.” The client also may mistake a serosanguineous vaginal discharge associated with pyometra with that of a normal estrus. Vaginal cytology helps to differentiate the prevailing hormonal events at the time of initial examination. Clinical history of bitches and queens with pyometra often includes depression, inappetence, polydipsia, polyuria, lethargy, and abdominal enlargement with or without vaginal discharge. Pyometra always should be in the differential diagnosis of a sick, intact bitch or queen. Bitches and queens with pyometra typically are afebrile. An elevated white blood count is typical, and hyperproteinemia and hyperglobulinemia also are common. An acute phase protein α-1-acid glycoprotein is elevated in the bitch with pyometra; however, this test is not readily available in clinical practice. Prerenal azotemia accompanies dehydration, but urine-concentrating ability may be impaired. Bitches with pyometra that have  urine protein creatinine ratio (UPC) greater than 1.0 or high ratios of urinary biomarkers may have clinically 967

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significant renal lesions and should receive follow-up monitoring of renal function after the resolution of the pyometra. Cystocentesis is associated with the risk of perforation of the fluid-filled uterus and possible spillage of uterine contents into the abdomen. The most common organism isolated from the uterus or vaginal discharge of a bitch with pyometra is Escherichia coli. Culture and sensitivity of the vaginal discharge or of intrauterine fluid at the time of ovariohysterectomy should be performed to guide antibiotic therapy. The vaginal discharge in the CEH/pyometra complex may be purulent, sanguinopurulent (the color and consistency of tomato soup), mucoid, or frankly hemorrhagic. Vaginal discharge of any description should alert the clinician to include pyometra in the differential diagnosis. Other causes of vaginal discharge include vaginitis, estrus, immune-mediated thrombocytopenia (bloody discharge), anticoagulant toxicity, metritis, and subinvolution of placental sites. Diagnosis is accomplished best with ultrasonography and/or radiography. The classic radiographic finding is a fluid-filled, tubular organ between the descending colon and the bladder that presents a sausage-like appearance. The uterus is visualized best with a lateral abdominal radiograph. A fluid-filled organ can be identified ultrasonographically, and the uterine wall thickness and proliferative changes also can be noted.

Therapy The preferred treatment for any aged or ill bitch or for a bitch or queen with closed cervix pyometra is complete ovariohysterectomy. Medical treatment of bitches with closed cervix pyometra may result in uterine rupture or in seepage of uterine contents into the abdomen. This author does not advocate the use of medical management for any bitch with a closed cervix pyometra. Surgical uterine drainage and lavage with a 5% povidone-iodine in saline solution via transcervical catheterization was successful in the treatment of eight bitches with pyometra. All eight bitches conceived and whelped after treatment (DeCramer, 2010). Bitches that are seriously ill should be stabilized medically with appropriate intravenous fluid therapy and broad-spectrum antibiotics before surgery. The clinician should be prepared to deal with bacteremia and endotoxemia. Disseminated intravascular coagulation is an infrequent but possible complication of pyometra. Young bitches or queens with breeding value and an open cervix, normal organ function, together with a compliant and reasonable owner, may be treated with prostaglandins. Prostaglandins increase myometrial contractility, encourage cervical relaxation, allow expulsion of the uterine contents, and with repeated doses result in lysis of the corpus luteum. Serum progesterone should be measured before treatment with prostaglandins. The most frequently administered drug is prostaglandin F2α (PGF2α) at a dosage of 250 µg/kg q12h SC until the uterus reduces to near normal in size, which typically takes 3 to 5 days. Therapy that requires a longer treatment period or a recurrence of fluid in the uterus signals a negative prognosis for prostaglandin treatment success. In 20

queens treated for open cervix pyometra with PGF2α, 90% responded to therapy and subsequently delivered a normal litter (Johnston, Kustritz, and Olson, 2001). A vaginal culture should be obtained before treatment, and appropriate antibiotics administered for 3 to 4 weeks after therapy. Many other protocols have been published, starting with doses of PGF2α as low as 50 µg/kg and gradually increasing to 250 µg/kg over the treatment period to decrease the side effects of panting, nausea, salivation, vomiting, and diarrhea—all of which are commonly seen 15 to 45 minutes after each injection. The side effects decrease in severity with each dose. One study described the use of PGF2α (150 µg/kg) in 17 bitches with pyometra administered by infusing 0.3 ml/10 kg of body weight into the vaginal canal one or two times daily for 4 to 12 days (Gabor, Siver, and Szenci, 1999). Bitches received intramuscular antibiotics and the intravaginal infusion. Treatment was effective in 86.6% of these bitches. It has been reported that cloprostenol, a PGF2α analog, has been used successfully for treatment of open cervix pyometra. However, this author does not use cloprostenol because it is far more potent and has great potential for accidental overdosage. Also, progesterone receptor blockers (e.g., mifepristone and aglepristone) have been used to treat open cervix pyometra in Europe. Aglepristone treatment was most effective in bitches under 5 years of age. These antiprogestins are not commercially available in the United States. Prostaglandins are not approved for small animal use in the United States; thus an informed consent form, including risks of treatment, should be obtained before therapy. In this author’s opinion, prostaglandins should never be dispensed for client administration because of the narrow safety index and the potential  for triggering asthmatic events and pregnancy loss in humans. Bitches treated with prostaglandins may have their interestrous interval shortened slightly. The bitch should have a vaginal culture, be treated with appropriate antibiotics, and be bred to a fertile male at her next estrous cycle. Success results in conception rates of 50% to 65%. Fertility in bitches after pyometra therapy is decreased when compared with normal bitches. Failure to conceive or failure to be bred results in a high incidence of recurrence of pyometra, with recurrence rates as high as 77%. This author has observed pyometra in subsequent generations of chow-chows and English setters of young age, suggesting a possible familial tendency toward early development of CEH in these animals.

References and Suggested Reading Bowen RA et al: Efficacy and toxicity of estrogens commonly used to terminate canine pregnancy, J Am Vet Med Assoc 186:783, 1985. De Cramer KG: Surgical uterine drainage and lavage as treatment for canine pyometra, J S Afr Vet Assoc 81:172, 2012. Egenvall A et al: Breed risk of pyometra in insured dogs in Sweden, J Vet Intern Med 15:530, 2001. Fukuda S: Incidence of pyometra in colony-raised beagle dogs, Exp Anim 50:325, 2001. Gabor G, Siver L, Szenci O: Intravaginal prostaglandin F2 alpha for the treatment of metritis and pyometra in the bitch, Acta Vet Hung 47:103, 1999.

CHAPTER  212  Vulvar Discharge Hagman R: Serum α-1-acid glycoprotein concentrations in 26 dogs with pyometra, Vet Clin Pathol 40:52, 2011. Hagman R et al: A breed-matched case-control study of potential risk-factor for canine pyometra, Theriogenology 75(7):1251, 2011. Johnston SD, Kustritz MV, Olson PNS: Disorders of the canine uterus and uterine tubes (oviducts). In Johnston SD, Kustritz MVR, Olson PNS, editors: Canine and feline theriogenology, Philadelphia, 2001, WB Saunders, p 206-469.

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Jurka P et al: Age-related pregnancy results and further examination of bitches after aglepristone treatment of pyometra, Reprod Domest Anim 45:525, 2010. Maddens B et al: Evaluation of kidney injury in dogs with pyometra based on proteinuria, renal histomorphology and urinary biomarkers, J Vet Intern Med 25:1075, 2011. Troxel MT et al: Severe hematometra in a dog with cystic endometrial hyperplasia/pyometra complex, J Am Anim Hosp Assoc 38(1):85, 2002.

212 

Vulvar Discharge RICHARD WHEELER, Fort Collins, Colorado

V

aginal discharge, more accurately described as vulvar discharge, is a common presentation of intact or spayed bitches. Too often it is diagnosed errone­ ously as vaginitis, when in fact it is a symptom of an underlying problem of the urogenital system. The dis­ charge actually may originate from the perivulvar region, vulva, vestibule, cervix, uterus, urethra, or urinary bladder with or without involvement of the vagina. Vulvar dis­ charge in queens is uncommon and usually has a uterine cause (e.g., pyometra). Inappropriate use of antibiotics (overuse or insufficient duration) and failure to address the inciting cause are the most common reasons for treat­ ment failure.

Clinical Signs Presenting complaints include vulvar discharge, vulvar licking, vulvar swelling and hyperemia, clitoral hypertro­ phy, “scooting,” pollakiuria, or recurrent urinary tract infections. Vulvar discharge may be mucoid, mucopuru­ lent, purulent, or hemorrhagic. Purulent discharge may be suppurative (indicating irritation or infection) or  lymphocytic (indicating allergic or immune mediated). Vaginal cytology rarely determines the etiology of the inflammation but confirms the presence of neutrophils. Degenerate neutrophils with swollen nuclei and intra­ cellular bacteria indicate a septic component, whereas  neutrophils with hypersegmented nuclei suggest a non­ infectious, reactive component. A speculum or vagino­ scopic exam is necessary to determine if the purulent discharge is confined to the vestibule or extends from the vagina. In spayed or nonestrous bitches, vaginal examina­ tion may require heavy sedation or anesthesia.

Etiology Uterine Causes In intact bitches, normal vulvar discharge originates from the uterus. It may be estral bleeding, cervical mucus during late gestation, fetal fluids at parturition, or lochia for up to 4 weeks after parturition. All other vulvar dis­ charges in intact female dogs and all vulvar discharges in spayed females are abnormal. Pathologic uterine causes of vulvar discharges in intact and spayed bitches are sum­ marized in Table 212-1. Involvement of the uterus must be ruled out when working up the complaint of vulvar discharge. Further insight into uterine diseases is beyond the scope of this chapter.

Lower Reproductive Tract Causes The causes of vulvar discharges (not originating from the uterus) are similar in intact or spayed dogs and can be categorized broadly as causing vaginitis (inflammation of the vaginal vault from the vaginovestibular junction to the cervix), vestibulitis (inflammation of the vestibule from the vulvar mucosal margin to the vaginovestibular junction), and perivulvar dermatitis (inflammation of the skin around the vulva). These three entities may occur independently or one may incite either or both of the other two conditions. Also, a bacterial component may or may not be present. Proper treatment relies on eluci­ dating and resolving the inciting condition. Vaginitis Vaginitis is inflammation, and commonly infection, of the mucosa cranial to the vaginovestibular junction

SECTION  X  Reproductive Diseases

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TABLE 212-1 

TABLE 212-2 

Pathologic Uterine Causes of Vulvar Discharges   in Intact Bitches and Spayed Bitches with a Uterine Stump

Aerobic Bacteria Isolated from the Vagina of Healthy Dogs Aeromonas

Alcaligenes faecalis

Intact

Spayed

Bacillus spp.

Bacteroides spp.

Subinvolution of placental site (SIPS)

Stump pyometra-ovarian remnant syndrome

Chlamydia psittaci*

Corynebacterium spp.

Clostridium perfringens*

Escherichia coli*

Pyometra

Suture reaction (granulomatous)

Enterococcus*

Enterobacter spp.*

Metritis

Infection (e.g., Brucella canis, enterics)

Flavobacterium

Lactobacillus

Ovarian diseases resulting in persistent estrus

Neoplasia

Haemophilus spp.

Klebsiella spp.*

Micrococcus

Moraxella

Neisseria

Pasteurella spp.

Proteus spp.*

Plesiomonas

Pseudomonas spp.

Staphylococcus aureus*

Staphylococcus intermedius*

Staphylococcus pseudintermedius

Streptococcus spp. (β-hemolytic)*

Streptococcus spp. (α-hemolytic)

Uterine neoplasia

Vagina

Ovaries

External uterine ostium of cervix Uterine body

Uterine horns

Fornix Bladder

Vaginovestibular junction Vestibule

Streptococcus pyogenes* *Bacteria isolated from dogs with vulvar discharge.

Clitoris Clitoral fossa

Figure 212-1  The canine female reproductive tract comprises

ovaries, uterus, cervix, vagina, vaginovestibular junction, vestibule, vulva, and clitoris. (Used with permission from Johnston SD, Root Kustritz MV, Olson PNS: Sexual differentiation and normal anatomy of the bitch. In Johnston SD. Root Kustritz MV, Olson PNS, editors: Canine and feline theriogenology, Philadelphia, 2001, WB Saunders, p 1 [Figure 1-5A on page 6].)

(Figure 212-1) and is most often the symptom of an underlying problem. It often presents as purulent or mucopurulent vulvar discharge, and it must be differenti­ ated from vestibulitis, pyometra, and other diseases that present as vulvar discharge. Direct visualization of the vaginal canal by speculum or vaginoscope helps to  elucidate whether the discharge is originating from the vestibule, vagina, or cranial to the cervix. Cytologic examination and culture of a guarded swab passed cranial to the vestibule may implicate vaginal involvement. Finally, a vaginal biopsy definitively indicates the pres­ ence or absence of inflammation in the vagina. Vaginitis often is categorized into juvenile (puppy) vaginitis or adult-onset vaginitis. Juvenile (Puppy) Vaginitis.  Juvenile vaginitis com­ monly is seen in bitches between 6 weeks and 1 year of age. It develops as the bitch establishes a symbiotic rela­ tionship with her endogenous bacteria and naïve vagina. Puppy vaginitis may persist for months without detri­ mental effects on the puppy. In fact, juvenile vaginitis usually poses greater distress to the owner than to the

puppy. Cytologic evaluation of the discharge usually demonstrates mature, hypersegmented, nondegenerate neutrophils; culture often results in no significant growth (that is, either no growth or low-level, mixed populations of normal vaginal flora [Table 212-2]). Owners often request antibiotic treatment; however, conservative treatment usually is advised. Antibiotic therapy may predispose to opportunistic bacterial over­ growth in the absence of normal bacterial flora and devel­ opment of antibiotic resistant strains of bacteria. If puppy vaginitis persists for more than 2 months or becomes excessive, irritating, or problematic, antibiotic therapy may be initiated based on culture and sensitivity results. However, discharge commonly returns when antibiotics are discontinued. Conflicting opinions exist whether to spay affected bitches before the first estrus. The rationale for waiting until after the first estrus is that the influence of estradiol on the vaginal mucosa increases vascular circulation and local immune function, thereby clearing up the vaginitis. No clear evidence supports or disparages this theory. Adult-Onset Vaginitis.  Adult-onset vaginitis in the dog is often idiopathic. Common etiologies for vaginitis in adults include primary infections (Brucella canis or canine herpesvirus), infection secondary to a foreign body, urinary incontinence or urine pooling, ascending infections from vestibulitis, tumors or masses of the vagina, and abnormal development of the vagina such as strictures or vaginal bands. Vestibulitis Vestibulitis, or inflammation of the vestibule, involves the region from the vulvar mucosal junction to the

CHAPTER  212  Vulvar Discharge

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B Figure 212-2  A hooded vulva predisposes the bitch to vestibulitis, perivulvar dermatitis, and

vulvar discharge. The dorsal vulvar fold envelops more than one third of the lateral folds of the vulva (A), which is surgically resolved with vulvoplasty (B).

vaginovestibular junction (see Figure 212-1). Vestibulitis is perhaps the most common cause of purulent vulvar discharge and vulvar licking. It frequently occurs as a primary condition without involving the vagina or peri­ vulvar region. Conformational abnormalities of the vulva (such as inverted vulvar folds, hooded vulva, clitoral hypertrophy, or ectopic hairs) and perineum (excessive perivulvar fat folds), or urinary incontinence (possibly subclinical) may induce mucosal irritation and subse­ quent vulvar discharge. Perivulvar Dermatitis Perivulvar dermatitis is inflammation of the skin around the vulva. Perivulvar dermatitis is caused commonly by allergies. Atopy commonly induces a histamine response associated with the perivulvar region as well as the axilla, interdigital spaces, and auricula. However, allergies do not appear to be associated with primary vestibulitis or vaginitis. Perivulvar dermatitis also may result from the same conformational defects and urinary incontinence that cause vestibulitis. The ensuing perivulvar irritation caused by any of these conditions induces chronic vulvar licking, which further maintains a moist environment, aggravates the condition, and often induces a swollen, erythematous vulva. Trapped or persistent moisture leads to secondary bacterial or yeast infections of the perivulvar skin, vestibule, or vagina. Yeasts isolated from the vagina and perineum of dogs include Candida spp., Rhodotorula spp., and Malassezia pachydermatis. These yeasts appear to be commensal organisms of the vagina and are not involved in causing vaginitis or vestibulitis. Chronic licking of the perivulvar region may result in develop­ ment of a secondary vestibulitis or ascending vaginitis. Conversely, vestibulitis or vaginitis may initiate chronic licking that then results in secondary perivulvar dermati­ tis. Treatment of perivulvar dermatitis requires resolving the inciting cause and long-term antibiotics (4 to 6 weeks) to resolve completely the associated dermatitis to avoid reoccurrence.

Predisposing Factors Conformational or Functional Hooded Vulva Hooded vulva (Figure 212-2), also called “juvenile vulva,” is a conformational defect in which the dorsal fold of the vulva envelops and covers more than one third of the lateral vulvar folds. The overhanging skin traps moisture and predisposes the bitch to perivulvar dermatitis and vestibulitis. The entrapped hair also causes chronic irrita­ tion of the vulvar mucosa, contributing to vestibulitis. Clinically, it presents with vulvar discharge and vulvar licking. It is treated successfully by vulvoplasty (see Chapter 213). Vestibulovaginal Stenosis Narrowing of the reproductive tract at the level of the vaginovestibular junction is conformationally and func­ tionally normal (see Figure 212-1). This narrowing pre­ vents or limits ascending infection and retrograde movement of urine or foreign bodies into the vaginal vault. In maiden bitches, this is the location of the hymen, which may or may not be intact. The vaginoves­ tibular junction is significantly narrow in bitches spayed before their first estrus (early [juvenile] spaying) because the reproductive tract has not matured; this should not be confused with vaginal stenosis. Vestibulovaginal ste­ nosis is defined as when the ratio between the maximum vaginal lumen diameter and the diameter of the vaginal lumen at the level of the vaginovestibular junction is less than 0.33 as measured by retrograde vaginourethrogra­ phy. A follow-up study showed no significance to narrow­ ing of the vagina until the ratio approached less than 0.20 (Crawford and Adams, 2002). Strictures commonly are diagnosed as the cause of vaginitis; however, they are most likely incidental findings to which a diagnosis is attributed (Wang et al, 2006a; Wang et al, 2006b). Surgi­ cal correction of these strictures has not been shown to significantly affect resolution of vaginitis.

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Vestibulovaginal Bands Vestibulovaginal bands are vertical bands at the level of the vaginovestibular junction. They are remnants of embry­ onic development, in which fusion of the cranial and caudal vagina is incomplete. Although they often are implicated in causing vaginitis, they are likely incidental findings because many normal bitches are diagnosed with similar bands and no history of vaginitis. Surgical correc­ tion of vertical bands has not been shown to significantly resolve vaginitis. Clitoral Hypertrophy Clitoral hypertrophy occurs as a primary condition in pseudohermaphrodites and as a result of fetal masculin­ ization from in utero exposure to exogenous progestins or testosterone. Clitoral hypertrophy also can develop from postnatal exposure to exogenous androgens (e.g., testosterone, mibolerone) or exogenous estrogens (e.g., diethylstilbestrol, topical human estrogen replacements). Chronic irritation and masturbation also can result in enlargement of the clitoris. Chronic exposure of the enlarged clitoris can result in desiccation, inflammation, and excoriation as well as ascending infection of the vestibule and vagina. If the inciting cause for clitoral hypertrophy cannot be determined and eliminated, clito­ ridectomy may be curative. Neoplasia The most common neoplasms affecting the vestibule and vagina are fibromas, polyps, leiomyomas, and transmis­ sible venereal tumors. These have been covered in more detail in Chapter 222. Foreign Body Incidence of vaginal foreign bodies as the cause of vagi­ nitis and vulvar discharge has been documented, but it is rare. Vaginoscopy is the diagnostic tool of choice. The most common foreign bodies are iatrogenic or fetal remains from prior pregnancies.

Infectious Viral Canine Herpesvirus.  Canine herpesvirus infection can cause vesicular lesions on the vaginal or vestibular mucosa surface and may result in a secondary bacterial infection and subsequent vulvar discharge. Canine her­ pesvirus infection usually is self-limiting and does not require treatment. Bacterial Culture of suppurative vulvar discharge or a vaginal swab usually results in mixed growth of normal vaginal bacte­ ria (see Table 212-2). Growth of a single type of bacteria may indicate bacterial overgrowth of a more virulent or opportunistic strain of bacteria, indicating an upset to normal bacterial flora. Culture rarely implicates a single bacterial agent and rarely elucidates the cause of vulvar discharge. Brucella canis.  Brucella canis is the only primary bac­ terial pathogen of the canine urogenital tract. It is an intracellular, gram-negative coccobacillus that localizes in

the reproductive tract, eye, and spinal column. The inci­ dence of B. canis is increasing in the United States in recent years because of the increased relocation of stray and abandoned dogs and increased breeding and use of shipped semen. B. canis rarely causes a primary vaginitis but should be considered in cases of chronic vulvar dis­ charge because infection of the uterus or uterine stump by B. canis is possible. Screening for B. canis is done routinely by a rapid card agglutination test or tube agglutination test. Both tests detect antibodies to Brucella spp. with a high sensitivity but low specificity. 2-Mercaptoethanol may be added to improve specificity and therefore rule out false-positive tests. Confirmation of all positive tests is recommended by agar gel immunodiffusion. The greatest limitation to serologic testing is the delay of seroconversion, which may take up to 12 weeks after exposure to be detectable. Chronically infected animals may have titers too low to detect (after 1 to 5 years), resulting in false negatives (e.g., negative test on a truly infected animal). Culture is the definitive positive diagnostic test; however, if the affected animal is not bacteremic at the time of sampling or if the bacteria go undetected because of low concentrations or overgrowth by other bacteria, false negatives can occur. Recent advances in ELISA and PCR technologies may make rapid detection of a very low concentration of B. canis possible and appear promising in the future diagno­ sis of B. canis. Serology and culture should be used in conjunction to identify reliably infected animals; testing should be repeated at multiple time points if indicated. Recommended treatment of animals infected with B. canis is euthanasia to prevent the spread of B. canis to other dogs or people. (B. canis is zoonotic but is not con­ tracted as easily as B. abortus or B. ovis.) The zoonotic potential of B. canis is becoming especially relevant with the increase in immune-compromised persons living with pets. Neuter (spay or castration) and long-term antibiotics can be attempted as treatment. However, the potential for transmission (although low) remains relevant because B. canis is not eliminated completely from the site of infec­ tion because antibiotic penetration into the cells is diffi­ cult. Antibiotic protocols include doxycycline (10 mg/kg q12h PO) in conjunction with rifampin (20 mg/kg q12h PO) for a minimum of 30 days; or enrofloxacin (5 mg/kg q12h PO) alone for a minimum of 30 days. However, owners who choose treatment over euthanasia should be warned of the potential for recurrence and transmission (to humans and other dogs). The dog should be isolated from all other dogs for the rest of its life and rechecked every 6 months by blood or vaginal swab culture for recrudescence and retreated if indicated. Mycoplasma Species.  Mycoplasma spp. are gramnegative, intracellular bacteria with no cell wall. They can be diagnosed easily and routinely in culture, but special requests using special media are necessary. Some Mycoplasma spp. do not grow well in culture and may go undetected. Mycoplasma is a commensal isolate from the canine vagina (23% to 73% normal dogs) and is consid­ ered normal bacterial flora (Box 212-1). The incidence of Mycoplasma isolation increases after antibiotic therapy. In addition to the reproductive tract, species of Mycoplasma have been isolated from the respiratory tract, oral cavity,

CHAPTER  212  Vulvar Discharge

BOX 212-1  Isolates within the Mycoplasma Family (Mycoplasmataceae) from Healthy Dogs Mycoplasma arginine Mycoplasma bovigenitalium* Mycoplasma canis*†‡ Mycoplasma cynos*‡ Mycoplasma felis Mycoplasma feliminutum* Mycoplasma gateae* Mycoplasma haemocanis Mycoplasma edwardii*† Mycoplasma molare*†‡ Mycoplasma maculosum*† Mycoplasma opalescens† Mycoplasma spumans*† Ureaplasma canigenitalium*†‖ Acholeplasma laidlawii*§‖ *Isolated from canine genital tract. †Canine specific. ‡Sialidase secreting. §Specific to canine genital tract. ‖Belonging to the same class of “Mollicutes” and genetically isolated with the same DNA primers used for Mycoplasma species.

and auricular canal. Mycoplasma canis is the species most commonly isolated from the vagina. Some disease conditions (e.g., canine infectious respi­ ratory disease, also known as kennel cough) may be caused by Mycoplasma synergistically working with other infectious agents. Mycoplasma has a known synergistic relation in inducing infertility and abortion in ruminants, but no distinct correlation has been made in dogs. Although it is suspected in cases of canine infertility, pregnancy loss, and chronic vaginitis, experimental infec­ tions with M. canis have failed to fulfill satisfactorily Koch’s postulates in reliably inducing disease. Further investigation is necessary to determine if specific Mycoplasma spp. are associated with infertility or abortion in bitches. Sialidase is a known virulence factor of bacteria and has been found in certain strains of Mycoplasma spp. in dogs. It functions by increasing microbial colonization and facilitating tissue invasion by inducing molecular damage to cell walls and extra cellular matrix. Sialidaseproducing Mycoplasma spp. may be more virulent and someday may be shown to affect fertility adversely. Anti­ biotic treatment (e.g., doxycycline [5 mg/kg q12h PO] or enrofloxacin [5 to 10 mg/kg q12h PO]) often is used empirically as a treatment against Mycoplasma spp. for chronic vaginitis or infertility.

Treatment Successful treatment of vulvar discharge is aimed at resolving the inciting cause. Many cases of adult-onset vaginitis and most cases of juvenile-onset vaginitis resolve with no specific treatment. Oral supplementation of pro­ biotics has been shown to help maintain or establish healthy bacterial flora in the gut, and extrapolation to the vagina has been suggested. Some species of Lactobacillus

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and Enterococcus alter the vaginal pH and may inhibit pathologic overgrowth of bacteria. Orally administered probiotic bacteria do transfer to the urogenital tract by fecal-oral transfer; but no benefit in treating or preventing vaginitis has been shown. Treatment with antibiotics is discouraged unless an inciting cause has been diagnosed and treated or if peri­ vulvar dermatitis is present. If antibiotics are used, their selection should rely on culture and sensitivity results. Numerous studies have isolated antibiotic-resistant bacte­ ria, including methicillin-resistant Staphylococcus pseudintermedius from the canine vagina. Some veterinarians have been advocates of dilute Betadine solution or chlorhexi­ dine solution lavage of the vagina in lieu of antibiotics. No evidence suggests that this facilitates a cure, and it has been implicated in delayed healing, supposedly from chronic irritation either from the retention of fluid or abrasion from the delivery device. In addition, dilute vinegar lavages or commercially available human vaginal douches are not indicated because canine vestibulitis and vaginitis have not been shown to be caused by yeasts. Corticosteroid therapy in conjunction with antibiotics seems beneficial when allergies or immune stimulation appears to be related to the cause. This is the case with perivulvar dermatitis or when lymphocytes are present on cytologic evaluation of the vulvar discharge. Some cases of vulvar discharge respond well to estro­ gen therapy. Estrogen increases the thickness of the vaginal mucosa (increasing resistance to bacteria) and increases blood supply to the vagina (improving immune function). Estrogen supplementation is most appropriate when urinary incontinence is present because it is prob­ ably the effect of diethylstilbestrol on urethral sphincter tone, which facilitates healing.

References and Suggested Reading Brito EHS et al: The anatomical distribution and antimicrobial susceptibility of yeast species isolated from healthy dogs, Vet J 182:320, 2009. Crawford JT, Adams WM: Influence of vestibulovaginal stenosis, pelvic bladder, and recessed vulva on response to treatment for clinical signs of lower urinary tract disease in dogs: 38 cases (1990-1999), J Am Vet Med Assoc 221:995, 2002. Johnston SD, Root Kustritz MV, Olson PNS: Sexual differentiation and normal anatomy of the bitch. In Johnston SD, Root Kus­ tritz MV, Olson PNS, editors: Canine and feline theriogenology, Philadelphia, 2001, WB Saunders, p 1. Keid LB et al: Comparison of agar gel immunodiffusion test, rapid slide agglutination test, microbiological culture and PCR for the diagnosis of canine brucellosis, Res Vet Sci 86:22, 2009. Makloski CL: Canine brucellosis management, Vet Clin North Am Small Anim Prac 41:1209, 2011. May M, Brown DR: Secreted sialidase activity of canine myco­ plasmas, Vet Microbiol 137:380, 2009. Rota A et al: Isolation of methicillin-resistant Staphylococcus pseudintermedius from breeding dogs, Theriogenology 75:115, 2011. Wang KY et al: Vestibular, vaginal, and urethral relations in spayed dogs with and without lower urinary tract signs, J Vet Intern Med 20:1065, 2006a. Wang KY et al: Vestibular, vaginal and urethral relationships in spayed and intact normal dogs, Theriogenology 66:726, 2006b. Wanke MM, Delpino MV, Baldi PC: Use of enrofloxacin in the treatment of canine brucellosis in a dog kennel (clinical trial), Theriogenology 66:1573, 2006.

CHAPTER 

213 

Surgical Repair of Vaginal Anomalies in the Bitch ROBERTO E. NOVO, Vancouver, Washington

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number of developmental and acquired conditions affect the canine vagina and vulva. Congenital conditions, which affect primarily younger dogs, include rectovaginal fistula; vulvar/vaginal hypoplasia; anovulvar cleft; clitoral enlargement; and vaginal septa, bands, or stenosis. Acquired conditions generally affect older dogs and include vaginal neoplasia and vaginal prolapse. Some acquired conditions such as vaginal hyperplasia and perivulvar dermatitis can affect younger dogs. Invariably congenital and acquired abnormalities overlap somewhat because some acquired anatomic problems may develop secondary to congenital abnormalities within the reproductive tract. Surgery to correct these abnormalities often corrects the presenting clinical signs. These procedures may be as simple as digital breakdown of a thin vaginal band or more complex (e.g., complete vaginal ablation).

Surgical Approaches to the Canine Vagina Most surgical procedures of the vagina (and vestibule) can be approached via a perineal or caudal episiotomy. More involved procedures may require a ventral approach, which may necessitate a combined abdominal approach with or without a pubic osteotomy. With either surgical approach, strong consideration should be given to management of postoperative pain. The use of a fentanyl patch or epidural analgesia should be considered before surgery. An appropriately sized fentanyl patch (4 µg/kg/ hr in dogs) should be applied the day before surgery. Alternatively, an epidural with the use of preservative-free morphine (0.1 mg/kg), bupivacaine (0.5 to 1 mg/kg), or a combination of both can be administered before or immediately after surgery. If epidural analgesia is elected, the surgeon should review the various techniques and dosing guidelines described in the veterinary literature.

Caudal Approach with Episiotomy When performing an episiotomy, the surgeon should place the animal in sternal recumbency with the pelvic limbs hanging over the end of the table. The edges of  the table should be well padded to avoid trauma to  the limbs. The table is tilted so that the animal’s head is down about 30 degrees and the vulva is at a comfortable working height. This head-down position may make ventilation of the patient more difficult, requiring assisted manual or mechanical ventilation to maintain adequate 974

oxygenation and anesthetic plane. These patients are also at increased risk of gastric reflux/regurgitation and subsequent aspiration. These animals must be fasted at least 12 hours before surgery and receive H2 blockers to decrease gastric acidity. A loading dose of metoclopramide (1 mg/ kg IV), followed by a constant rate infusion (1 mg/kg/hr) during anesthesia also may reduce the incidence of gastroesophageal reflux. In addition, a cuffed endotracheal tube should be used, and the pharynx should be evaluated and suctioned at the end of the procedure. A pursestring suture is placed around the anus to prevent fecal contamination of the surgical field. A piece of surgical tape marked “purse string” should be placed on the patient’s head to remind the surgeon and anesthetist to remove the sutures once the procedure is finished. The vestibule and caudal vagina is flushed with dilute povidone-iodine solution as part of the surgical scrub. Three to four flushes of a 1 : 10 dilution of povidoneiodine with sterile water should be used to minimize vaginal mucosal irritation. An incision along the median raphe is made from the level of the caudodorsal aspect of the horizontal vaginal canal, descending to the dorsal commissure of the vulvar cleft. The incision is continued along the same plane of the skin incision through the vaginal musculature and mucosal layers. Placement of a flat instrument (e.g., scalpel handle) in the vestibule can be used to stabilize the tissues while the incision is made through the dorsal vestibular mucosa. Alternatively, Metzenbaum scissors can be used to cut the mucosal layer. Cautery, vessel ligation or compression of the vestibular wall using two Doyen bowel clamps (positioning one on each side with one blade in the vestibular lumen and one on the skin surface) can be used for hemostasis (Figure 213-1). Hemorrhage often is associated with surgery to this region because of the increased vascularity to the vaginal tissues. Exposure is maintained with the use of self-retaining retractors (i.e., Gelpi, Weitlander, or ring retractors) or stay sutures. A urinary catheter should be placed if there is potential for tissue manipulation around the urethra and urethral tubercle. Closure of the episiotomy is performed in four layers: mucosa, muscular tissue, subcutaneous tissue, and skin. A simple interrupted or continuous pattern of 3-0 monofilament absorbable suture is used for the mucosa. The muscular and subcutaneous tissues can be closed together or separately, depending on the size of the animal, using a simple continuous pattern of 3-0 or 4-0 absorbable

CHAPTER  213  Surgical Repair of Vaginal Anomalies in the Bitch suture. The skin edges can be closed with sutures (simple interrupted or cruciates) or surgical staples.

Perineal Approach with Episiotomy In some cases, the episiotomy can be modified by limiting the approach to the perineum. This approach allows access to the vestibulovaginal region without incising into the dorsal aspect of the vestibule, therefore limiting

Figure 213-1  An episiotomy over the dorsal aspect of the vulva

allows access to the lumen of the vestibule/vagina. Two Doyen bowel clamps are placed on the edges of the incision (positioning one on each side with one blade in the vestibular lumen and one on the skin surface to control hemorrhage and allow visualization).

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the intraoperative hemorrhage and minimizing postoperative pain. It can be used for resection and anastomosis of vestibulovaginal stenosis and to access pedunculated masses of the vagina or vestibule. This approach also can be combined with a ventral abdominal approach for vaginal ablation. An incision along the median raphe is made from the level of the caudodorsal aspect of the horizontal vaginal canal, descending to the dorsal commissure of the vulvar cleft. Digital palpation during the approach facilitates identification of the vagina and helps identify the location of interest (Figure 213-2, A). The incision is continued along the same plane of the skin incision until the muscular wall of the vagina/vestibule is reached. Cautery vessel ligation should be used for hemostasis. Exposure is maintained with the use of self-retaining retractors. Blunt dissection can be performed around the vagina as needed (Figure 213-2, B). Careful dissection along the ventral aspect of the vagina is necessary to avoid trauma to the urethra. A urinary catheter should be placed if there is potential for tissue manipulation around the urethra and urethral tubercle. Closure of the perineum is performed in two layers: subcutaneous tissues and skin. The subcutaneous tissues can be closed together or separately, depending on the size of the animal, using a simple continuous pattern of 3-0 or 4-0 absorbable suture. The skin edges can be closed with sutures (simple interrupted or cruciates) or surgical staples. Ventral Approach Fortunately, the ventral approach to the canine vagina is not used often because it requires a pelvic osteotomy. The ventral approach often is used for vaginal ablations.

B

Figure 213-2  Perineal approach to the vestibule/vagina. A, Digital palpation of the vestibule

with an incision along the median raphe. B, Continued dissection along the midline to the vagina and careful dissection circumferentially around the vagina using right-angled forceps. A red rubber catheter is placed in the urethra for identification and protection during dissection.

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SECTION  X  Reproductive Diseases

However, surgery through an abdominal or caudal/ perineal approach often is possible to avoid the need for a pelvic osteotomy (see next section). The urethra should be catheterized to aid in identification and prevent iatrogenic trauma. A standard ventral midline approach is performed in the caudal abdomen up to the cranial pelvic rim. The urinary bladder can be manipulated aside to provide access to the vagina. The pelvic osteotomy is performed to increase the exposure to the vagina and urethra. The incision is extended caudally over the midline of the pubic symphysis. The adductor muscles are elevated laterally with periosteal elevators to expose the pubic and ischial rami. A partial or complete pelvic osteotomy can be performed, depending on the location and amount of exposure needed. A partial pelvic osteotomy involves osteotomies through the pubic rami and across the pubic symphysis at the level of the obturator foramen. A complete pelvic osteotomy through both pubic rami and ischial rami gives the greatest exposure. Once the surgeon has determined the location of the osteotomy, holes are predrilled on either side of the osteotomy site. It is much easier to drill these holes before performing the osteotomy, especially if using a hand chuck and pin. The osteotomy is performed with Gigli wire, rotating burr, sagittal saw, or bone cutters. The internal obturator muscle is elevated off the pubic symphysis on one side of the pelvis and hinged on the contralateral internal obturator muscle to expose the pelvic canal. Alternatively an osteotomy through the pubic symphysis, separating the hemipelvis, can be performed. The flexibility of the pelvis allows the placement of retractors to separate the hemipelvis, giving exposure to the pelvic canal. Holes can be predrilled on either side of the pubic symphysis. Self-retaining retractors (i.e., Finochietto retractors) facilitate exposure (Figure 213-3). Care must be taken not to put excessive stress on the hemipelvis, which can create a fracture or sacroiliac luxation (especially in young dogs or cats). Closure of this approach begins  with reduction of the pelvic floor, using 18- to 20-gauge cerclage wire. The predrilled holes allow for rapid and

accurate alignment of the pubic and ischial rami. The obturator and adductor muscle fascia from either side is sutured to its contralateral partner along the midline. Closure of the linea, subcutaneous tissue, and skin is performed routinely. Because of the osteotomy, activity should be restricted for 4 months after surgery. In small patients the pubic symphysis does not have to be replaced. Closure of the obturator and adductor muscles along the midline provides adequate support of the pelvic floor. Combined Abdominal and Caudal/Perineal Approach In most cases, the cranial aspect of the vagina can be accessed through a caudal abdominal approach combined with a caudal or perineal approach, avoiding the need for a pubic osteotomy. This approach can be used for vaginal ablation secondary to a vaginal neoplasia and can be combined with an ovariohysterectomy if the patient is intact. Once the caudal abdomen is approached via a routine midline laparotomy, the bladder can be retroflexed to allow exposure to the vagina and associated structures. Fascial and peritoneal attachments between the vagina and rectum are bluntly dissected free. Similarly, dissection of attachments between the vagina and the urethra is performed, avoiding any disruption of the craniolateral aspect of the urethra and the periurethral tissues and avoiding damage to the ureters and urethral innervations. The cranial and caudal branches of the vaginal artery and vein are ligated. Once the vagina is dissected free, a stay suture can be placed through all layers of the vagina and the loop of the suture pushed caudally or passed into the vaginal lumen. The laparotomy is closed routinely. The intraluminal stay suture then can be grasped via a caudal approach with episiotomy; the extraluminal stay suture can be grasped via a perineal approach. Once the stay suture is identified, it is retracted caudally, withdrawing the cranial vagina into the perineal site, allowing for complete resection of the vagina.

Congenital Abnormalities Anovulvar Cleft

Figure 213-3  A ventral approach to the female urogenital system via a pubic symphysis osteotomy. Finochietto retractors increase exposure and allow for visualization of the structures within the pelvic canal.

A cleft or trough is located between the ventral anus and dorsal vulva. This rare defect occurs as a result of inappropriate fusion of the urogenital folds and can be observed in sexually normal female dogs or dogs with intersex disorders. The vestibular floor and clitoris are exposed, resulting in fecal contamination and hyperemia. Correction of this defect with a perineoplasty reduces infection and abrasion of the exposed mucous membranes and provides a more cosmetic appearance. An H-shaped or inverted V-shaped incision is made along the mucocutaneous junction of the anovulvar cleft. The vestibular mucosal margin and skin edge must be separated. Interrupted sutures of an absorbable suture are used to close the vestibular mucosa and submucosa. This is followed by subcutaneous and skin sutures. Because of the proximity of the incision to the anus, the incision may become infected. The area must be kept clean  until sutures are removed. Prophylactic antibiotics may be used, but they are not necessary. An Elizabethan 

CHAPTER  213  Surgical Repair of Vaginal Anomalies in the Bitch

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and, if the vulva is still recessed, creating a wider incision to remove more skin. This prevents unnecessary tension on the incision line. Excessive subcutaneous fat dorsal to the vulva is removed. This is critical in obese animals. Hemorrhage is controlled with cautery and ligation. The subcutaneous tissues are closed using absorbable suture in a simple interrupted pattern. The first subcutaneous suture should be placed at the dorsal midpoint, followed by additional sutures at the midpoints of the remaining defect. The skin is closed with simple interrupted nonabsorbable sutures. Again skin sutures are placed at 12, 9, and 3 o’clock positions to ensure a cosmetic closure.

Rectovaginal and Rectovestibular Fistula Figure 213-4  Dog with vulvar excoriations secondary to selfmutilation associated with perivulvar fold dermatitis.

collar is recommended to prevent self-mutilation to the incision.

Vulvar Hypoplasia Vulvar hypoplasia occurs frequently in spayed female dogs. The vulva is small and recessed into the perineal skin folds. This condition is also referred to as a juvenile/ infantile vulva. Dogs with juvenile vulva often have peri­ vulvar moist dermatitis (Figure 213-4), which is aggravated by retention of urine and/or feces within the folds of skin. A similar condition occurs in obese dogs when the redundant perineal skin covers the vulvar cleft. Recurrent vaginitis and urinary tract infections are common in these patients. Surgical removal of the perivulvar folds and antibiotic management help to alleviate clinical signs. In obese patients weight reduction may help alleviate the perivulvar dermatitis. However, before surgery is recommended, medical management should be instituted to decrease the inflammatory and infectious process around the vulva. The affected area is cleansed gently with a benzoyl peroxide shampoo and a mild topical astringent. The use of oral antibiotics and topical antibiotic-steroid cream also can be recommended. Once the inflammatory reaction has subsided, an episioplasty can be performed. An episioplasty is performed to remove the excess perivulvar skinfolds and the underlying subcutaneous fat. Before surgery the perivulvar skin is plicated to determine how much skin should be removed. The goal is to remove enough skin so that the vulva is no longer recessed without creating excessive tension on the incision site. A crescent-shaped skin incision is made around the vulva, starting lateral to the ventral vulvar commissure, extending laterally and dorsally to a point about 1 cm dorsal to the dorsal vulvar commissure, and then extending ventrolaterally to the contralateral side. A second crescentshaped incision begins and ends at the same points as the first incision; however, this incision extends wider than the first (Figure 213-5). The perivulvar skin between the incisions is excised with Metzenbaum scissors. If uncertain about how much skin to remove, the surgeon should consider starting the second incision with a narrow arch

This fistula is an abnormal communication between the rectum and the dorsal aspect of the vagina or vestibule. Affected dogs often have atresia ani or an imperforate anus. The dogs present because of passage of soft feces through the vulva. Severity of clinical signs varies with size of the fistula, type of diet, and presence of atresia ani. Dogs with atresia ani may have megacolon as a complicating factor. Vaginography or a barium sulfate enema can be used to demonstrate the location and size of the fistula. Repair of this defect is twofold, involving restoration of the vaginal/vestibular lumen followed by restoration of the rectal lumen and anal orifice. Surgery is performed via a perineal approach. An incision is made between the anus (or region of the anus) and the dorsal vulvar cleft, along the median raphe. The subcutaneous tissues are dissected bluntly until the fistula is identified. A red rubber catheter placed within the fistula may aid in identification. The communications with the rectum and vagina/vestibule are ligated and resected. The rectal mucosa should be oversewn to ensure a tight seal. If the fistula is short and wide, ligation may not be possible. The stoma should be resected and then closed primarily with absorbable simple interrupted sutures. Again the defects should be oversewn. The subcutaneous tissues and skin should be closed routinely. In the event of anal atresia, surgery must be performed to recreate a stoma between the rectum and anus (if present). The degree of anal abnormalities may vary from an imperforate anus in which a membrane remains at the level of the anus to complete anal atresia, in which the anus and associated anal muscles are absent. Patients with an imperforate anus require opening of the anal canal. This can be performed by breaking down the membrane digitally, by blunt dissection, or by surgical resection of the membrane. Dogs with an imperforate anus must be evaluated carefully with a barium contrast study to differentiate the disorder from anal atresia, which may clinically appear the same. Dogs with an imperforate anus generally have normal anal function and tone. If anal atresia is present, evidence of an anus is minimal to nonexistent, and on contrast radiography of the colon a section of rectum caudal to the fistula is absent. A rectal pull-through procedure is performed, creating a new anal orifice. Because the anal musculature and innervation are absent, these animals have fecal incontinence. Muscle

SECTION  X  Reproductive Diseases

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B

C

D Figure 213-5  Episioplasty for correction of a recessed juvenile vulva or for redundant perivulvar skin. A, Appearance of a dog with a recessed vulva. Note that the vulva is not visible under the redundant skin folds. B, The redundant skin is retracted to visualize the vulva. The excess skin is plicated to determine the amount of skin that will have to be excised. C, Two crescent-shaped skin incisions are made around the vulva. D, The subcutaneous tissue and skin are closed with multiple simple interrupted sutures.

flaps can be attempted to increase tone to the new opening; however, results have been inconsistent.

Clitoral Hypertrophy Clitoral hypertrophy may occur in dogs with intersex disorders, dogs receiving anabolic steroids, or dogs with hyperadrenocorticism; however, this condition also may be found in normal females. Some dogs with chronic vaginitis may present with clitoral hypertrophy caused by excessive vulvar licking. The clitoris often protrudes through the vulvar cleft (Figure 213-6). These dogs generally are presented by an owner for cosmetic reasons, clitoral irritation and vestibular inflammation, or mutilation of the protruded clitoris. Treatment of hyperadrenocorticism or termination of steroid administration may cause resolution of clitoral hypertrophy. In cases in which the clitoris is protruding through the vulvar cleft, amputation of the clitoris is recommended. Clitoral amputation is performed by simple submucosal dissection. Dogs with

Figure 213-6  Dog with clitoral hypertrophy. The end of the enlarged clitoris is extruded between the vulvar cleft.

CHAPTER  213  Surgical Repair of Vaginal Anomalies in the Bitch intersex disorders may have significant bleeding during the dissection because of the presence of erectile tissue. Performing an episiotomy may improve visualization and assist with hemostasis.

Vaginal Band, Septum, and Stenosis A number of vaginal and vestibular congenital abnormalities occur as a result of imperfect joining of the genital folds, genital swellings, or müllerian ducts. These conditions may be incidental findings on a physical examination, or occasionally they cause a variety of clinical presentations. Bitches with stenosis or bands may present with clinical signs of chronic vaginitis, which may be associated with urine pooling in the anterior portion of the vagina. Other bitches may present for artificial insemination after unsuccessful attempts at natural breeding. The female and/or male may demonstrate pain when attempting to breed. Vaginal bands also are associated frequently with dogs having ectopic ureters. A digital vaginal examination may be most informative because visual inspection with speculums or otoscopes may bypass the abnormality. A vaginogram may be  necessary to determine the extent and severity of the abnormality. A persistent or imperforate hymen can be corrected with digital breakdown of the membrane. Vaginal bands or septa that cannot be corrected digitally may require an episiotomy and surgical resection (Figure 213-7). Depending on the extent of the mucosal defect remaining after surgical removal of the band or septa, the defect can be left to heal by second intention or surgically closed using an absorbable suture in a simple continuous manner. Vestibulovaginal stenosis is diagnosed as a palpable submucosal fibrous ring at the level of a persistent hymen. Vaginal stenosis is a region of vaginal hypoplasia, in which the lumen over a given area is narrower than the rest of the vagina or vestibule. Bitches with stenosis of

the vestibulovaginal junction that exhibit clinical signs tend to respond poorly to digital and surgical attempts at dilation. If surgery is indicated, a vaginogram should be performed to determine the extent of the affected region and to determine the vestibulovaginal ratio. The vestibulovaginal junction should be larger than a third of the diameter of the vagina. The measurement guideline that has been used is the vestibulovaginal ratio, which is calculated by dividing the height of the vestibulovaginal junction by the maximum height of the vagina on a lateral vaginourethrogram (Figure 213-8). A ratio of less than 0.20 is considered severe stenosis; 0.20 to 0.25 moderate stenosis; 0.26 to 0.35 mild stenosis; and more than 0.35 anatomically normal. Three surgical techniques have been recommended  for correction of these defects: T-vaginoplasty, stenosis

Figure 213-7  Episiotomy performed for visualization of a

vaginal band. A urinary catheter identifies the urethral opening at the base of the vestibulovaginal junction.

II

II I

A

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I

B Figure 213-8  A positive contrast vaginourethrogram. The height of the vestibulovaginal junc-

tion (I) and the maximum height of the vagina (II) are measured on lateral vaginourethrographic views to calculate the vestibulovaginal ratio (I divided by II). A, Normal vaginogram. B, Patient with vestibulovaginal stenosis.

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SECTION  X  Reproductive Diseases

resection, and partial/complete vaginectomy. Resection of the stricture/stenosis has a better outcome than the T-vaginoplasty for complete resolution of clinical signs; however, the procedure is more difficult technically and therefore can have higher surgical complications. The T-vaginoplasty has been shown to resolve clinical signs in some dogs. Surgical recommendations vary with severity of the stenosis. Severe stenosis most likely would respond to resection and anastomosis, whereas the  milder stenosis probably would respond to a less invasive T-vaginoplasty. The T-vaginoplasty is performed via a standard caudal approach with episiotomy or perineal approach. A longitudinal incision is made on the dorsal aspect of the vaginal stenosis, followed by a T-shaped closure to increase the vaginal diameter. However, this procedure has met with variable results. Bitches with submucosal fibrous rings may not require full-thickness incisions. These annular stenoses located at the vestibulovaginal junction require only resection of the fibrous tissue through a mucosal incision. The fibrous ring is resected, and the remaining mucosal defect is closed so that none of the deeper vaginal tissues are exposed. In spayed bitches only the ventral 180 degrees of the stenosis is removed in mild cases to allow adequate drainage of vaginal fluids. Positive postoperative results have been reported on the few cases in which complete resection and anastomosis of the defect were performed. This technique is technically more difficult because it requires a 360-degree dissection of the stenosis. A standard caudal with episiotomy or perineal approach provides the surgeon with adequate visualization of the defect. Full-thickness excision of vaginal stenosis is recommended for moderate to severe stenosis, as determined by the vestibulovaginal ratio and clinical signs. Two circumferential incisions are made cranial and caudal to the defect. Catheterization and protection of the urethra are critical when performing a vaginal resection and anastomosis. Ligation and cautery of superficial and muscular vessels are mandatory. The remaining defect can be closed once the stenosis is resected, using absorbable suture in a simple interrupted pattern. A complete vaginectomy is the final option for correction of vaginal stenosis in bitches that are not intended for breeding. Results with this technique seem favorable. A standard caudal with episiotomy or perineal approach, combined with a caudal midline laparotomy may be used. The vagina is resected anterior to the urethral tubercle, making sure that the entire stenotic vagina is removed. A Parker-Kerr oversew or other inverting suture patterns are used to close the vagina.

Acquired Abnormalities Vaginal Prolapse Vaginal prolapse includes two different disease processes. One process involves prolapse of edematous mucosa  on the floor of the vaginal vault. This disease also is referred to as vaginal edema and previously was referred to as vaginal hyperplasia. The second process involves a true prolapse of the vagina, in which the prolapse is

circumferential and often includes the cervix. These dogs have true vaginal prolapse. For ease of discussion, the terms vaginal edema and true vaginal prolapse are used when discussing the two disease processes.

Vaginal Edema and Hyperplasia Young, intact bitches in proestrus or estrus frequently are reported with this condition. Large and brachycephalic breeds are overrepresented. Normally during the follicular phase of the estrous cycle the vaginal and vestibular mucosa become thickened and edematous. Occasionally an exaggerated response occurs, resulting in excessive edema. The submucosal tissue edema and redundant mucosa at the floor of the vagina just cranial to the urethral tubercle can protrude through the vulvar labia as a fleshy red mass (Figure 213-9). The exposed tissue is prone to trauma, desiccation, and self-mutilation. The urethra is not exteriorized and can be catheterized at the base of the edematous tissue. The location of the urethral tubercle helps distinguish vaginal edema from vaginal prolapse, in which the urethral opening may be exteriorized with the prolapsed vagina. Conservative management consists of protection of the exteriorized portion of the mass with lubricants and prevention of self-mutilation with an Elizabethan collar. Vaginal edema is seen most commonly during the first estrous period and regresses spontaneously during the luteal phase. However, recurrence is common during subsequent estrous cycles. Owners should be cautioned that the edematous tissue also may recur at parturition, resulting in dystocia. Hormonal therapy with megestrol acetate (2 mg/kg q24h PO for 7 days) or gonadotropin-releasing hormone (2.2 µg/kg IM) also may be attempted. Owners should be advised of specific side effects of hormonal therapy. Ovariohysterectomy is curative and should be considered to prevent recurrence. Surgical resection of the  mass should be considered if the bitch is intended for breeding or if the tissues are traumatized. A standard caudal approach with episiotomy is performed to expose the base of the edematous tissue. The mass is lifted off of the vestibular floor, and the urethra catheterized to prevent iatrogenic trauma. A transverse elliptical incision is made around the base, and the redundant vaginal tissue is amputated. The vaginal mucosal defect is closed with absorbable suture in a simple continuous pattern, carefully avoiding the urethral orifice.

True Vaginal Prolapse True vaginal prolapse occurs less frequently than vaginal edema and can be either partial or complete. In a complete true vaginal prolapse, the cervix is exteriorized. In both cases the vaginal tissues demonstrate a doughnutshaped eversion. This is differentiated from vaginal edema in that there is circumferential involvement of the vaginal mucosa and the urethral tubercle. Brachycephalic breeds in normal estrus are predisposed to vaginal prolapse. No treatment may be necessary in cases with mild prolapse because spontaneous regression occurs during diestrus. More severe prolapses may require protection of

CHAPTER  213  Surgical Repair of Vaginal Anomalies in the Bitch

A

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B

Figure 213-9  Hyperplasia of the vaginal floor. A, An episiotomy is performed to expose the

base of the hyperplastic tissue. B, The pedunculated hyperplastic tissue is elevated, exposing the urethral opening. A urinary catheter is inserted to maintain visual recognition and protection of the urethra during resection of the hyperplastic tissue.

exposed tissues. General anesthesia is required if attempting to replace the prolapsed mucosa. The everted tissue is cleaned with a dilute antiseptic solution or saline. If the edema is severe, manual compression or application of 50% dextrose solution to the mucosal surface may decrease its size, therefore facilitating reduction. A lubricated plastic syringe can be used to reduce the tissues. An episiotomy may be necessary to provide better exposure for reduction. Reduction also can be assisted by traction on the uterus via a ventral abdominal approach. Once the vagina is reduced, reprolapse can be minimized by suturing the uterine body or the broad ligament to the abdominal wall. A urinary catheter should be maintained until the vaginal swelling resolves. Dogs with long-standing prolapses may have secondary necrosis, infection, or hemorrhage of the prolapsed tissues. These dogs should be evaluated and treated as necessary for hypotension and/or sepsis. Surgical resection of the devitalized tissues is indicated in these patients to prevent further sepsis and self-mutilation. An episiotomy helps with exposure and placement of a urinary catheter. A stepwise full-thickness circumferential incision is made in the vaginal wall. A section of 1 to 2 cm of the outer mucosal layer is incised, followed by resection of the inner noninverted mucosal layer. Horizontal mattress sutures are used to close the incision edges. Hemorrhage can be significant and should be controlled with cautery and ligation. This is continued circumferentially in small sections until the entire prolapsed tissue is resected.

References and Suggested Reading Crawford JT, Adams WM: Influence of vestibulovaginal stenosis, pelvic bladder, and recessed vulva on response to treatment for clinical signs of lower urinary tract disease in dogs: 38 cases (1990-1999), J Am Vet Med Assoc 221:995, 2002. Hammel SP, Bjorling DE: Results of vulvoplasty for treatment  of recessed vulva in dogs, J Am Anim Hosp Assoc 38:79, 2002. Hedlund CS: Surgery of the female reproductive tract. In Fossum TW et al, editor: Small animal surgery, ed 3, St Louis, 2007, Mosby, p 729. Kieves NR, Novo RE, Martin RB: Vaginal resection and anastomosis for treatment of vestibulovaginal stenosis in 4 dogs with recurrent urinary tract infections, J Am Vet Med Assoc 239:972, 2011. Mathews KG: Surgery of the canine vagina and vulva, Vet Clin North Am Small Anim Pract 31: 271-290, 2001. Pettit GD: Vagina and vulva: surgical treatment of vaginal and vulvar masses. In Bojrab MJ, Ellison GW, Slocum B, editors: Current techniques in small animal surgery, ed 4, Baltimore, 1998, Lippincott, Williams & Wilkins, p 503. Rahal SC et al: Rectovaginal fistula with anal atresia in 5 dogs, Can Vet J 48:827, 2007. Wang KY et al: Vestibular, vaginal and urethral relations in spayed dogs with and without lower urinary tract signs, J Vet Intern Med 20:1065, 2006. Wang KY et al: Vestibular, vaginal and urethral relationships  in spayed and intact normal dogs, Theriogenology 66:726, 2006. Wykes PM, Olson PN: Vagina, vestibule, and vulva. In Slatter D, editor: Textbook of small animal surgery, ed 3, Philadelphia, 2002, WB Saunders, p 1502.

CHAPTER 

214 

Early Age Neutering in Dogs and Cats MICHELLE ANNE KUTZLER, Corvallis, Oregon

P

et overpopulation in the United States is an ongoing problem. Surgical removal of the gonads (gonadectomy) in dogs and cats has long been a basis of population control and part of routine veterinary health maintenance programs for animals not intended for breeding. In the United States, neutering is the most common surgical procedure performed in dogs and cats younger than 1 year of age. However, the optimal age to neuter female and male dogs and cats is not defined by the veterinary literature. For the purposes of this chapter, the term neutering is used to describe ovariohysterectomy (spay) and orchidectomy (castration). Although these elective surgical procedures traditionally are delayed until the patient is 6 to 7 months old (but still before puberty), mandatory preadoption neutering as early as 6 to 14 weeks of age occurs in many animal shelters throughout the United States. Recently, the Society for Theriogenology (SFT) and the American College of Theriogenologists (ACT) developed a consensus statement opposing mandatory neutering programs, stating that “the pet overpopulation problem that exists in the United States [compared to other developed countries] is due to cultural differences on the importance of pets, the responsibility of pet owners, and the ability of the government and national agencies to properly educate the public.” Early age castration is forbidden in Germany under the Law for Prevention of Cruelty to Animals (Tierschutzgesetz) (Günzel-Apel, 1998). Many veterinarians and pet owners are starting to ask, “What are the long-term effects of early age gonadectomy?” Several long-term effects must be taken into consideration. The focus of this chapter is to compare the benefits (Table 214-1) and concerns (Table 214-2) between early age and traditional age neutering of dogs and cats as well as briefly illustrate some technical differences when performing early age neutering. For the purposes of this chapter, early age neutering is defined as neutering between the ages of 6 to 23 weeks (before 6 months), and traditional age neutering is defined as neutering after 24 weeks (6 months) of age. Regardless of whether it is performed at an early or a traditional age, most elective neutering in female dogs and cats occurs prepubertally because puberty typically occurs after 8 months of age in male and female dogs and cats. Benefits and concerns of early age neutering are discussed. 982

Benefits Short-term advantages of early age neutering include a quicker recovery and shorter surgery time for the patient (Howe, 1997). Fewer surgical complications are reported when patients are neutered before 12 weeks of age compared with after 24 weeks of age (Howe, 1997). In addition, long-term benefits are associated with early age neutering. In cats, up to 70.5% of litters from owned cats are unplanned (Murray et al, 2009), and neutering these animals before adoption completely eliminates the possibility of unplanned offspring stemming from poor owner compliance of neutering at the traditional age. With respect to the health effects, cats neutered before 23 weeks of age had a decreased incidence of asthma, gingivitis, and abscesses (Spain, Scarlett, and Houpt, 2004a). Moreover, cats neutered at an early age had decreased incidence of sexual behavior, urine spraying, and aggression toward veterinarians compared with cats neutered at the traditional age (Spain, Scarlett, and Houpt, 2004a). Some investigators have found that early age neutering in dogs decreases separation anxiety, escaping behavior, and inappropriate elimination when frightened (Spain, Scarlett, and Houpt, 2004b) compared with traditional age neutering. However, the influence of the age at neutering on behavior in dogs is controversial: some investigators have found no behavioral differences between early age and traditional age neutered dogs (Howe et al, 2001).

Concerns Behavioral Some investigators have reported increased noise phobia and sexual behavior in dogs neutered before 23 weeks of age compared with traditional age neutered dogs. Cats neutered before 23 weeks of age had a higher incidence of shyness compared with traditional age neutered cats.

Immunologic Dogs neutered before 24 weeks of age are more likely  to contract an infectious disease later in life compared with dogs neutered after 24 weeks of age (Howe et al, 2001).

CHAPTER  214  Early Age Neutering in Dogs and Cats

TABLE 214-1  Summary of Long-Term Health Risks Decreased with Early Age Neutering Compared with Traditional Age Neutering System

Species Affected

Health Risks

Behavioral

Feline

Aggression towards veterinarians Sexual behavior Urine spraying Escaping behavior Inappropriate elimination when frightened Separation anxiety

Canine

Immunologic

Feline

Abscesses Asthma Gingivitis

puberty for potential canine athletes. Increased physeal growth also has been reported in cats neutered at an  early age.

Urogenital Early age neutering results in an increased rate of cystitis and urinary incontinence in dogs compared with traditional age neutering (Spain et al, 2004b; Stöcklin-  Gautschi et al, 2001). The risk of urinary incontinence is greatest in dogs spayed before 3 months of age. In addition incidence of perivulvar dermatitis and vaginitis is increased in bitches neutered at an early age compared with those neutered at the traditional age. Early age neutering in male dogs permanently arrests the normal development of the balanopreputial fold, resulting in preputial hypoplasia and an increased incidence of paraphimosis. Neutering male cats at 7 weeks of age causes a phimosis by permanently preventing complete penile extrusion, which complicates urinary catheter placement and management of feline urologic syndrome.

Surgical Technique

TABLE 214-2  Summary of Long-Term Health Risks Increased with Early Age Neutering Compared with Traditional Age Neutering System

Species Affected

Health Risks

Behavioral

Canine Feline

Noise phobias Shyness

Immunologic

Canine

Contraction of an infectious disease

Musculoskeletal

Canine, feline Canine Canine

Growth plate closure delay Cranial cruciate ligament rupture Hip dysplasia

Canine Canine Canine Canine Canine Canine Feline

Cystitis Paraphimosis Perivulvar dermatitis Preputial hypoplasia Urinary incontinence Vaginitis Phimosis

Urogenital

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Musculoskeletal Dog neutered at 7 weeks of age have a greater delay in radius and ulna growth plate closure compared with dogs neutered at 7 months of age, resulting in longer bone length in dogs neutered at 7 weeks of age (Howe et al, 2001; Salmeri et al, 1991). The effect of increased physeal growth is believed to be responsible for the increased incidence of hip dysplasia and cranial cruciate ligament rupture (Duerr et al, 2007) reported in early age neutered dogs compared with those neutered at the traditional age. Because of these increases risks, the SFT and ACT recommend that neutering should be postponed until after

Many physiologic differences between young and older patients must be considered before surgery. Younger dogs and cats do not have the ability to concentrate urine and have a greater fluid requirement relative to body mass than older patients. In addition, hepatic glycogen is minimal and declines rapidly during fasting, resulting in hypoglycemia. For these reasons, water and food restriction before surgery should not exceed 1 hour and 4 to 8 hours, respectively. Early age ovariohysterectomy is performed in a similar manner to the procedure in older patients with a few exceptions. The ventral midline abdominal incision should be made in the middle third of the distance between the umbilicus and pubis rather than the cranial third used for older dogs. Inside the abdominal cavity, kittens and puppies less than 16 to 20 weeks old normally have a substantial amount of clear fluid in the peritoneal cavity. The reproductive tracts from puppies and kittens are small, lack vasculature, and lack adipose tissue. Tissues in general are more delicate in puppies and kittens and therefore require gentle handling. In 6- to 14-week-old male kittens, it also has been suggested not to use castration techniques in which the spermatic cord is tied onto itself or the vas deferens and spermatic artery are tied together because the spermatic artery is allegedly too small and fragile (Goeree, 1998). Soft, nonirritating suture materials, such as polyglactin 910, are recommended for a suture material for spermatic cord and pedicle ligation. Multifilament or coated nonabsorbable suture materials should be avoided. Polydioxanone suture also should be avoided for ligation because it has been reported to cause calcinosis circumscripta in two young dogs (Kirby et al, 1989).

References and Suggested Reading Duerr FM et al: Risk factors for excessive tibial plateau angle in large-breed dogs with cranial cruciate ligament disease, J Am Vet Med Assoc 231(11):1688, 2007.

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Goeree G: Pediatric neuters can be technically challenging, Can Vet J 39:244, 1998. Günzel-Apel AR: Early castration of dogs and cats from the point of view of animal welfare, Dtsch Tierarztl Wochenschr 105(3):95, 1998. Howe LM: Short-term results and complications of prepubertal gonadectomy in cats and dogs, J Am Vet Med Assoc 211:57, 1997. Howe LM et al: Long-term outcome of gonadectomy performed at an early age or traditional age in dogs, J Am Vet Med Assoc 218:217, 2001. Kirby BM et al: Calcinosis circumscripta associated with polydioxanone suture in two dogs, Vet Surg 18:216, 1989. Murray JK et al: Survey of the characteristics of cats owned by households in the UK and factors affecting their neutering status, Vet Rec 164:137, 2009. Salmeri KR et al: Gonadectomy in immature dogs: effects on skeletal, physical, and behavioral development, J Am Vet Med Assoc 198:1193, 1991.

CHAPTER 

Society for Theriogenology, American College of Theriogenologists: Basis for position on mandatory spay-neuter in the canine and feline, accessed December 31, 2011, from http:// therio.org/associations/2746/files/Basis%20for%20Position%  20on%20Mandatory%20Spay%20SFT%20ACT%20FINAL.pdf. Spain CV, Scarlett JM, Houpt KA: Long-term risks and benefits of early-age gonadectomy in cats, J Am Vet Med Assoc 224:372, 2004a. Spain CV, Scarlett JM, Houpt KA: Long-term risks and benefits of early-age gonadectomy in dogs, J Am Vet Med Assoc 224:380, 2004b. Stöcklin-Gautschi NM et al: The relationship of urinary incontinence to early spaying in bitches, J Reprod Fertil Suppl 57:233, 2001.

215 

Estrus Suppression in the Bitch PATRICK W. CONCANNON, Ithaca, New York

T

he use of estrous cycle suppressing hormone therapy should be proposed only for animals intended for breeding within 1 to 3 years of initiating treatment. Animals not intended for breeding are best managed by surgical sterilization. In North America, no new methods or products for estrus prevention or suppression in dogs and cats have been introduced in the last three decades. The oral progestin megestrol acetate (Ovaban) remains the only drug marketed for suppression of ovarian cycles in dogs. The only indication is for use in adult dogs.  In Europe and some Latin American countries, other progestins are marketed for estrus suppression in small animals, including proligestone and medroxyprogesterone acetate (MPA). These progestins often are marketed with an indication for use in prepubertal dogs and  adults. Drugs marketed for human use sometimes are administered as contraceptive treatments in small animals by or at the request of owners; practitioners should  be aware of these and their possible application and  side effects. In North America these include depot MPA and various anabolic androgens, including testosterone  and mibolerone. Mibolerone, previously marketed as  a brand-name dog contraceptive, was withdrawn from  the market after its labeling as a regulated anabolic  steroid but remains in use in a generic oral liquid formulation available from compounding pharmacies. Annual or

semiannual administration of gonadotropin-releasing hormone (GnRH) agonist implants that down-regulate pituitary secretion of gonadotropic hormones also can be used to suppress ovarian cycles in bitches. Such implants containing deslorelin (Suprelorin) are marketed for suppression of testis function in dogs in Europe, Scandinavia, Australia, and New Zealand. The extent of off-label use for estrus suppression in females is not known. Such application has been demonstrated safe and effective but with the side effect of inducing estrus in adult bitches treated during anestrus and in young bitches in the late prepubertal period. These implants are also marketed for treatment of adrenocortical disease in ferrets in the United States but extralabel use in other species is prohibited. Practitioners should be aware of all possible modalities of contraception previously available to animals they are treating and the potential side effects particularly of gonadal steroids.

Steroid Contraceptive Mechanism of Action Progestins When progestins are given by serial administration or depot injection to bitches, the result is an artificial luteal phase that mimics many of the effects of the progesterone

CHAPTER  215  Estrus Suppression in the Bitch

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secreted during the 2-month luteal phase that normally follows ovulation in the ovarian cycle. Mechanisms include an antigonadotropic action potentially resulting in lowered luteinizing hormone (LH) and folliclestimulating hormone (FSH) pulsatile secretion and plasma concentrations; an antiestrogen action achieved by reducing the concentrations of intracellular estrogen receptors in many tissues, including those regulating gonadotropin secretion; and progestational actions on the reproductive tract occurring out of the normal sequence of the ovarian cycle, resulting in altered endometrial growth and secretion, altered cervical secretion, reduced sperm transport, and altered uterine-tube motility. In addition, progestins can have an antiovulatory effect by preventing a preovulatory surge release of gonadotropins (LH and FSH) from the pituitary, the normal stimulus for ovulation, if administered before a large rise in estrogen. However, administration at or immediately after the follicular phase peak in estrogen can facilitate and advance the preovulatory LH surge and ovulation. When administered beginning several days or more before the peak in estrogen would have occurred, progestins typically prevent the LH surge, possibly by interfering with hypothalamic and pituitary responses to estrogen. However, none of these actions provides an explanation of how the typical clinical administration of a progestin during anestrus causes an apparent prolongation of anestrus and prevents and delays the occurrence of a new ovarian follicular phase or an associated proestrus. Long-term progestin administration in bitches does not lower the systemic concentrations of LH below those typically observed during most of normal anestrus and actually may result in a small increase in basal LH (Colon et al, 1993), perhaps by acting as an antiestrogen and partially interfering with the normal negative feedback effects of estrogen. During normal ovarian cycles, elevated progesterone reduces GnRH pulsatility, and thus reduces LH and FSH pulsatility. As a result, the luteal phase prevents any increase in gonadotropin pulsatility that would stimulate the next follicular phase. Contraceptive progestin treatment has the same effect. The progestin prevents any increase in gonadotropin pulsatility sufficient to initiate another estrus cycle. Why the effect lasts 1 to several months after withdrawal of progestin is not understood, but it is similar to what is observed after luteolysis during the normal ovarian cycle. In dogs, proestrus does not occur until after many weeks or months of an obligate anestrus after the end of the 7- to 10-week luteal phase and the decline in progesterone concentrations to nearly undetectable levels. A contraceptive progestin treatment mimics a luteal phase and postpones and reestablishes the onset of anestrus.

with other steroid receptors. Androgen receptors have been observed in estrogen target tissues, and androgen binding can result in reduced responsiveness to estrogen. The duration of effect after hormone withdrawal may vary among androgens. Androgen therapy including testosterone reportedly is followed often by rapid return to estrus within a few weeks after withdrawal (England, 1998), although some androgen therapy such as mibolerone typically has required 2 to 3 months for return to estrus, with a range of 1 to 7 months, as with progestins. In addition, termination of long-term androgen use in bitches, especially with testosterone, can result in a prolonged or even permanent anestrus, as observed in some racing greyhound bitches.

Androgens

Megestrol acetate is marketed in North America as Ovaban tablets for the prevention and postponement of proestrus and estrus in anestrus bitches and for the curtailment of proestrus and prevention of ovulation and estrus in early proestrus bitches. Ovaban is marketed in bottles of 5- or 20-mg tablets for oral administration. The generic drug tablets are available in those sizes and others from  compounding pharmacies. The recommended dosage is

The estrous cycle postponing effects of androgens, like those of progestins, appear to involve primarily a negative feedback effect at the level of the hypothalamus and possibly the pituitary. The contraceptive and other effects of androgens in females may be the same as in males by binding to androgen receptors or may involve cross-talk

Side Effects of Contraceptive Steroids Progestin side effects can occur from excessive dosing, prolonged exposure to lower doses, or an idiosyncratic sensitivity and responsiveness of some bitches to a particular regimen. These side effects have included uterine hyperstimulation, development of mammary tumors, diabetes mellitus, gallbladder disease, growth hormone hypersecretion, and acromegaly. Stimulation of the endometrium can result in mucometra, cystic endometrial hyperplasia, and eventually pyometra. Uterine effects may be more pronounced when progestin is administered during or after stimulation by endogenous estrogen during proestrus or estrus. Insulin resistance occurs possibly as a direct effect of the progestin but also is related to increased serum growth hormone in some bitches. Progestin-induced growth hormone secretion can result in signs of acromegaly of varying severity and appears to mimic luteal phase induction of signs of acromegaly reported in some older intact bitches. Progestin-induced increased serum growth hormone concentrations appear to result from hypersecretion of growth hormone by mammary tissue, although pituitary growth hormone activity increases as well. Reduced adrenal size and reduced concentrations of cortisol also have been observed with high doses of progestin. Side effects of androgens include increased muscle mass and strength, aggression, and clitoral hypertrophy. Anal gland inspissation and excessive lacrimation have been noted with at least one androgen, mibolerone. Androgens and progestins can result in masculinization of female fetuses if administered to pregnant bitches.

Progestin Products and Applications Megestrol Acetate Tablets

986

SECTION  X  Reproductive Diseases

0.55 mg/kg/day (or 0.25 mg/lb/day) for 32 days in anestrus bitches. Higher dosages of 2.2 mg/kg/day (or 1 mg/ lb/day) for 8 days are given to bitches already in early proestrus. The indication is for use in adult bitches for up to two successive cycles. In some countries, including the United Kingdom, megestrol acetate is used in pubertal dogs as well as adults. Diabetes mellitus, mammary tumors, uterine disease, and liver disease are contraindications to the use of megestrol acetate. Bitches with an unknown or ill-defined reproductive history should be confirmed to be in anestrus by vaginal cytology and progesterone assay before treatment. Administration during pregnancy can result in masculinization of female fetuses. Treatment should not be repeated beyond two successive estrous cycles without allowing an intervening normal cycle. Administration during anestrus should be initiated 1 to 2 weeks or more before the next expected proestrus. If initiated too late in anestrus, a spontaneous proestrus may occur and require changing to the higher, proestrusregimen dosing. If treatment is started immediately before the onset of proestrus, the subsequent proestrus may occur a few weeks after withdrawal. If megestrol acetate is initiated too early in anestrus, there may be no apparent postponement of the next cycle. The next proestrus typically occurs 4 to 6 months after treatment, with a range of 1 to 7 months. The advantages of the oral formulation are ease of administration and administration by the owner; concerns include compliance by the owner and potential for underdosing or overdosing. The bitch’s body weight should be determined with exactitude, and the precise number of tablets or partial tablets of a specific formulation to be administered each day should be provided with written instructions. Administration of megestrol acetate in early proestrus should begin within 3 days of proestrus onset. Client education regarding the signs of early proestrus is important. A bitch with a normal proestrus usually lasting less than 4 days or longer than 20 days is reportedly not a good candidate for megestrol acetate treatment during proestrus. Early proestrus status can be confirmed by vaginal cytology showing less than 50% superficial cells, increasing rather than decreasing vulval turgidity, and serum progesterone concentrations less than 0.5 ng/ml. Proestrus treatment with megestrol acetate should be combined with isolation of the bitch from males for 3 to 8 days and until the end of serosanguineous discharge, following the recommendation of the manufacturer. The suppression of proestrus symptoms occurs by 3 to 8 days after initiation of treatment. The subsequent proestrus is expected in 4 to 6 months but ranged from 1 to 7 months in clinical trials. Administration too late in proestrus can likely result in induction of ovulation, failure to prevent ovulation, or the occurrence of estrus. Megestrol acetate is currently the only cycle preventive or estrus preventive marketed for dogs in the United States and is approved for use in two successive cycles. In the United Kingdom similar dosages of megestrol acetate (Ovarid) are recommended, including 0.55 mg/kg/day for 40 days in anestrus, or 2 mg/kg/day for 8 days in early proestrus. However, for the bitch in pubertal proestrus, or with a history of pseudopregnancy, or housed with other

bitches and susceptible to pheromone effects, the recommendation has been to use a dose of 2 mg/kg for 4 days and then 0.55 mg/kg for 16 days. The onset of proestrus must be determined accurately for use in proestrus, especially in pubertal bitches. The treatment of bitches in anestrus also includes the option to continue treating with lower doses of 0.2 mg/kg twice weekly for up to 4 months after the initial 40 days of treatment but then allowing a normal estrus to occur before retreating. The 40-day regimen also can be followed with an early proestrus treatment at the next estrous cycle. In other countries, generic megestrol acetate is marketed under many brand names for use in dogs and/or cats in tablets of various content (5, 10, or 20 mg), sometimes of a single content (10 mg). The 10-mg tablets can make it difficult to dose accurately smaller animals. The drug should be administered according to the manufacturer’s recommendation, unless assuming that a lower dose or shorter period of treatment will be effective is reasonable based on recommendations of other manufacturers or review articles. Side effects in dogs most frequently mentioned by manufacturers include increased appetite and weight gain, decreased aggression, increased docility, and mammary enlargement. Megestrol acetate tablets also are marketed as a human product (Megace). Megestrol acetate at the higher proestrus dose also has been proposed and used to prevent the induction of proestrus at the onset of a treatment with a GnRH-agonist subcutaneous implant administered for long-term estrus suppression (see below).

Medroxyprogesterone Acetate Injections A depot injectable formulation of MPA (dMPA) was marketed as a female dog contraceptive (Promone) in North America several decades ago but removed from the market because of a high incidence of uterine disease (namely, pyometra). However, dMPA marketed as a human contraceptive (Depo Provera) has been administered to bitches. Several dMPA products are marketed for veterinary use in Europe and other locales under various trade names (Promone-E, Perlutex Injection, Supprestal, Vetoquinol) with an indication for prevention of estrous cycles in bitches during anestrus. Various regimens for dosage and injection intervals have been recommended. They include 2.5 to 3 mg/kg every 5 months and 50 mg/bitch every 6 months. Side effects appear to be dose dependent, and dosing on a body weight basis would be more appropriate. Side effects of dMPA in high-dose toxicity tests or with long-term treatment with lower doses include cystic endometrial hyperplasia, pyometra, acromegaly, gallbladder calculi and mucosal hyperplasia, and mammary tumors (Concannon et al, 1980). The mammary tumors, although sometimes large, were mostly benign, but adenocarcinomas have been observed. Development of diabetes also has been reported. Injectable dosages near the minimal effective dose (e.g., 2 mg/kg every 3 months, 2.5 mg/kg every 5 months) are clinically more appropriate than higher doses. If used in dogs, depot MPA  should be administered only during confirmed anestrus. Administration during mid-proestrus, late-proestrus, or early estrus can result in ovulation, in pregnancy, and in

CHAPTER  215  Estrus Suppression in the Bitch possibly failure of parturition, in pyometra, or in pseudopregnancy. Directions to use dosages much greater than those mentioned previously are likely inappropriate, although anecdotal evidence suggests that the same progestin from different manufacturers may have different biopotencies per unit of product weight.

Proligestone Injections Proligestone is available as a depot injectable progestin in Europe (Delvosteron, Covinan) and other locations, with indications for estrus prevention in female dogs, cats, and ferrets. It is not marketed in North America. Dosages  of 10 to 33 mg/kg vary inversely with body weight.  For example, for bitches that are 20 kg the dose is  17.5 mg/kg but for those over 60 kg the dose is 10 mg/ kg. The manufacturer’s recommended dosing frequency for bitches is at 0, 3, and 7 months of treatment and subsequently at 5-month intervals. It also is indicated during proestrus to prevent ovulation and estrus. Both published reports (Selman et al, 1995) and anecdotal evidence have suggested that uterine disease, including pyometra, mammary tumors, and acromegaly, are side effects of proligestone, as with other progestins, and that administration is initiated best during anestrus with an appreciation of potential occurrences of side effects similar to those observed with other progestins.

Other Progestin Formulations Oral formulations of MPA are marketed as human drugs in the United States and elsewhere (Provera, Farlutal) and as veterinary drugs in many countries (Perlutex Vet Tablets). A suggested dosing regimen in dogs is reported to be 10 mg/bitch for 4 days and then 5 mg/bitch for 12 days, doubling the doses for bitches weighing over 15 kg (England, 1998). As with any drug, dosing on a bodyweight basis would be more appropriate.

Contraceptive Steroid Implants Subcutaneous silastic implants that release a progestin have been used experimentally, especially for the contraception of exotic carnivores in zoos. Such implants can have a functional life of up to several years. Contraceptive steroids that have been incorporated into such implants have included progesterone, melengestrol acetate, megestrol acetate, and levonorgestrel. Uterine side effects have been reported. None are marketed commercially. Silastic implants formulated to steadily release natural progesterone in low doses were reported to have contraceptive efficacy without side effects over a 4-year treatment period, with treatment initiated during anestrus in all cases. However, plans for commercial development have not been reported.

Androgen Products Natural androgens, including testosterone, and synthetic androgens are by definition all masculinizing and anabolic steroids, and effects are dose dependent. None are

987

marketed with an indication for prevention of ovarian cycles in small animals in the United States, and none can be considered to be recommended or appropriate. Several are marketed in Europe and elsewhere with such indications.

Mibolerone The androgen mibolerone, an androgen receptor-specific steroid previously was marketed in the United States for cycle prevention in dogs. The liquid oral formulation (Cheque drops) was recommended at a dosage of 30, 60, 120 or 180 µg/day continuously for up to 2 years, with the dose depending on body weight (45 kg, respectively) and all Alsatians or Alsatianderived bitches receiving the highest dosage. Withdrawal from market likely was related to abuse by athletes and listing as an anabolic steroid controlled substance in several states. Mibolerone has anabolic effects on skeletal muscle and is sometimes encountered as a contraceptive used in working and racing bitches. Mibolerone liquid (100 µg/ml) for oral administration is available from some veterinary compounding pharmacies. Considerations include confirmation of anestrus status before treatment initiation, potential masculinization of fetuses in pregnant bitches, possible increased incidence in ovarian fibromas with long-term use, clitoral hypertrophy, and potential for anal gland inspissation with overdosage. Another extralabel use of mibolerone is to postpone estrus briefly (i.e., for 3 to 6 months)  in bitches with a history of abnormally short estrous cycles.

Testosterone Testosterone in various chemical states and formulations and several other androgens are marketed as anabolic steroids for use in human geriatric, surgical, and anemia patients, among others, and are also subject to abuse. Testosterone particularly has been used by animal owners to effect estrous cycle prevention and contraception in dogs used in sporting events, including sled dogs and racing greyhounds. In greyhounds, weekly oral administration of 25 mg of methyl testosterone for up to 5 years also has been used. Masculinizing and anabolic side effects are common. Permanent or prolonged anestrus may be a complication after treatment. The extent to which anabolic steroids are used in sporting dogs is not known. Androgen use should be considered as a possible complication in racing bitches with clitoral hypertrophy or anal gland inspissation. In Europe, available androgen products used for pet contraception include methyl testosterone and mesterolone tablets for oral administration and injectable  solutions of testosterone propionate, testosterone phenylpropionate, and mixtures of testosterone esters. The most common use of androgens as an estrous cycle preventive administered during anestrus is the depot injection of mixed testosterone esters (25 mg/kg), typically every 4 to 6 weeks, often supplemented with oral dosages of methyl testosterone at 0.25 to 0.50 mg/kg (England, 1998).

988

SECTION  X  Reproductive Diseases

Gonadotropin-Releasing Hormone Agonists and Antagonists Gonadotropin-Releasing Hormone Agonist Implants GnRH agonist (deslorelin)-releasing biodegradable, lipophilic-matrix implants that result in the downregulation of LH and FSH secretion and suppression of gonadal function in male dogs (Suprelorin) currently are marketed in Australia, New Zealand, and more than a dozen European countries for use in male dogs only. The implants have been marketed as 6-month implants (SL-6, containing 4.7 mg) and more recently also as 12-month implants (cSL-12, containing 9.4 mg; Suprelorin-12). The implants (2 mm × 12 mm and 2 mm × 25 mm, respectively) come preloaded in an insertion device. The recommended site of implant placement is subcutaneously between the shoulder blades. Use in female dogs remains extralabel and unapproved. Implants are also available on an experimental basis for use in zoo animals. The 4.7-mg implant is also marketed as an Indexed Product in North America as “Suprelorin F” for treatment of adrenal hyperplasia in ferrets. However, extralabel use in other species is forbidden by the Food and Drug Administration (FDA). Suprelorin 9.4 mg is also marketed in European countries both for adrenal suppression and for reproduction suppression in ferrets. A GnRH agonist like deslorelin in the circulation  binds to GnRH receptors on the pituitary cells and, after an initial transient phase of stimulation of LH and  FSH release, the agonist down-regulates gonadotrope  cell GnRH-receptors and chronically prevents release of gonadotropins in the amounts and patterns needed to support normal gonadal function. Experimental and extralabel use of implants of deslorelin and other GnRH agonists in bitches have demonstrated efficacy and safety as a female contraceptive despite the potential problem of initial induction of a fertile estrus and ovaries subsequently are maintained in an anestrous-like state. Continuous treatment with down-regulating (i.e., desensitizing) doses of a GnRH agonist initiated in young (3 1 2 to 5 months) prepubertal bitches has been shown to be 100% effective in suppressing ovarian cycles throughout treatments of 1 year and longer. It is without any obvious side effects and allows for a return to a normal puberty (albeit at an adult age) and fertility following implant removal (Rubion et al, 2006). In adult bitches and in prepubertal bitches 7 months of age or older, the same treatment is equally effective long term and likewise reversible, except that typically an initial ovarianstimulation response results in a proestrus and fertile estrus during the first 2 weeks after treatment onset. The induced estrous cycle involves increased estrogen secretion in response to the initial stimulation of LH and FSH release and can result in a spontaneous ovulationinducing LH surge and fertile ovulation. However,  pregnancies that result from breeding at the induced estrus typically fail to proceed much beyond implantation because of abnormal luteal function that occurs during continued GnRH agonist administration and gonadotropin suppression. The same technology, with

discontinuation of treatment following estrus induction and mating in adult bitches, has been used experimentally to synchronize pregnancies and treat prolonged anestrus in research dogs (Concannon et al, 1993; Walter et al, 2011). A nonbiodegradable (silastic-agonist matrix) implant releasing the GnRH agonist azaglynafarelin (Gonazon CR) initially was proposed for marketing as a pet contraceptive in Europe. However, the drug is being marketed as a spawning-regulation product for the fish farming industry and is unlikely to be promoted for use in small animals. Interestingly, Gonazon-induced suppression of puberty in bitches and the resulting delay in puberty onset to 18 months of age and older had no effect on growth or body weight measured at 22 months of age when compared with untreated control bitches (Rubion et al, 2006). The investigators speculate that perhaps weight gains sometimes associated with surgical spaying are less likely to occur with the GnRH-agonist mode of contraception. The undesirable GnRH agonist side effect of estrus induction in adult bitches is typically not seen when bitches are treated during early or mid-metestrus (diestrus) and when progesterone is above 5 ng/ml. Some reports suggest that the estrus induction effect can  be suppressed or inhibited by pretreatment with megestrol acetate at 2 mg/kg but not 1 mg/kg daily for 2 weeks (but not 1 week) before and 1 week after initiation of agonist treatment. The progestin blunts the LH response to deslorelin (Sung et al, 2006). Megestrol for 4 days before implant prevented estrus (but not proestrus) induction in most but not all bitches (Corrada et al, 2006). Prolonged estrus and follicular cysts following administration of a deslorelin implant has been reported in a mature bitch.

Gonadotropin-Releasing Hormone Agonist versus Antagonist A single injection of a GnRH antagonist (acyline) in early proestrus can transiently block GnRH-dependent gonadotropin secretion, suppress proestrus, and delay the occurrence of estrus for 2 to 5 weeks (Valiente et al, 2009). Furthermore, it may be useful for acute management of estrous cycles in bitches in which planned breeding is preferably delayed without using a more prolonged or unpredictable contraceptive regime.

The Future of Small Animal Contraception As reviewed earlier (in the previous edition of Current Veterinary Therapy; Kutzler and Wood, 2006), several alternative technologies are currently being tested, including immunization against GnRH, GnRH-multimers, LH receptor, or ovarian zona pellucida or other oocyte proteins, and the administration of GnRH (or other reproductive hormones or hormone analogs) conjugated to cytotoxins and thus targeting the destruction of pituitary gonadotroph cells (or other reproductive cell types) as cells required for normal cycles and/or fertility. No marketable method has resulted to date. GonaCon, a USDA researchdeveloped, GnRH-mollusk blue protein conjugate vaccine

CHAPTER  216  Medical Termination of Pregnancy is approved for use in multiple wild and feral animal species in the United States and is being studied coadministered with rabies vaccine to feral dogs. Similar testing has involved the vaccination of feral dogs with a biosynthetic rabies virus protein into which two copies of GnRH-peptide sequence are incorporated.

References and Suggested Reading Colon J et al: Effects of contraceptive doses of the progestagen megestrol acetate on luteinizing hormone and folliclestimulating hormone secretion in female dogs, J Reprod Fertil Suppl 47:519, 1993. Concannon P: Reproductive endocrinology, contraception and pregnancy termination in dogs. In Ettinger S, Feldman E, editors: Textbook of veterinary internal medicine, Philadelphia, 1995a, Saunders, p 1625. Concannon P et al: Growth hormone, prolactin, and cortisol in dogs developing mammary nodules and an acromegaly-like appearance during treatment with medroxyprogesterone acetate, Endocrinology 106:1173, 1980. Concannon PW: Contraception in the dog. In Raw ME, Parkinson TJ, editors: The veterinary annual, Oxford, UK, 1995b, Blackwell Scientific, p 177. Concannon PW: Reproductive cycles of the domestic bitch, Anim Reprod Sci 124:200, 2011. Concannon PW et al: Synchronous delayed oestrus in beagle bitches given infusions of gonadotrophin-releasing hormone superagonist following withdrawal of progesterone implants, J Reprod Fertil Suppl 47:522, 1993.

CHAPTER 

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Corrada Y et al: Short-term progestin treatments prevent estrous induction by a GnRH agonist implant in anestrous bitches, Theriogenology 65:366, 2006. England G: Pharmacological control of reproduction in the bitch. In Simpson G, England GE, Harvey MJ, editors: Manual of small animal reproduction and neonatology, Birmingham, UK, 1998, British Small Animal Association, p 197. Kutzler M, Wood A: Non-surgical methods of contraception and sterilization, Theriogenology 66:514, 2006. Romagnoli S, Concannon P: Clinical use of progestins in bitches and queens: a review. In Concannon P, England G, Verstegen J, Linde-Forspurg C, editors: Recent advances in small animal reproduction, (ePub:International Veterinary Information Service), 2003, accessed June 27, 2013 from www.ivis.org. Rubion S et al: Treatment with a subcutaneous GnRH agonist containing controlled release device reversibly prevents puberty in bitches, Theriogenology 66:1651, 2006. Selman PJ et al: Comparison of the histological changes in the dog after treatment with the progestins medroxyprogesterone acetate and proligestone, Vet Q 17:128, 1995. Sung M, Armour AF, Wright PJ: The influence of exogenous progestin on the occurrence of proestrous or estrous signs, plasma concentrations of luteinizing hormone and estradiol in deslorelin (GnRH agonist) treated anestrous bitches, Theriogenology 66:1513, 2006. Valiente C et al: Interruption of the canine estrous cycle with a low and a high dose of the GnRH antagonist, acyline, Theriogenology 71:408, 2009. Walter B et al: Estrus induction in Beagle bitches with the GnRHagonist implant containing 4.7 mg Deslorelin, Theriogenology 75:1125, 2011.

216 

Medical Termination of Pregnancy BRUCE E. EILTS, Townsville, Australia

A

perfect pregnancy termination drug could be given at any stage of estrus or pregnancy, would be 100% effective, would cause no vaginal discharge, would have no side effects, would not impair future fertility, would be readily available, and would be inexpensive. Unfortunately such a drug does not exist. In cases in which the patient is not a valuable breeding animal, the client should be counseled that the best option is to ter­ minate the pregnancy and to prevent future pregnancies surgical sterilization is recommended. Drugs available for pregnancy termination are discussed under the general categories of those used after pregnancy is confirmed  and those used before pregnancy is confirmed. A

comprehensive list of drugs to terminate pregnancy com­ monly available in the United States is discussed.

Drugs Used After Confirmed Pregnancy If the bitch mated or is thought to have mated, a preg­ nancy diagnosis should be performed before proceeding to terminate the pregnancy. Even though conception rates in controlled breeding situations resulted in a preg­ nancy rate of about 90% when only a single mating was allowed on any day of estrus (up to the last 2 days of estrus) (Holst and Phemister, 1974), only 38% of bitches presented for mismate actually may be pregnant (Feldman

990

SECTION  X  Reproductive Diseases

et al, 1993). A pregnancy examination should be per­ formed at least 30 to 40 days after the last possible breed­ ing to minimize false-negative diagnoses caused by errors in calculating the gestation duration from a mating that occurred early in estrus. Therapy is instituted only if a bitch is pregnant. Drugs that terminate pregnancy can cause premature luteal demise by acting as a direct luteo­ lytic, inhibiting prolactin secretion, or blocking the pro­ gesterone receptors or unknown mechanisms.

Complete pregnancy termination 5 days after starting treatment with minimal adverse effects (tachypnea lasting less than 15 minutes) was reported after administration of natural PGF2α at a dose of 0.012 mg/kg q6h SC at 30 days of gestation (Len et al, 2011). Clients must be able to administer safely multiple injections to their animals, or the animals must be hospitalized. The safety and effi­ cacy of this protocol makes it the author’s primary choice as an abortifacient in the bitch.

Prostaglandins

Prolactin Inhibitors

Protocols Prostaglandin F2α (PGF2α) induces lysis of the corpora lutea. In dogs, the natural PGF2α (Lutalyse) given at a dosage of 0.1 to 0.25 mg/kg q8-12h SC is effective at terminating pregnancy after pregnancy confirmation. One protocol reported to have few side effects is admin­ istration of PGF2α at 0.1 mg/kg q8h SC for 2 days and then 0.2 mg/kg q8h SC until abortion is complete (Feldman et al, 1993). Abortion usually is complete within 9 days, but some dams still have live fetuses after 9 days. It is extremely important to continue the treatments until abortion is complete. In queens, natural PGF2α is most effective after 40 days of gestation. Beginning at 45 days of gestation, PGF2α (0.2 mg/kg q12h SC first day, 0.5 mg/ kg q12h SC for up to 5 days) caused abortion in 75% of queens. Synthetic PGF2α analogs are more potent and have fewer side effects than natural PGF2α. Cloprostenol (Estru­ mate) at a dosage of 1 to 2.5 µg/kg q24h SC for 4 to 5 days was 100% effective at inducing abortion (Verstegen, 2000). Once-per-day treatments with synthetic PGF2α analogs provide an advantage over the three-times-perday treatments required with natural PGF2α. Hospitaliza­ tion or frequency of injections adds greatly to client cost when using PGF2α as an abortifacient. To shorten the treatment period required to induce abortion with PGF2α, PGF2α (0.1 mg/kg q8h SC for 2 days and then 0.2 mg/kg q8h SC to effect) can be combined with PGE1 (misoprostol, Cytotec) at a dosage of 1 to 3 µg/ kg q24h deposited into the cranial vaginal vault. The mean time to complete abortion using this combination was 2 days shorter compared with PGF2α alone (5 days vs. 7 days, respectively) (Davidson et al, 1997). Similar results have been reported using PGE1 with the synthetic PGF2α, alfaprostenol (Agaoglu et al, 2011).

Dopaminergic drugs are prolactin inhibitors. Com­ mercially available prolactin inhibitors include bro­ mocriptine, cabergoline, and metergoline. Bromocriptine (Parlodel) administered at a dosage of 62.5 µg/kg q12h PO to dogs at 43 to 45 days after ovulation resulted in only 50% of bitches aborting; side effects included emesis and loose stools (Wichtel et al, 1990). Because the dosage is so low and the tablets contain so much active drug the bromocriptine tablets can be crushed and dissolved in water to ease dosing. Cabergoline at a dose of 1.65 µg/kg q24h SC for 5 to 6 days at 25 to 40 days after the first mating resulted in abortion for 100% of bitches greater than 40 days of gestation but only for 25% and 67% at 25 days and 30 days of gestation, respectively. Side effects were minimal, and bitches that aborted became pregnant after treatment. In the United States, cabergoline is avail­ able in a 0.5-mg tablet. When given at a dose of 160 µg PO to a 32-kg German shepherd dog after 40 days of gestation, it resulted in abortion after 7 days with no side effects (Arbeiter and Flatscher, 1996). Although cabergo­ line is not expensive for each dose, it may be difficult to administer because of the amount of drug per tablet (0.5 mg) is considerably higher than the dose for a 10-kg dog (0.05 mg). Metergoline (0.6 mg/kg q12h PO starting after the onset of cytologic diestrus and continued to effect) induced abortion in 89% of bitches with no side effects (Nöthling et al, 2003). Cabergoline (5 to 15 µg/kg q24h PO) administered to feral cats 36 to 40 days of pregnancy for 4 to 9 days caused abortion in 100% of queens (Jochle and Jochle 1993).

Adverse Effects Adverse effects of natural PGF2α are more common in dogs than cats and include vomiting, diarrhea, and pos­ sibly circulatory collapse. The adverse effects usually subside within 20 minutes, but the bitch should be moni­ tored carefully during this time. To minimize caloric loss, bitches should be fed at least 1 hour after treatment. Minimal to no adverse effects are observed when using PGF2α analogs at a 1 µg/kg q24h SC dosage. Drugs used to decrease the adverse effects of natural PGF2α include a combination of atropine sulfate (0.025 mg/ kg), prifinium bromide (0.1 ml/kg), and metopimazine (0.5 mg/kg) SC 15 minutes before PGF2α administration. Lower doses of natural PGF2α also decrease adverse effects.

Prolactin Inhibitors in Combination with Prostaglandin F2α Analogs Combining prolactin inhibitors with PGF2α increases the efficacy of pregnancy termination and reduces the side effects of treatment. Cloprostenol (1 or 2.5 µg/kg q24h SC once) in combination with cabergoline (1.65 µg/kg q24h SC for 5 days) from midgestation induced abortion with no adverse side effects (Onclin et al, 1995). After an average of 9 days, cabergoline (5 µg/kg q24h PO) 1 hour after cloprostenol (1 µg/kg q48h SC) caused fetal death with no side effects when started at 25 days of gestation peak (Onclin and Verstegen, 1996). Treatment with cab­ ergoline (5 µg/kg q24h PO) for 10 days combined with either one dose (2.5 µg/kg SC) or two doses (1 µg/kg SC repeated 4 days later) of cloprostenol at the start of the treatment was successful at inducing pregnancy termina­ tion. Similarly, bromocriptine (30 µg/kg q8h PO) for 10 days with either one dose (2.5 µg/kg SC) or two doses (1 µg/kg SC repeated 4 days later) of cloprostenol at the

CHAPTER  216  Medical Termination of Pregnancy start of the treatment was successful at inducing preg­ nancy termination (Onclin and Verstegen, 1999). All bitches in the aforementioned study became pregnant during the subsequent estrous cycle, which occurred sooner than normally anticipated. As with PGF2α alone, using PGE1 with the cabergoline combined with a syn­ thetic PGF2α decreased the time to abortion compared with those not receiving PGE1. Oral cabergoline (5 µg/kg q24h PO) combined with cloprostenol (5 µg/kg q48h SC) starting at the thirtieth day after coitus caused abor­ tion in 100% of queens after an average of 9 days of treatments.

Progesterone Receptor Blockers The progesterone receptor blocker mifepristone (Mifeprex), more commonly known as RU486 or RU38486 for its use in preventing human pregnancies, administered at a dosage of 2.5 mg/kg q12h PO for 4 1 2 days starting at day 32 of gestation resulted in no side effects and 100% abor­ tion in bitches with pregnancy loss occurring 3 days after treatment initiation (Concannon et al, 1990). Doses as low as 8.3 mg/kg and up to 20 mg/kg q24h PO for one or two treatments resulted in abortion within 2 to 11 days at days 35 to 39 of pregnancy (Linde-Forsberg et al, 1992). In the United States, mifepristone is available only in a 200-mg tablet. Aglepristone (Alizine) is another progesterone receptor blocker that is commercially available in several European countries but not in the United States. Two doses of agle­ pristone (9.9 mg/kg q24h SC) caused uncomplicated abortions within 14 days in 94.4% of bitches after 26 days of pregnancy (Fieni et al, 2003) Side effects included slight depression, transitory anorexia, and mammary gland congestion. Similar to PGF2α alone, administration of PGE1 (200 to 400 µg q24h) intravaginally in combina­ tion with aglepristone reduced the time to abortion when compared with aglepristone alone. In cats, aglepristone (10 mg/kg q24h SC) administered twice caused abortion in 5 ± 2 days in 100% of queens (Favre et al, 2007).

Unknown Mechanisms Although the mechanism of action is not completely known, dexamethasone was effective at terminating preg­ nancy from midgestation after a 10 1 2-day dosage schedule (Table 216-1). Pregnancies lasting less than 40 days gener­ ally had no fetuses expelled with mild vaginal discharge seen in about 34% of the bitches (Wanke et al, 1997; Zone et al, 1995). Pregnancy loss generally was complete 10 to 23 days after the treatment started. The main side effects of dexamethasone treatment included anorexia, polydip­ sia, and polyuria. The side effects usually begin around 2 to 3 days after treatment is initiated, are most pronounced 4 to 5 days later, and then subside 3 to 4 days after the termination of treatment. Successful pregnancies were obtained in 90% of bitches bred during the first estrus after treatment. In the author’s experience, dexametha­ sone (0.2 mg/kg q12h PO) until pregnancy termination has occurred (with no tapering of the dose) has similar results with no greater side effects. The advantages of dexamethasone treatment for pregnancy termination

991

TABLE 216-1  Dosing Schedule for Canine Pregnancy Termination with Dexamethasone Treatment Days

Dexamethasone Dose or Dosage

Days 1 to 7

0.2 mg/kg q12h PO

Day 8 (AM)

0.16 mg/kg PO

Day 8 (PM)

0.12 mg/kg PO

Day 9 (AM)

0.08 mg/kg PO

Day 9 (PM)

0.04 mg/kg PO

Day 10 (AM)

0.02 mg/kg PO

over the previously mentioned drugs include that it elimi­ nates most of the side effects reported with other preg­ nancy termination drugs, avoids the requirement for hospitalization or office visits for injections, is inexpen­ sive, is readily available, can be administered easily by clients, is effective, and has few side effects. However, this author is aware of anecdotal reports of prolonged treat­ ment times, treatment failures, and even patient death associated with dexamethasone pregnancy termination. The author is unaware of its effect on pregnancy termina­ tion in the queen. Several other drugs have been used to terminate preg­ nancy in the bitch, including tamoxifen citrate (Noladex), which acts as an estrogen; epostane, which inhibits steroid synthesis by inhibition of 3β-hydroxysteroid dehydrogenase; and Δ5-4 isomerase and isoquinolones L-12717 (Lotifren). These are either not efficacious or not available in the United States.

Drugs Used Before Confirmed Pregnancy During Diestrus Before pregnancy confirmation, prolactin inhibitors are ineffective at terminating pregnancy because of their mechanism of action (as discussed above). Although PGF2α can be used to terminate pregnancy before preg­ nancy confirmation, the dosage required to induce lute­ olysis at this stage of diestrus approaches the LD50. Progesterone receptor blockers should be effective at this stage of gestation in dogs and cats, but controlled studies to demonstrate their efficacy before pregnancy confirma­ tion have not been performed.

During Estrus The only drugs available to terminate pregnancy during estrus are the estrogens, which act by blocking embryo transit in the oviducts. The use of estrogens for mismate management is cited in many texts and by many acade­ micians as being unsafe to the extent of being malprac­ tice; however, little published data substantiate these statements. Estrogens should be used only during estrus because their use during diestrus significantly increases

992

SECTION  X  Reproductive Diseases

the chance of inducing a pyometra. A vaginal cytology examination having 90% to 100% cornified cells shows that the bitch is truly in estrus, whereas if the cells are not cornified, the bitch is not in estrus. Side effects such as prolonged estrus, pyometra, and aplastic anemia (pan­ cytopenia) are possible; therefore it should be docu­ mented that the bitch actually was bred based on owner observation of a mating or laboratory identification or the presence of sperm cells in a vaginal swab. Sperm cells can be identified in 100% of bitches mated within 24 hours and 75% of bitches mated within 48 hours by placing the tip of the vaginal cytology swab into a tube containing 0.5 ml saline for 10 minutes, squeezing the swab dry into a tube and centrifuging the fluid at 2000 × g for 10 minutes, and finally staining the sediment. Estradiol cypionate (ECP, Depo-Estradiol) was shown to have 100% efficacy and no side effects during the study period when administered at a dose of 44 µg/kg intramus­ cularly one time during estrus; however, a 25% ( 1 4) inci­ dence of pyometra was seen when administered during diestrus (Bowen et al, 1985). Although the drug marketed as ECP is no longer available, estradiol cypionate can still be obtained from compounding pharmacies. Estradiol benzoate (oestradiol benzoate) at a dosage of 0.01 mg/kg IM at 3 and 5 days (and occasionally 7 days) after mating in 358 bitches resulted in only 4.5% (16/358) of the bitches actually whelping; in none of the bitches was bone marrow aplasia reported. The 7.3% incidence of pyometra reported was not different from the normal prevalence reported as 2% to 10%. Although a more recent study showed a statistically higher incidence of pyometra associated with estradiol benzoate pregnancy termination treatment (8.7% in estradiol benzoate– treated bitches compared with 1.3% in untreated bitches) (Whitehead, 2008). Administration of diethyl stilbestrol is not effective at terminating pregnancy (Bowen et al, 1985). In queens, ECP (250 µg/cat IM) administered 6 days after coitus retarded uterine tubal embryo transport and development. Administration of ECP (125 to 250 µg/cat IM) 40 hours after coitus has been suggested to be an effective mismating regimen in queens; however, no data are available on its actual efficacy (Heron and Sis, 1974). This author does not encourage estrogen use for routine pregnancy termination because alternative treat­ ments are available once the bitch is diagnosed pregnant. However, the use of estrogens for pregnancy termination is not condemned unconditionally as malpractice.

References and Suggested Reading Agaoglu AR et al: The intravaginal application of misoprostol improves induction of abortion with aglepristone, Theriogenology 76:74, 2011. Arbeiter K, Flatscher C: Induction of abortion in the bitch using cabergoline (Galastop), Kleintierprax 41:747, 1996. Bowen RA et al: Efficacy and toxicity of estrogens commonly used to terminate canine pregnancy, Amer Vet Med Assn 186:783, 1985.

Cetin Y et al: Intravaginal application of misoprostol improves pregnancy termination with cabergoline and alfaprostol in dogs, Berl Munch Tierarztl Wochenschr 123:236, 2010. Concannon PW, Yeager A, Frank D: Termination of pregnancy and induction of premature luteolysis by the antiprogestagen, mifepristone, in dogs, J Reprod Fertil 88:99, 1990. Davidson AP, Nelson RW, Feldman EC: Induction of abortion in 9 bitches with intravaginal misoprostol and parenteral PGF2α, J Vet Intern Med 11:123, 1997. Favre RN et al: Induction of abortion in queens by administra­ tion of aglepristone (Alizine): preliminary results, Theriogenology 68:499, 2007. Feldman EC et al: Prostaglandin induction of abortion in preg­ nant bitches after misalliance, J Amer Vet Med Assn 202:1855, 1993. Fieni F et al: Clinical use of anti-progestins in the bitch, Int Vet Inform Serv, accessed October 30, 2011, from http://www.ivis .org/advances/Concannon/fieni/ivis.pdf. Heron MA, Sis RF: Ovum transport in the cat and the effect of estrogen administration, Amer J Vet Res 35:1277, 1974. Holst PA, Phemister RD: Onset of diestrus in the Beagle  bitch: definition and significance, Amer J Vet Res 35:401, 1974. Jochle W, Jochle M: Reproduction in a feral cat population and its control with a prolactin inhibitor, cabergoline, J Reprod Fertil Suppl 47:419, 1993. Len JA et al: Low dose prostaglandin F2a for luteal regression in the bitch, Clin Theriogenol 2:362, 2011. Linde-Forsberg C, Kindahl H, Madej A: Termination of mid-term pregnancy in the dog with oral RU 486, Small Anim Pract 33:331, 1992. Nöthling J et al: Abortifacient and endocrine effects of metergo­ line in beagle bitches during the second half of gestation, Theriogenology 59:1929, 2003. Onclin K, Silva LDM, Verstegen JP: Termination of unwanted pregnancy in dogs with the dopamine agonist, cabergoline, in combination with a synthetic analog of PGF2Alpha, either cloprostenol or alphaprostol, Theriogenology 43:813, 1995. Onclin K, Verstegen JP: Comparisons of different combinations of analogues of PGF2à and dopamine agonists for the termina­ tion of pregnancy in dogs, Vet Rec 144:416, 1999. Onclin K, Verstegen JP: Practical use of a combination of a dopa­ mine agonist and a synthetic prostaglandin analogue to ter­ minate unwanted pregnancy in dogs, Small Anim Pract 37:211, 1996. Sutton DJ, Geary MR, Bergman JGHE: Prevention of pregnancy in bitches following unwanted mating: a clinical- trial using low-dose estradiol benzoate, J Reprod Fertil Supp 51:239, 1997. Verstegen JP: Overview of mismating for the bitch. In Bonagura JD, editor: Current veterinary therapy: small animal practice, ed 13, Philadelphia, 2000, WB Saunders, p 947. Wanke M et al: Clinical use of dexamethasone for termination of unwanted pregnancy in dogs, J Reprod Fertil Supp 51:233, 1997. Whitehead M: Risk of pyometra in bitches treated for mismating with low doses of oestradiol benzoate, Vet Rec 162:746, 2008. Wichtel JJ et al: Comparison of the effects of PGF2a and bro­ mocryptine in pregnant beagle bitches, Theriogenology 33:829, 1990. Zone M et al: Termination of pregnancy in dogs by oral admin­ istration of dexamethasone, Theriogenology 43:487, 1995.

CHAPTER 

217 

Inherited Disorders of the Reproductive Tract in Dogs and Cats VICKI N. MEYERS-WALLEN, Ithaca, New York

Normal Sexual Development Normal sexual development depends on successful completion of three consecutive steps: (1) establishment of chromosomal sex, (2) development of gonadal sex, and (3) development of phenotypic sex. Chromosomal sex, which corresponds to genetic sex in normal animals, is established at fertilization. The zygote receives either two X chromosomes or an X and a Y chromosome and maintains this chromosomal constitution in all cells by mitotic division. Morphology of early XX and XY embryos is sexually indifferent. Both have a genital ridge, from which the testis or ovary develops. They also have müllerian and wolffian ducts, a urogenital sinus, a genital tubercle, and genital swellings, from which the internal and external genitalia will arise (Figure 217-1). Differentiation of the genital ridge into a testis or an ovary defines gonadal sex and marks the end of the sexually indifferent stage. Although several genes are necessary for normal development through the sexually indifferent stage, genes that determine gonadal sex have a pivotal role in sexual development. Gonadal sex typically is determined by sex chromosome constitution: presence of the Y chromosome results in testis development, whereas its absence results in ovarian development. The sex-determining region Y gene, SRY, is located normally on the Y chromosome, and the SRY protein is the signal for initiating testis differentiation in the genital ridge (Jakob and Lovell-Badge, 2011). In the absence of the Y chromosome and SRY, the genital ridge normally becomes an ovary. However, ovarian induction is not a passive process: testispromoting and ovary-promoting signaling pathways are responsible for gonadal sex determination (Quinn and Koopman, 2012). Phenotypic sex is controlled normally by gonadal sex. If the genital ridges are removed from XX or XY embryos before gonadal differentiation occurs, a female phenotype develops, indicating that the embryo is programmed to develop as a female and must be diverted from this pathway to develop as a male. The critical diverting step is testis development. The testis secretes two substances that act within embryonic critical periods to induce masculinization: (1) müllerian-inhibiting substance/antimüllerian hormone (MIS/AMH), which causes the müllerian

ducts to regress, and (2) testosterone, which stimulates formation of the vasa deferentia and epididymides from the wolffian ducts (see Figure 217-1). In the external genitalia, testosterone is converted to dihydrotestosterone (DHT) by the enzyme 5α-reductase. Dihydrotestosterone stimulates formation of the prostate and male urethra, penis, and scrotum from the urogenital sinus, genital tubercle, and genital swellings, respectively (see Figure 217-1). Descent of the testes into the scrotum completes the male external genitalia, but the genetic and hormonal control of this process is incompletely understood. Testosterone and insulin-like 3 factor (INSL3), both secreted by Leydig cells, are required for testis descent, as are their receptors, but other unknown factors also likely are involved. In the absence of testicular secretions, female genitalia develop (see Figure 217-1).

Diagnosis of Disorders of Sexual Development For the purpose of pursuing a diagnosis, it is useful to identify the initial step at which development differs from normal, either at the level of chromosomal sex, gonadal sex, or phenotypic sex (Table 217-1). A more precise diagnosis defines the disorder according to its etiology, preferably by the specific gene mutation responsible for the defect. To eliminate older, confusing terms such as pseudohermaphrodite and facilitate incorporation of molecular diagnoses, a new nomenclature has been established (Pasterski, Prentice, and Hughes, 2010). With this terminology, intersex individuals are described as having a disorder of sexual development (DSD), a nonspecific term. All DSDs are categorized initially by karyotype, with sex chromosome DSD including all errors at the level of chromosomal sex. Errors occurring at the level of gonadal sex or phenotypic sex now are divided according to karyotype, either XX DSD or XY DSD (see Table 217-1). Regardless of the nomenclature used, the diagnostic plan for any DSD includes a karyotype (dog 78,XX or 78,XY; cat 38,XX or 38,XY). The presence or absence of the SRY gene in dogs and cats can be tested by polymerase chain reaction (PCR). Gonadal sex is determined by histology and may require serial gonadal sections for identification of ovotestes. A concise description of the 993

994

SECTION  X  Reproductive Diseases

Chromosomal sex:

XX

?

XY

Indifferent embryo

Sry

Gonadal sex: Gonad

Ovary

Testis MIS

Phenotypic sex: Oviduct Uterus Cranial vagina

Müllerian ducts

Regress

Wolffian ducts

Remains open: Caudal vagina Vestibule

Urogenital sinus

Clitoris

Genital tubercle

Regress Testosterone

Vas deferens Epididymis

DHT

DHT

Closes: Urethra Prostate

Penis Insl3

Remains open: Vulva

Genital swellings

DHT

Closes: Scrotum

Testis Descent

Figure 217-1  Major steps in normal sexual development. (Modified with permission from: Meyers-Wallen VN, Patterson DF: Disorders of sexual development in the dog. In Morrow DA, editor: Current therapy in theriogenology, ed 2, Philadelphia, 1986, WB Saunders, p 567.)

internal and external genitalia is necessary to define  phenotypic sex. Assays of peripheral hormones may be helpful but are not a substitute for gonadal histology. Gonadotropin-releasing hormone (GnRH) or human chorionic gonadotropin (hCG) stimulation tests, rather than single peripheral samples, are necessary in many cases, particularly those in which peripheral androgen concentrations are of concern.

Sex Chromosome Disorders of Sexual Development Many disorders of sexual differentiation have been reported, in which the primary cause was an abnormality in the number or structure of the sex chromosomes. To summarize, animals with abnormalities in sex chromosome number, such as those with XXY and XO syndromes and their variants, generally have underdeveloped genitalia and are sterile but are unambiguously male or female in phenotype (see Table 217-1). However, some XXX dogs have exhibited estrous cycles, and pregnancy was reported in an XXX variant cat. The gonadal sex of

chimeras and mosaics depends on the distribution of XX and XY cells within the genital ridge. Phenotypic sex then is determined by the presence and amount of functional testicular tissue in the gonad. Sex chromosome DSDs usually are caused by errors in chromosome segregation or by fusion of zygotes. Therefore familial aggregation of affected individuals is not expected.

XX Disorders of Sexual Development All animals with XX disorders of sexual development (XX DSDs) have a female karyotype and are separated according to whether the primary defect occurs at or below the level of the gonad (see Table 217-1). Disorders of Gonadal Development For those individuals with the primary defect occurring at the level of the gonad, these animals develop testicular tissue (ovotestis or testis) despite having a normal female karyotype. This has been reported in dogs but not in  cats. Such animals previously were termed sex-reversed because the chromosomal sex and the gonadal sex of the

CHAPTER  217  Inherited Disorders of the Reproductive Tract in Dogs and Cats

995

TABLE 217-1  Main Features of Selected Disorders of Sexual Development Reported in Dogs or Cats

Abnormality of Chromosomal Sex

Karyotype

Gonads

XO

Streak gonad

XXX

Ovary ± hypoplastic Testis

XXY

Abnormality of Gonadal Sex

Abnormality of Phenotypic Sex

Müllerian Duct Derivatives

Wolffian Duct Derivatives

External Genitalia

Diagnosis

Uterus, uterine tubes, vagina Uterus, uterine tubes, vagina None

None

Female

None

Female

Epididymis, vas deferens Varies with amount of functional testis

Male

Sex chromosome DSD Sex chromosome DSD Sex chromosome DSD Sex chromosome DSD

Female or enlarged clitoris Cryptorchid, hypospadias, displaced prepuce Ambiguous

Female ± ambiguous or male

XX/XY

Ovary or ovotestis or testis

Varies with amount of functional testis

XX

Ovotestis

Uterus ± uterine tube

Epididymis (±)

XX

Testis

Uterus

Epididymis ± vas deferens

XY

Uterus (±)

Epididymis (±)

XY

Testis lacking germ cells Ovotestis

Uterus, uterine tube

Epididymis ± vas deferens

Male

XX

Ovary

Uterus, uterine tube

None

Ambiguous or Male

XX

Ovary

None

Female

XY

Testis

Uterus: unicornuate, hypoplastic or segmental aplastic (+ renal agenesis or ectopy) None

None or epididymis

Female or ambiguous

XY

Testis

Uterus, uterine tube, cranial vagina

Epididymis, vas deferens

Male

XY

Testis

None

XY

Testis

None

Epididymis, vas deferens Epididymis, vas deferens

Male with hypospadias only Male with cryptorchidism only

individual disagree. Affected dogs have at least one ovotestis (ovotesticular XX DSD) or bilateral testes (testicular XX DSD) and previously were called XX true hermaphrodites or XX males, respectively. Both phenotypes can appear in the same family. Phenotypic masculinization depends on the amount of testicular tissue in the affected individual. Thus those with ovotestes may have normal female external genitalia, an enlarged clitoris with an os clitoris that resembles a penis, or any phenotype in between. Those with bilateral testes generally have a caudally displaced prepuce and a penis with hypospadias and are bilaterally cryptorchid. This DSD has been reported as a familial trait in at least 28 canine breeds and two mixed breeds (Box 217-1). In the American cocker spaniel, this DSD is inherited as an autosomalrecessive trait, but the mode of inheritance has not been determined in all breeds. The Y-linked SRY gene is absent in all affected dogs reported, ruling out translocation as the cause.

XX DSD, ovotesticular XX DSD, testicular

XY DSD, testicular dysgenesis (partial) XY DSD, ovotesticular XX DSD, androgen excess XX DSD, müllerian agenesis, or hypoplasia

XY DSD, androgen insensitivity syndromes XY DSD, persistent müllerian duct syndrome XY DSD, isolated hypospadias XY DSD, isolated cryptorchidism

BOX 217-1  Canine Breeds in Which Testicular or Ovotesticular XX DSD Has Been Reported American cocker spaniel Afghan hound American pit bull terrier American Staffordshire terrier Australian shepherd Basset hound Bernese mountain dog Beagle Border collie Brussels griffon Doberman pinscher English cocker spaniel French bulldog German pinscher

German shepherd dog German shorthaired pointer Golden retriever Jack Russell terrier Kerry blue terrier Norwegian elkhound Podenco dog Pug Soft-coated wheaten terrier Tibetan terrier Vizsla Walker hound Weimaraner Wheaten terrier

996

SECTION  X  Reproductive Diseases

Diagnosis depends on confirmation of a 78,XX karyotype and histology demonstrating at least one ovotestis or testis. To define the etiology more precisely and aid in genetic counseling, the diagnostic workup should include a molecular test for SRY. Whereas elevation in peripheral testosterone concentrations in response to GnRH or hCG stimulation strongly suggests that testicular tissue is present, it is not diagnostic. The inability to provoke testosterone elevation by a stimulation test does rule out the diagnosis. In addition to dogs, ovotesticular or testicular XX DSD in which the individuals are SRY negative has been reported in several mammals. Mutations that cause SOX9 or SOX3 overexpression or reduce RSPO1 expression have been identified in affected humans and mice (Jakob and Lovell-Badge, 2011). This form of canine XX DSD has been studied most extensively in a pedigree derived from the American cocker spaniel, in which an autosomal-recessive mode of inheritance was identified through experimental matings (Meyers-Wallen, 2012). A genome-wide linkage analysis in this model pedigree identified linkage to CFA29. A candidate gene has not been identified, and SOX9, RSPO1, and SOX3 are not located in this region. The causative mutation is likely to be the same in American and English cocker spaniels because they share recent common ancestry. It is unclear whether the same gene locus is responsible in other breeds. Treatment is limited to surgical removal of the gonads and uterus and, if the dog is uncomfortable, excision of the enlarged clitoris and os clitoris. Although all dogs with testicular XX DSD and most with ovotesticular XX DSD are sterile, some of the latter have exhibited estrous cycles and reproduced as females. Nevertheless, the mating of affected dogs of any breed is discouraged strongly because it will increase the frequency of the causative mutation within the breed and lead to production of more affected dogs. Similarly, parents of affected dogs should not be bred. As the causative mutation is unknown, a laboratory test to detect carriers and affected dogs is not available. Androgen Excess These animals have a female karyotype and bilateral ovaries but develop ambiguous genitalia in response to androgen exposure during development (see Table 217-1). They are categorized according to the androgen source, either fetal or maternal. These are errors of phenotypic sex, formerly categorized as female pseudohermaphroditism. Fetal Origin.  Although adrenal enzyme defects (adrenogenital syndromes) are a common cause of fetal androgen excess in humans, they are apparently rare in dogs and cats. Steroid precursors accumulate at the enzyme block and are shunted to the androgen synthesis pathway. Excess adrenal androgen production from 11 betahydroxylase deficiency has been reported in a 38,XX calico cat that presented with male external genitalia, but the testes were not palpable. Internal genitalia consisted of ovaries, bicornuate uterus, and uterine tubes. Clinical signs included polydipsia, polyuria, and inappropriate urination. After ovariohysterectomy, penile spines persisted and peripheral testosterone concentrations were  in the normal range of an intact male. Subsequent 

to prednisone treatment, testosterone concentrations decreased and clinical signs ceased. This DSD has not been reported in dogs. Maternal Origin.  Canine cases of androgen excess have been 78,XX individuals with bilateral ovaries, a complete uterus, and phenotypic masculinization ranging from mild clitoral enlargement to nearly normal male external genitalia and a prostate gland internally. An iatrogenic cause was known in some cases: either an androgen (testosterone, mibolerone) or a progestagen had been administered to the pregnant dam. Presenting signs were related to bleeding at the onset of proestrus, urinary incontinence, or uterine infection. Feline cases have not been reported. Diagnosis of XX DSD, androgen excess depends on confirmation of a female karyotype, bilateral ovaries, and evidence of androgen-dependent masculinization. Before gonadectomy, the diagnostic workup could include tests for endogenous androgen production. Elevation of serum testosterone in response to GnRH or hCG would suggest testicular androgen production, which along with a female karyotype would suggest a diagnosis of ovotesticular or testicular XX DSD (above). Gonadal histology is necessary for distinguishing the difference. Abnormal elevation of serum androgens in response to adrenocorticotropic hormone (ACTH) stimulation would suggest adrenal androgen production and androgen excess of fetal origin, as in adrenogenital syndromes (above). If no evidence of endogenous androgen production is found, historical confirmation of exogenous androgen exposure to the pregnant dam should be sought. Ovariohysterectomy, with gonadal histopathology, is recommended. However, when urinary abnormalities  are present, contrast studies are recommended before surgery to determine whether additional surgical treatment is necessary. Because the most common cause in dogs is iatrogenic androgen administration prevention is achieved by avoidance of steroid administration, such as androgens or progestagens, during gestation. Because the canine internal and external genitalia normally develop between gestational days 34 and 46, counting from the serum luteinizing hormone (LH) peak of the dam, it is prudent to avoid steroid administration particularly during this period. Müllerian Agenesis or Hypoplasia Müllerian duct aplasia or hypoplasia in humans is associated strongly with renal agenesis or ectopy and cervicothoracic somite dysplasia: if one component is identified, the other anomalies should be investigated. This syndrome in humans is referred to as MURCS (müllerian duct aplasia, unilateral renal agenesis, and cervicothoracic somite anomalies). A survey of cats and dogs undergoing elective ovariohysterectomy identified several cases of unicornuate uterus, unilateral uterine segmental aplasia, and uterine horn hypoplasia. In 29.4% of cats and 50% of dogs with uterine abnormalities in which the kidneys were also evaluated, ipsilateral renal agenesis was present (McIntyre et al, 2010). This suggests that further study, including a karyotype and evaluation of the cervical spine and thoracic skeleton, is needed in such cases to determine whether there is a feline or canine counterpart of MURCS.

CHAPTER  217  Inherited Disorders of the Reproductive Tract in Dogs and Cats

XY Disorders of Sexual Development All animals with XY disorders of sexual development (XY DSDs) have a male karyotype and are separated according to whether the primary defect occurs at the level of the testis, the androgen-dependent tissues, or the remaining genitalia (see Table 217-1). Disorders of Gonadal Development Partial Testicular Dysgenesis.  These animals have defects in testis induction or early differentiation, which affects masculinization that is dependent upon testicular hormones. This has been reported rarely in dogs and has not been reported in cats (Meyers-Wallen, 2012). An SRY-positive 78,XY poodle presented with ambiguous external genitalia, consisting of an enlarged clitoris protruding from the vulva. The undescended testes contained seminiferous tubules lined by Sertoli cells, but germ cells were absent. The testes were attached to the horns of a bicornuate uterus, in which the endometrial glands were small in size and number. Because androgen and MIS-dependent masculinization were incomplete in this case, the diagnosis is likely XY DSD partial testicular dysgenesis. The molecular cause is unknown. Another case was an SRY-positive 78,XY Labrador retriever that presented with an enlarged clitoris protruding from the vulva. One testis was located near the vulva, whereas the other was in the abdomen. Both testes contained Leydig cells and seminiferous tubules lacking spermatogenesis. Incompletely developed epididymides were adjacent to each testis, but vasa deferentia were absent. No müllerian duct derivatives were identified. Because partial androgen-dependent masculinization and complete müllerian duct regression were confirmed, this case could be either XY DSD partial testicular dysgenesis or an XY DSD of androgen synthesis or action (below). The molecular cause is unknown. Ovotestes.  These animals have a male karyotype but develop ovotestes. They now are classified as ovotesticular XY DSD but were classified formerly as XY sex reversal (XY true hermaphrodite). One cat has been reported, which was a 1-year-old mixed breed, phenotypic male presented as bilaterally cryptorchid (Schlafer et al, 2011). The karyotype was 38,XY and the SRY sequence was the same as a normal male control. Ovotestes, located at the caudal pole of the kidneys, were composed primarily of testis, with a thin rim of ovarian tissue in the cortex. Epididymides were adjacent to each gonad, but vasa deferentia were found adjacent only to the cranial uterine horns. There was complete failure of müllerian duct regression; a bicornuate uterus, uterine tubes, and fimbria were present. The causative mutation is unknown. Disorders in Androgen Synthesis or Action These animals have a normal male karyotype, testes, and normal müllerian duct regression. However, genitalia that require androgens for masculinization fail to develop normally because of defects in androgen production, 5α-reductase, or the androgen receptor. Complete Androgen Insensitivity Syndrome.  Complete androgen insensitivity syndrome (CAIS) disorders are caused by androgen receptor (AR) defects and formerly

997

were called androgen resistance syndromes or testicular feminization. One affected 38,XY cat has been reported (Meyers-Wallen et al, 1989). The external genitalia were unambiguously female at 6 months of age when presented for routine ovariohysterectomy. Bilateral abdominal testes were present, but there were no epididymides or vasa deferentia. The uterus was absent, which is expected in such cases because MIS production and response is unaffected. High-affinity binding of DHT was virtually undetectable in cultured genital fibroblasts, confirming receptor malfunction. Partial Androgen Insensitivity Syndrome.  One case of canine partial androgen insensitivity syndrome (PAIS) was reported in a 78,XY mixed-breed dog (Peter et al, 1993). It was phenotypically female at 6 months of age, but scrotal-like swellings containing testes later were identified on each side of the vulva, which opened into a blind vaginal pouch. Peripheral testosterone and DHT concentrations were normal after hCG stimulation. Epididymides were present adjacent to the testes, indicating that T-dependent masculinization was unimpaired during embryonic development. High-affinity binding of DHT was undetectable in cultured genital fibroblasts. These data suggest that DHT binding was abnormal but testosterone binding was not. Testosterone and DHT bind to the same androgen receptor, which is encoded by a single gene. Nevertheless, there is pharmacologic evidence that the androgen receptor can exhibit different binding affinity preference for DHT relative to testosterone in adult canine tissues. Therefore an AR mutation could affect DHT-dependent masculinization but not testosteronedependent masculinization, as the findings in this case would suggest. Diagnosis of CAIS or PAIS is dependent on confirmation of a normal male karyotype, bilateral testes, and abnormal androgen binding in androgen-responsive tissues. GnRH/hCG stimulation tests in the intact animal confirm that peripheral androgens are present, providing further evidence for androgen insensitivity. It is now possible to diagnose these defects at the level of the canine or feline AR gene. Castration is recommended for affected dogs and cats. Prevention is limited to genetic counseling regarding the X-linked inheritance of this disorder. Because carrier females are fertile, 50% of their male offspring are affected, whereas 50% of the female offspring are carriers, on average. However, 50% of the male offspring will not receive the X chromosome bearing the AR mutation, will have normal genitalia, and can be used in a breeding program. Other Causes This category includes persistent müllerian duct syndrome, isolated hypospadias, and isolated cryptorchidism (see Table 217-1). Persistent Müllerian Duct Syndrome.  Persistent müllerian duct syndrome (PMDS) has been reported in the miniature schnauzer in several continents, the basset hound in Europe, and a mixed-breed dog; it also may occur in the Persian cat (Meyers-Wallen, 2012). Affected miniature schnauzers are XY males with bilateral testes and normal androgen-dependent masculinization of the internal and external genitalia. However, because of a

SECTION  X  Reproductive Diseases

998

P

C UB

P

Figure 217-2  Caudal reproductive tract of a dog with persis-

tent müllerian duct syndrome (PMDS). This fixed specimen is bisected longitudinally to show the uterine body (UB), the cervix (C), and the cranial vagina entering the craniodorsal aspect of the prostate gland (P). Note the thin separation between the vagina and prostatic urethra. In some PMDS dogs there is a small diameter connection here between the vagina and the urethra. (Reprinted with permission from Wu X et al: A single base pair mutation encoding a premature stop codon in the MIS type II receptor is responsible for canine persistent müllerian duct syndrome, J Androl 30:46, 2009.)

defect in the MIS receptor, they also have bilateral uterine tubes, a complete uterus with cervix, and the cranial portion of the vagina, which terminates within the craniodorsal aspect of the prostate gland (Figure 217-2). Approximately 50% of PMDS dogs have unilateral or bilateral cryptorchidism, whereas the remainder have bilateral descended testes and are fertile. Although PMDS rarely is detected by physical examination alone, PMDS dogs are diagnosed most frequently when clinical signs arise related to pyometra, urinary tract infection, prostate infection, or neoplasia in cryptorchid testes. The dilated uterus and cranial vagina can be misdiagnosed as a large prostatic abscess. Diagnosis of PMDS depends on confirmation of a normal male karyotype, bilateral testes, and the presence of all müllerian duct derivatives (see Table 217-1). However, diagnosis in the miniature schnauzer can be obtained by DNA testing. In this breed, a mutation in the MIS type 2 receptor (MISRII/AMhR2) eliminates receptor function (Wu et al, 2009). PMDS dogs are homozygous for this mutation, which appears to be widely distributed in this breed. Treatment is limited to castration and hysterectomy, taking care to remove the cervix and cranial vagina at the craniodorsal aspect of the prostate gland (see Figure 217-2). In some cases, a small-diameter communication between the cranial vagina and the prostatic urethra is present and should be ligated since it could allow ascending infection into the uterus. In the miniature schnauzer, PMDS is inherited as a sex-limited, autosomal-recessive trait; only homozygous males express the affected phenotype. A mutation test is commercially available (Pujar and Meyers-Wallen, 2009). Members of this breed should be tested before entering a breeding program to identify noncarriers, affected males, carrier males, and carrier females. Affected dogs and homozygous females should be removed from the breeding 

population because they will transmit the mutation to  all of their offspring, producing only carriers or affected dogs. Furthermore, to prevent production of affected dogs, male or female carriers should be bred only to noncarriers or be removed from the breeding population. Isolated Hypospadias.  Hypospadias is an abnormality in location of the urinary orifice caused by incomplete masculinization of the urogenital sinus during formation of the male urethra. As a result, the urethral opening may be located anywhere along the embryologic course of the urogenital sinus to the genital tubercle. Because hypospadias can occur in association with other defects, such as testicular or ovotesticular XX DSDs, these should be included in the differential diagnosis, particularly when cryptorchidism, scrotal abnormalities, anorectal defects, or a uterus is present. However, isolated hypospadias refers to hypospadias not associated with other DSDs. Isolated hypospadias has been reported as a familial defect in some dog breeds, particularly in the Boston terrier. Rare reports in cats include the domestic shorthair and two cases in the Himalayan breed. The diagnostic plan includes karyotype, gonadal histology, and ruling out association with other DSD. Surgical correction of mild hypospadias is usually unnecessary because hypospadias usually does not cause urinary difficulties. However, cosmetic repair may be indicated for severe hypospadias. Although affected animals with mild hypospadias may be able to breed normally, affected dogs should be removed from the breeding program to prevent further dissemination of familial hypospadias. Isolated Cryptorchidism.  Cryptorchidism is associated with other DSDs, such as testicular XX DSD and PMDS above, but also can appear as the only defect of the reproductive system, which is isolated cryptorchidism (see Table 217-1). Feline cryptorchidism has been reported infrequently and appears to be uncommon. Hospital surveys of male cats admitted for neutering reported that 1.3% to 1.7% were affected; most are unilateral cryptorchid (MeyersWallen, 2012). In contrast, isolated cryptorchidism is the most common disorder of the reproductive tract reported in dogs, ranging from 6.8% of males presented for neutering to 1.4% of dogs at 6 to 12 months of age. A diagnosis of canine cryptorchidism is warranted if either testis is not palpable within the scrotum at 8 weeks of age because the testes normally descend by 10 days after birth. Although canine testis descent later than 10 days is known anecdotally to most veterinarians, the frequency of delayed descent is unknown. In one study, pups with cryptorchidism were examined every 2 weeks from 6 to 14 weeks of age, then again at 6 and 12 months of age. They observed that 24.6% of cryptorchid testes descended by 6 months of age, with the majority descending by 14 weeks of age (Dunn et al, 1968). Testis descent after 6 months of age was not observed in any case monitored. Evidence in humans and mice shows that delayed testis descent is a variation of cryptorchidism rather than a variation of normal. For example, delayed testis descent is observed in men with heterozygous INSL3 mutations (Tomboc et al, 2002). Dogs with bilateral cryptorchidism are sterile, whereas those with unilateral cryptorchidism can be fertile.

CHAPTER  217  Inherited Disorders of the Reproductive Tract in Dogs and Cats However, the recommended treatment for both is bilateral castration. First, the risk of Sertoli cell tumor is increased in cryptorchid testes. Second, isolated cryptorchidism is clearly a familial trait in several breeds and is likely to be inherited in dogs, as it is in other mammals. Although mutations in INSL3 and its receptor have been identified to cause isolated cryptorchidism in mice and humans, such mutations have not been identified in cryptorchid dogs. Furthermore, mutations in those genes account for a small number of human cases (1.4%), indicating that additional genes are likely to play a role in cryptorchidism. Although the genetic cause presently is unknown, it is being pursued. Inheritance of isolated cryptorchidism as a sex-limited recessive trait is consistent with available data, but it may be a polygenic trait that is genetically heterogeneous between breeds. Using this model, the first recommendation is that affected dogs be removed from the breeding population. The second is that both the father and mother of affected dogs should be considered carriers. Therefore removing carrier parents and affected males from the breeding population is probably the minimum program that should be pursued in dogs. As some full siblings of the affected dog are also carriers, it also may be necessary to remove these from the breeding program, but there is no practical way at present to determine which are carriers. Although medical regimens have been suggested to induce testicular descent in cryptorchid dogs, no published reports confirm that these are more successful than no treatment, in which 24.6% of cryptorchid testes could descend by 6 months of age. Furthermore, even if delayed testis descent occurs, the genes responsible for cryptorchidism remain unchanged and are transmitted to the offspring. Therefore cryptorchid

999

dogs and those with late testicular descent should be removed from the breeding program to reduce the frequency of the causative mutations in the population.

References and Suggested Reading Dunn ML, Foster WJ, Goddard KM: Cryptorchidism in dogs: a clinical survey, J Am Anim Hosp Assoc 4:180, 1968. Jakob S, Lovell-Badge R: Sex determination and the control of Sox9 expression in mammals, FEBS J 278:1002, 2011. McIntyre RL et al: Developmental uterine anomalies in cats and dogs undergoing elective ovariohysterectomy, J Am Vet Med Assoc 237:542, 2010. Meyers-Wallen VN: Gonadal and sex differentiation abnormalities of dogs and cats, Sexual Development 6:46, 2012. Meyers-Wallen VN et al: Testicular feminization in a cat, J Am Vet Med Assoc 195:631, 1989. Pasterski V, Prentice P, Hughes IA: Impact of the consensus statement and the new DSD classification system, Best Pract Res Clin Endocrinol Metab 24:18, 2010. Peter AT, Markwelder D, Asem EK: Phenotypic feminization in a genetic male dog caused by nonfunctional androgen receptors, Theriogenology 40:1093, 1993. Pujar S, Meyers-Wallen VN: A molecular diagnostic test for persistent Müllerian duct syndrome in miniature schnauzer dogs, Sex Devel 3:326, 2009. Quinn A, Koopman P: The molecular genetics of sex determination and sex reversal in mammals, Semin Reprod Med 30(5):351, 2012. Schlafer DH et al: A case of SRY-positive 38,XY true hermaphroditism (XY Sex Reversal) in a cat, Vet Pathol 48:822, 2011. Tomboc M et al: Insulin-like 3/Relaxin-like factor gene mutations are associated with cryptorchidism, Clin Endocr Metab 85:4013, 2002. Wu X et al: A single base pair mutation encoding a premature stop codon in the MIS type II receptor is responsible for canine persistent Müllerian duct syndrome, J Androl 30:46, 2009.

CHAPTER 

218 

Ovarian Remnant Syndrome in Small Animals CARLOS M. GRADIL, Amherst, Massachusetts ROBERT J. MCCARTHY, North Grafton, Massachusetts

O

varian remnant syndrome (ORS) is a reported complication after ovariohysterectomy (OHE), a common surgical procedure to prevent estrus, pregnancy, and pyometra and to decrease the incidence of tumors. Failure to remove all ovarian tissue may result in the continued secretion of reproductive hormones with overt signs of proestrus or estrus, uterine stump pyometra, or neoplasia of the ovary, mammary gland, and/or the vagina. Dogs with ORS have a higher rate (23.8%) of neoplasms (e.g., sex-cord stromal tumors in the residual ovarian tissue) than the reported incidence of 6.25% in sexually intact female dogs. Recognizing bitches with ORS can be challenging, depending on the phase of the reproductive cycle. Most dogs with ORS are presented with periodic or continuous symptoms of vulvar swelling, serosanguineous vaginal discharge, and attractiveness to male dogs. The actual interval from OHE to the time of examination and diagnosis of ORS is highly variable and is attributed partially to failure of owners to recognize clinical signs of proestrus or estrus. The interval between OHE and diagnosis of ORS in animals with neoplasm is significantly longer than in animals without neoplasms.

Potential Causes for Ovarian Remnant Syndrome Because remnant ovarian tissue is found in typical anatomic locations and is not considered ectopic tissue in dogs, surgical error is suspected as the cause of ORS. In dogs, location of remnant ovarian tissue is found more frequently in the region of the right ovarian pedicle, probably because the more cranial position of the right ovary and difficulty in exposure and removal of the right ovary during OHE. However, Miller (1995) found remnant ovarian tissue to be distributed equally between the right and left side. Differences between dogs and cats provide further support for surgical error as the cause of ORS and may account for more dogs than cats being affected. Dogs have more adipose tissue surrounding the ovaries that can obscure exposure. The suspensory ligament of the ovary in dogs is more difficult to rupture to achieve adequate exposure, compared with cats. In addition, dogs typically have a deeper abdominal cavity, which makes it more challenging to exteriorize each ovary (Figure 218-1). Other possible causes of ORS that have been proposed include the revascularization and autotransplantation of 1000

free-floating ovarian tissue that becomes separated from the ovary at the time of OHE or surgical inexperience (e.g., veterinarian with 1 ng/ml) LH concentrations on 2 separate days are consistent with the presence of remnant ovarian tissue and help eliminate  false positives resulting from pulsatile secretion of gonadotropins. Among bitches with remnant ovarian tissue, basal plasma LH concentration is higher in those in which the interval between ovariectomy and the appearance of estrus is more than 3 years. The LH response to GnRH stimulation is lower in bitches with remnant ovarian tissue than in ovariectomized bitches or those in anestrus. In bitches with granulosa cell tumor (GCT), the pituitary-ovarian axis is affected and is characterized by relatively high plasma LH concentrations in GCT-ORS bitches and a subnormal LH response to GnRH stimulation in GCT bitches compared with those in anestrus and ovariectomized bitches. The relatively high proportion of dogs with remnant ovarian tissue in GCT bitches may point to a pathogenic role for elevated gonadotropin secretion in the pathogenesis of GCT. Estrogen and Progesterone When there is behavioral evidence of an increased plasma estradiol, estrus may be confirmed by vaginal cytology; checking the progesterone concentration 2 to 3 weeks later verifies luteinization or ovulation. In cases of no behavioral or clinical evidence of an increased plasma estradiol concentration, recognition of bitches with remnant ovarian tissue is challenging. The production of estradiol and of progesterone decreases markedly after ovariectomy, but basal plasma concentrations of both hormones in anestrous and ovariectomized bitches overlap. A preoperative diagnosis of ORS can be attained by the use of hormone stimulation tests. Stimulation of the pituitary-ovarian axis with GnRH may help to distinguish between ovariectomized bitches and those in anestrus, because administering GnRH causes a significant rise in plasma estradiol concentration only if ovarian tissue is present. In dogs and cats with behavioral estrus, stimulation of ovulation and luteinization can be induced with GnRH (Table 218-1). Elevated Estrogen.  Diagnosis of ORS during the follicular phase should show an elevated plasma concentration of estradiol, produced by granulosa cells in developing ovarian follicles. Estradiol concentration of more than

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TABLE 218-1  Gonadotropic-Releasing Hormone and Human Chorionic Gonadotropin Stimulation Protocol Dogs

50 µg GnRH IM or 400 IU hCG IV or 500 IU IM and 500 IU IV

2-3 weeks later

P4 >2 ng/ml

Cats

25 µg GnRH IM

2-3 weeks later

P4 >2 ng/ml

hCG, Human chorionic gonadotropin; GnRH, gonadotropin-releasing hormone; P4, progesterone.

20 pg/ml is consistent with follicular activity for bitches and queens. For animals with suspected adrenal gland disease, an ACTH stimulation test or low-dose dexamethasone suppression test should be performed. However, adrenal diseases associated with high estrogens are less common than ORS as a cause of vaginal cornification in spayed bitches. Elevated Progesterone.  During the late follicular phase, ovulation, and the luteal phase, the plasma concentration of progesterone (secreted by partially luteinized granulosa cells before ovulation and by mature luteal cells after ovulation) is increased, providing evidence for remnant ovarian tissue. Progesterone concentration more than 2 ng/ml is consistent with luteal activity for bitches and queens. Antimüllerian Hormone.  Antimüllerian hormone (AMH) is produced by the fetal testes in mammals. It inhibits müllerian (paramesonephric) duct development in the male embryo. However, following the development of the müllerian ducts into the oviduct, uterus, and upper vagina in female mammals, the ovaries produce AMH, which can be measured in the peripheral circulation. The ovaries appear to be the sole source of AMH in the circulation. A commercially available human-based assay is available for measurement of AMH concentration in dogs and cats.

Ultrasonographic Examination Ultrasonography (US) may be helpful as an adjunct diagnostic test in animals with or without signs consistent with proestrus or estrus, or with mammary gland enlargement. The success or failure of being able to identify ovarian tissue by use of US may be related to the expertise of the ultrasonographer, stage of the estrous cycle of the animal at the time of examination, and size of the remnant ovarian tissue. Clinical signs of proestrus or estrus or its absence do not appear to affect the ability to identify correctly remnant ovarian tissue at the time of US exam. US examinations may present as acoustic enhancement, echogenic fluid, hyperechoic septations, and anechoic follicles. Some US features of remnant ovarian tissue may resemble simple cysts or cysts with multiple septations. These cystlike structures also can have a rim of presumed ovarian tissue with arterial and venous blood flow.

One differential diagnosis for a false-positive identification of remnant ovarian tissue during US is a suture granuloma at the site of ligation of the ovarian pedicle. Suture material can cause a localized immunologic and inflammatory reaction. Suture granulomas have been identified by US as clearly defined hypoechoic lesions with or without double or single hyperechoic lines within the lesion. Suture granulomas frequently involve nonabsorbable suture material; however, suture granulomas involving absorbable suture also have been reported, as well as granulomas involving metallic surgical staples. Although most suture granulomas would be expected to develop and resolve within a short period after surgery, suture granulomas have been identified in humans for months and possibly years. Remnant ovarian tissue detected during US and found subsequently during surgery should be confirmed histologically.

Laparotomy Exploratory laparotomy for suspected remnant ovarian tissue, if present, will be most likely in the region of the right or left ovarian pedicles, and bilaterally in the region of both ovarian pedicles in a small number of animals. Statistically, it would be expected that remnant ovarian tissue would have an equal chance of being found on the right or the left side (50% for each side). However, the presence of remnant ovarian tissue in the region of  the right ovarian pedicle is significantly higher than the expected 50%. Histologic Examination Histologic examination performed on suspected remnant ovarian tissue excised from suspected ORS may confirm ovarian tissue (Figure 218-2). Histopathologic findings include differentiated ovarian tissue singly, or a combination of ovarian follicles or follicular cysts, corpora lutea, ovarian neoplasms, adenomatous hyperplasia, and paraovarian cysts. Uterine remnants excised and evaluated histologically may be enlarged and may show evidence of cystic endometrial hyperplasia. Microbial culture of uterine remnants may yield bacteria (e.g., Escherichia coli, Enterococcus spp.), which indicates a uterine stump pyometra. Some dogs may have neoplasms of the reproductive system, including the ovaries, mammary glands, and vagina. Ovarian tumors may include sex-cord stromal or granulosa cell tumors, cystadenoma, mammary gland tumor, adenoma, vaginal tumors, and leiomyoma.

Treatment The preferred treatment for ORS is surgical removal of remnant ovarian tissue. To facilitate visualization of the ovarian remnant surgery should be performed when the animal is in proestrus, estrus, or diestrus because of follicles or corpora lutea in the ovarian tissue and prominence of ovarian blood vessels. Surgical removal of remnant ovarian tissue results in resolution of clinical signs of estrus or proestrus.

CHAPTER  219  Pregnancy Loss in the Bitch and Queen

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References and Suggested Reading

Figure 218-2  Excised ovarian tissue from a mixed breed

dog spayed at 4 12 years of age. Six months after ovariohysterectomy, the bitch displayed proestrous clinical signs (vaginal bleeding, attractive to males, licking vulva) but otherwise was clinically normal. Vaginoscopy was performed and revealed edematous vaginal folds and brownish-yellow watery discharge. The serum progesterone concentration was 3.2 ng/ml. Eight months later, she was again in heat, which was confirmed by exfoliative vaginal cytology (70% superficial, cornified epithelial cells). After the end of estrus, a laparotomy was performed and ovarian tissue was removed. (Photo courtesy Dr. Tuire Tamminen, Faculty of Veterinary Medicine, University of Helsinki, Finland.)

CHAPTER 

Ball R et al: Ovarian remnant syndrome in dogs and cats: 21 cases (2000-2007), J Am Vet Med Assoc 236:548, 2010. Beijerink NJ et al: Basal and GnRH-induced secretion of FSH and LH in anestrous versus ovariectomized bitches, Theriogenology 67:1039, 2007. DeNardo GA et al: Ovarian remnant syndrome: revascularization of free-floating ovarian tissue in the feline abdominal cavity, J Am Anim Hosp Assoc 37:290, 2001. Fleischer AC et al: Sonographic features of ovarian remnants,  J Ultrasound Med 17:551, 1998. Jeffcoate IA: Gonadotrophin-releasing hormone challenge to test for the presence of ovaries in the bitch, J Reprod Fertil Suppl 47:536, 1993. Löfstedt RM, Vanleeuwen JA: Evaluation of a commercially available luteinizing hormone test for its ability to distinguish between ovariectomized and sexually intact bitches, J Am Vet Med Assoc 220:1331, 2002. Magtibay PM, Magrina JF: Ovarian remnant syndrome, Clin Obstet Gynecol 49:526, 2006. Miller DM: Ovarian remnant syndrome in dogs and cats: 46 cases (1988-1992), J Vet Diagn Invest 7:572, 1995. Okkens AC, Dieleman SJ, v d Gaag I: Gynaecological complications following ovariohysterectomy in dogs, due to: (1) partial removal of the ovaries. (2) inflammation of the uterocervical stump [in Dutch], Tijdschr Diergeneeskd 106:1142, 1981. Place NJ et al: Measurement of serum anti-Müllerian hormone concentration in female dogs and cats before and after ovariohysterectomy, J Vet Diagn Invest 23:524, 2011. Wallace MS: The ovarian remnant syndrome in the bitch and queen, Vet Clin North Am Small Anim Pract 21:501, 1991.

219 

Pregnancy Loss in the Bitch and Queen LINDA K. KAUFFMAN, Ames, Iowa CLAUDIA J. BALDWIN, Ames, Iowa

C

onception rates in a normal bitch can exceed 95% with the proper breeding management. Breeding of a fertile queen and tom should result in attainment of pregnancy 70% of the time. The exact number of bitches and queens that undergo embryonic and fetal loss is difficult to determine if pregnancy is suspected but not confirmed before the loss occurs. Methods for pregnancy diagnosis are discussed in Chapter 207. Making a diagnosis of pregnancy loss is also difficult because females may consume the fetuses and show few clinical signs. Pregnancy loss during the second half of gestation often is associated with a hemorrhagic vulvar discharge.

Some females that experience fetal death in late gestation do not abort but retain their dead fetuses. Mummification results when fetal death occurs under sterile autolytic conditions. This includes absorption of the placental and fetal fluids and does not occur in the first half of gestation because fetal bone mineralization does not begin until day 40 to 45 of gestation (England, 2006). Mummification can occur in the presence of other live fetuses while maintaining the pregnancy until birth of the live fetuses or all the fetuses can be mummified and be retained past the whelping or queening date. Actual incidence of mummification in the bitch and queen is unknown but it is

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thought to be low. Retained dead fetuses that are not mummified can become macerated and emphysematous; these require surgical removal. These females may be systemically ill and have a foul vulvar discharge.

Historical Findings of Pregnancy Loss A bitch or queen with the complaint of pregnancy loss or conception failure requires the clinician to obtain a complete medical history to assess the individual female and the colony. Dietary records as well as details about how the female is housed, housing practices of the breeding facility (pregnant vs. nonpregnant vs. neonates), and isolation protocols should be discussed in depth. Vaccine history, deworming history, serologic testing for heartworm disease, Brucella canis testing status (bitches only), feline leukemia virus (FeLV) and feline immunodeficiency virus (FIV) (queens), and any other important medical history of the female in question as well as other animals at the facility should be reviewed carefully. Breeding dates, type of breeding management used, stud or tom used and his breeding history (breeding soundness results if any), and the relationship of the stud to the female are important factors for review. Past reproductive history of the female, her relatives, and the rest of the colony are important to evaluate. All medications, supplements, holistic therapies, and preventives (flea, tick, heartworm, gastrointestinal anthelmintics) prescribed or used must be recorded. Specific history related to pregnancy loss may be variable. There may be no additional history other than a bitch or queen that fails to produce offspring at the time of expected end of gestation. Other findings related to pregnancy loss may include decreased appetite, weight loss, vomiting, diarrhea, or simply a decrease in abdominal size. If the owners have witnessed the abortion, they should be instructed to collect materials carefully, wearing gloves and placing material in plastic bags or containers, and refrigerate at 1.7° to 3.3° C (35° to 38° F). They should be questioned about fetal material delivered, viability of fetuses at the time of delivery, and placental passage. Owners may have noticed only a vulvar discharge (mucoid, greenish, or serosanguineous) and nothing more at the time of pregnancy loss. In rare cases, a client may bring in a female that has delivered one or more stillborn or mummified fetuses.

Clinicopathologic Findings of Pregnancy Loss To determine if a reproduction problem exists, a complete physical examination of the bitch or queen using observation, auscultation, and palpation should be performed. A closer examination of the reproductive system should include vaginal inspection (in bitches) via a speculum or via vaginoscopy to look for discharge or the presence of a fetus, whereas careful vaginal inspection via rectal palpation and digital vulvovaginal inspection and vaginoscopy should be performed in the queen. Abdominal palpation, radiographs, or ultrasonography may be used to confirm pregnancy loss. Confirmation of early embryonic loss in the bitch before implantation is not possible

currently in clinical practice, but pregnancy loss after day 21 of gestation may result in a positive relaxin test that persists up to a week after complete pregnancy loss has occurred. Early in gestation, anechoic gestational sacs are visible via ultrasound imaging. In the queen, uterine segmental swellings associated with gestational sacs, fetal poles, heartbeat, and fetal membranes may be seen as early as days 11, 15, 16, and 21, respectively, using ultrasound imaging (Davidson, Nyland, and Tsutsui, 1986). If the gestational sacs fail to develop embryonic structures over time, this confirms pregnancy loss. Later in gestation, fetal death can be confirmed by the absence of a heartbeat and fetal movement during the last 7 to 14 days of pregnancy, which can be confirmed by ultrasound if necessary. Radiographic imaging also can be used to look for signs of fetal death, assess presence and location of remaining fetuses, and estimate the stage of gestation and size of the remaining fetuses. A final form of pregnancy loss is the stillborn. This is well recognized and much easier to confirm. Stillbirths may represent an average of 13% of total kitten births. The mammary glands should be examined for stage of development and presence of colostrum or milk. The primiparous queen tends to develop earlier than the multiparous queen, which can be confusing to the cat owner, making the client concerned about pregnancy loss or undetected abortion. Any fetal, placental, or neonatal materials available should be inspected closely and handled aseptically to allow for further diagnostics (e.g., bacterial culture, virus isolation, karyotyping). Any abnormalities should be noted and investigated. Diagnostic testing may be indicated to assess the general health of the bitch and queen. Repeating a careful history of the individual bitch and queen and the population, health maintenance practices, and housing may  be helpful. Abnormalities in hematology, serum biochemistries, and urinalysis may reflect specific underlying disease. The bitch and queen normally develop a dilutional normochromic, normocytic anemia during gestation with a significant decrease in the percentage packed cell volume. Serum protein concentrations also decrease. These changes are at their greatest by 8 weeks’ gestation and quickly return to normal after parturition. Brucella canis status of the bitch and the breeding facility is indicated if not yet performed and reassessed if the breeding facility is not closed. Canine herpesvirus titer may provide useful information if elevated. Reassessment of FeLV and FIV status is useful in the queen.

Diagnosis of Disorders Associated with Pregnancy Loss Differential diagnoses for pregnancy loss in the bitch and queen are numerous, but some owners have a hard time discerning normal pregnancy events from an abortive event. The history, physical examination findings, and imaging should be able to confirm the current pregnancy status. Occasionally, a late gestation bitch or queen may have a mucoid vulvar discharge. Cytology of this discharge may reveal numerous nondegenerate neutrophils with minimal bacteria present; this can be a normal finding. If the clinician suspects a normal pregnancy, the

CHAPTER  219  Pregnancy Loss in the Bitch and Queen owner should be instructed to isolate the bitch or queen and monitor for signs of labor (e.g., temperature drop [bitch], nesting behavior, straining). If the bitch or queen is presented already in stage II of parturition, noted by active straining and passage of term offspring, then the clinician must determine if normal delivery can occur or if a problem requires assistance. If the bitch or queen has presented with one or more stillborn full-term fetuses, then it is necessary to determine if they are a result of dystocia and if the remaining fetuses require assistance (cesarean section). Owners must be counseled about their diagnostic options and potential outcomes in the following instances:

1005

TABLE 219-1  Causes of Pregnancy Loss Condition

Species

Inflammatory Cystic endometrial hyperplasia

Bitch and queen

Pyometra

Bitch and queen

Metritis

Bitch and queen

Infectious Bacterial

1. No evidence of pregnancy after breeding 2. Uterine changes suggesting disease 3. Mummified fetuses found 4. Resorbed fetuses or placentation sites in an otherwise healthy bitch or queen

Staphylococcus spp.

Bitch and queen*

Streptococcus spp.

Bitch only

Escherichia coli

Bitch and queen

Mycoplasma spp.

Bitch and queen†

First and foremost, optimal breeding management should be discussed at length with the owner. The owner should be advised to confirm the pregnancy after the next breeding so that it can be monitored closely. Older bitches and queens may benefit from additional diagnostic testing (e.g., complete blood count, serum biochemistries, urinalysis, thyroid levels [T4/TSH] in the bitch) along with ultrasonographic imaging of the reproductive tract. A single differential diagnostic plan cannot be followed when working through a case of pregnancy loss in the bitch or queen. Pregnancy loss can be caused by maternal disorders that result in the death of developing embryos or fetuses. This may be caused by disease of a single organ system or be multisystemic. Pregnancy loss also can be caused by fetal disorders that cannot be attributed solely to the bitch or queen (Table 219-1).

Coxiella burnetii

Queen only

Brucella spp.

Bitch only

Campylobacter spp.

Bitch and queen*

Group G Streptococcus

Bitch and queen‡

Leptospira spp.

Bitch only

Salmonella spp.

Bitch and queen*

Maternal Disorders Maternal causes of pregnancy loss include obvious and subtle disorders. A careful history and physical examination should help identify underlying diseases (e.g., renal, cardiac, endocrine, respiratory). Cardiac disease should be suspected in females with murmurs or irregular rhythms or poor perfusion or pulse quality. Endocrine disease should be suspected in females with signs of polyuria, polydipsia, weight loss, or weight gain. Diagnostic blood work should be performed as a screening tool if underlying disease is suspected. Parasite load should be assessed by fecal floatation, fecal PCR, or antigen testing when available; testing for heartworm should be repeated in endemic areas. Cats should be reassessed for FeLV or FIV status. In addition, knowledge of the genetic or medical conditions that some breeds are predisposed to is helpful when working with these types of cases. Other congenital or developmental diseases not associated with breed may compromise pregnancy maintenance as well. Treatment of these conditions depends on the specific disease identified. Primary uterine disease that is inflammatory or infectious may be responsible for pregnancy loss or may mimic pregnancy in some cases (Figure 219-1). Cystic endometrial hyperplasia, pyometra, and metritis are types of

Viruses Canine herpesvirus (CHV)

Bitch only

Canine parvovirus (type 1)

Bitch only

Canine distemper virus (CDV)

Bitch only

Feline panleukopenia (FPLV)

Queen only

Feline leukemia virus (FeLV)

Queen only

Feline herpesvirus-1 (FHV-1)

Queen only

Feline immunodeficiency virus (FIV)

Queen only

*Uncommon. †Experimental in cats. ‡Reported to cause toxic shock and neonatal sepsis in cats.

Figure 219-1  Photograph of segmental pyometra in a queen that could have been mistaken for normal segmental swelling of the uterus because of pregnancy. Ovarian pedicle is located in the upper right of the photograph.

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SECTION  X  Reproductive Diseases

inflammatory lesions that can be found in the uterus and may be related to early embryonic death. The lesions may be segmental, likely associated with sites of fetal resorption, or the lesions may be more diffuse, involving one horn or the entire uterus. The bitch or queen may show no clinical signs of disease even when the pathology in the uterus is sufficient enough to prohibit implantation and support of the pregnancy. In other cases abdominal distention may be a notable sign. When the cervix is open, a purulent to serosanguineous vulvar discharge may be present. Cytology of the discharge would reveal an abundance of degenerate neutrophils with intracellular bacteria, suggestive of a septic condition. Numerous bacteria, including normal vaginal flora (e.g., Staphylococcus spp., Streptococcus spp., Escherichia coli, Mycoplasma spp., and in the queen Coxiella burnetii) and pathogens (e.g., Brucella spp., Campylobacter spp., group G Streptococcus, Leptospira spp., and Salmonella spp.), have been associated with pregnancy loss in the bitch or queen (Pretzer, 2008). More severe clinical signs such as fever, anorexia, dehydration, collapse, and shock can be seen in the bitch and queen when these bacteria cause pregnancy loss. Viral agents are the most commonly reported infectious causes of abortion in queens and include feline panleukopenia (FPLV), FeLV, FIV, and feline herpesvirus-1 (FHV-1). Some of these agents are thought to produce abortion because of the maternal illness and fever in the (FHV-1) infected queen, whereas others, such as FeLV, FIV, and FPLV, cause placental lesions, early embryonic death, and viremia in the fetus (Verstegen, Dhaliwal, and Verstegen-Onclin, 2008). Viral agents involved in pregnancy loss in the bitch include canine herpesvirus (CHV), canine parvovirus (CPV type 1), and canine distemper virus (CDV). Hematologic and biochemistry abnormalities associated with pregnancy loss can include leukopenia or leukocytosis along with a varying degree of azotemia as well as other abnormalities (see Table 219-1). Ultrasonographic examination of the uterus should assist in diagnosis of pregnancy loss. Segmental areas of inflammation may not compromise the pregnancy but can be a reason for concern. Metritis or pyometra, with or without pregnancy, requires medical or surgical treatment (see Chapter 211). Dystocia must be considered as a cause of pregnancy loss in the bitch and queen (see Chapter 208). Other causes of pregnancy loss include uterine displacement, torsion, and uterine rupture, although these conditions do not occur often. Uterine torsion can occur when one or both horns twist along the long axis or around the opposite horn, or the entire uterine body can rotate around itself. Clinical signs can vary depending on the type of torsion that occurs and range from almost no symptoms to those consistent with an acute abdomen. Severe uterine torsions can obstruct blood supply to the uterus, leading to possible rupture of uterine vessels, shock, and fetal or maternal death. Diagnosis is based on clinical signs, diagnostic imaging, and exploratory surgery. Treatment includes hysterotomy to remove the fetuses and correct the torsion or ovariohysterectomy if the uterus is not salvageable. Uterine rupture can follow a uterine torsion or trauma, although this condition is rare. If fetal circulation is not compromised,

this condition may go undiagnosed until dystocia results because of the fetuses failing to enter the birth canal. Fetuses expelled into the peritoneal cavity may die immediately and be resorbed (if before fetal bone mineralization has occurred) or become retained fetal mummies. Maternal peritonitis secondary to the uterine rupture is a possible sequel. Treatment includes surgical correction of the uterine rupture, removal of any retained fetuses, and correction of the uterine torsion, if needed. Failure to maintain the pregnancy may result from insufficient production of progesterone (hypoluteoidism/ inadequate luteal phase). Progesterone concentrations greater than 1.5 to 2 ng/ml are thought to be required for pregnancy maintenance. This condition could be suspected in a bitch or queen that suffers from repeated pregnancy loss once infectious and other causes of pregnancy loss have been ruled out, although not definitively documented in the queen (Verstegen, Dhaliwal, and Verstegen-Onclin, 2008). Confirmation requires serial progesterone testing. It has been suggested that giving these bitches supplemental progestogen (type and dose remain a source of debate) after day 40 of gestation until 1 week before anticipated whelping date can prevent pregnancy loss. Owners must be warned that progestogen supplementation can cause masculinization of female offspring (pseudohermaphrodism) (Johnson, Root Kustritz, and Olson, 2001) and male offspring that become cryptorchid (England et al, 2006). In addition a decrease in progesterone concentration can be a normal response to terminate an abnormal pregnancy for either maternal (e.g., placentitis, intrauterine infections) or fetal (e.g., primary abnormality, infection) reasons. Pharmaceutic maintenance of an abnormal pregnancy could result in pyometra, dystocia, and even septicemia of the bitch, so caution is important when offering this option to clients. Maternal Polysystemic Disorders: The DAMNITT Approach The development of differential diagnoses often is approached best in a systematic way. The DAMNITT (Degenerative, Allergic, Metabolic, Neoplastic, Iatrogenic, Toxic, Traumatic) scheme has been used for many years in medicine to categorize causative diagnoses as Degenerative, developmental; Allergic, autoimmune (immunemediated); Metabolic; Neoplastic, nutritional; Iatrogenic, ischemic, idiopathic, infectious/noninfectious, inflammatory, or immune-mediated; Toxic; or Traumatic puts this diagnostic approach to use when considering potential causes of pregnancy loss in the bitch and queen. Developmental/Genetic.  More than 400 genetic diseases have been reported in dogs that have survived gestation, so it is presumed when these defects are more severe, resorption or abortion occurs. Inbreeding lines of dogs and cats also can play a part in neonatal mortality; mixedbreed dogs have a higher reproductive performance than purebred dogs (Johnson, Root Kustritz, and Olson, 2001). Genetic defects are seen with close inbreeding in the cat and may be responsible for 15% of infertility or pregnancy loss or in abortion of domestic animals, including cats. Owners should be advised about the availability of genetic counseling before the start of breeding so that they are less likely to make choices that produce high-risk

CHAPTER  219  Pregnancy Loss in the Bitch and Queen

1007

Figure 219-2  Photograph of a full-term puppy with cleft palate,

which is a developmental defect. (Photo courtesy Dr. Lawrence Evans.)

Figure 219-4  Photograph of a kitten delivered vaginally near term. This kitten was affected by Hydrops fetalis or anasarca.

Figure 219-3  Photograph of two full-term puppies both affected with thoracic ectromelia, another type of developmental defect. (Photo courtesy Dr. Lawrence Evans.)

pregnancies or offspring with genetic abnormalities. Conditions such as cleft palate, thoracic ectromelia, and anasarca are examples of such developmental defects (Figures 219-2 through 219-4). Autoimmune.  Although immune factors are considered a contributing factor to human abortions, the role of immunologic factors in early embryonic death and abortion in companion animals remains unknown at this time. A female with underlying immune disease (e.g., immune-mediated thrombocytopenia or multisystemic polyarthropathy) most likely should not be considered for breeding stock because of the potential for high-risk pregnancy and possible pregnancy loss. Owners should be advised of these considerations when making choices regarding whether to breed a female. Metabolic.  Metabolic disorders can occur in any breed and at any age. Effects of these disorders, if severe and widespread, can threaten the bitch’s or queen’s ability  to reproduce or maintain a pregnancy. A thorough  history and complete physical examination are helpful in diagnosis along with the appropriate diagnostic tests. 

Diabetes mellitus, hypothyroidism (bitches), hyperthyroidism (queens), adrenal insufficiency, and hyperadre­ nocorticism are diseases that can affect fertility and embryonic and fetal development. Owners of females diagnosed with these diseases should be advised of the risk of infertility and pregnancy loss plus the potential of maternal loss in severe cases (e.g., DKA with diabetes mellitus) if they choose to breed this female. Neoplastic.  Neoplastic disease that may occur in a breeding female certainly could lead to pregnancy loss. Neoplasia causes dysfunction of the organs involved and promotes metabolic changes and possibly fever; all of which can compromise the pregnancy, resulting in resorption or abortion. Affected bitches and queens must be identified so that treatment can be implemented, which normally means they are no longer part of a breeding program. Nutritional.  Proper nutrition is important to reproductive health (see Chapter 210). Nutritional lack or excess can play a role in reproductive disturbance. In addition, oversupplementing of vitamins, minerals, or nutraceuticals may alter the developmental process of pregnancy (Verstegen, Dhaliwal, and Verstegen-Onclin, 2008). Assessing the body condition score of a bitch and queen before breeding along with knowledge of her normal activity level is important prebreeding information because an overweight, sedentary female may be more difficult to impregnate. While taking the history from an owner, the clinician should use care in questioning about the diet. Many “natural foods” are marketed as premium line but may not provide needed nutrition for adult canines, much less the nutrition needed for gestating or lactating dams. “Raw diets” may be another area of contention with some owners because of veterinary concerns about Salmonella and E. coli infections.

1008

SECTION  X  Reproductive Diseases

Education of the owner about appropriate dietary intake for a breeding female is an ongoing process. Taurinedeficient rations (10 WBC/hpf).

Treatment of Prostatitis Treatment strategies for canine prostatitis center on an appropriate antimicrobial therapy with other supportive treatments. Antimicrobial therapy is based upon the result of bacterial culture and sensitivity from prostatic fluid collected by ejaculation, prostatic massage, or prostatic aspiration. If the prostatic fluid culture cannot be performed, the antibiotic selection then is based on the results of antibiotic sensitivity from the urine culture.  The antimicrobial drug diffusion into the prostatic fluid may be enhanced by treatments to decrease prostatomegaly caused by BPH and should be combined with antibiotic therapy. Finasteride, deslorelin, or castration is appropriate. Antimicrobial drugs for prostatitis treatment should have high lipid solubility, low protein binding in plasma, and low pKa, allowing diffusion of the nonionized form of the drug across the lipid prostatic membrane. Antimicrobial drugs that are highly lipid soluble include trimethoprim-sulfa, chloramphenicol, and the fluoroquinolones. These drugs are effective against susceptible aerobic bacterial infections. Fluoroquinolones (e.g., enrofloxacin, ciprofloxacin) are also effective against Mycoplasma spp. infection. Chloramphenicol is effective against anaerobic infections; however, chloramphenicol is used infrequently in companion animal practice. One retrospective study of canine prostatitis found that 58% of bacteria cultured from prostatitic fluid were susceptible to amoxicillin-clavulanate and doxycycline. Treatment with a specific antimicrobial drug should be continued for at least 4 to 6 weeks. Before and 1 week after antimicrobial therapy is withdrawn, a complete blood count, blood chemistry profiles, quantitative bacterial prostatic fluid and urine culture, grading inflammatory cells in the prostatic fluid sediment, and comparison measurement of prostatic or abscess size by ultrasonography should be evaluated. If the selected antibiotic is appropriate, clinical signs will resolve and prostatic abscessation will be reduced in size or resolve. The number of CFUs/ml from prostatic bacterial culture, numbers of inflammatory cells on prostatic fluid sediment, and total white blood cell count will be decreased. Prostatic fluid and or urine also should be recultured 7 to 10 days after cessation of treatment and again at 30 days once antibiotic treatment is concluded to ensure resolution of the bacterial infection. Some dogs with prostatitis may require antimicrobial therapy for up to 8 to 24 weeks. Adverse effects associated with long-term antibiotic therapy should be considered when treating cases requiring prolonged antibiotic therapy.

Treatment of Prostatitic Abscesses In the author’s opinion, some large prostatic abscesses or cysts may be aspirated using ultrasound guidance to obtain prostatic fluid for bacterial culture and cytology as well as to decompress the abscess or cyst to reduce abdominal pressure and pain. However, the dog should

CHAPTER  221  Methods and Availability of Tests for Hereditary Disorders of Dogs and Cats be under heavy sedation or general anesthesia during aspiration. The clinician should begin treatment with an appropriate antimicrobial drug immediately if it is an abscess. Long-term antimicrobial therapy (up to 4 months) with concomitant finasteride treatment may be necessary to achieve medical resolution. Prostatic ultrasonography and complete blood counts should be performed every 3 to 4 weeks to monitor resolution of an abscess. Treatment should continue until the abscess is no longer visible ultrasonographically. After resolution of the prostatic abscess castration, finasteride treatment or deslorelin implantation should be used to further decrease prostate size and likelihood of recurrence. If the prostatic abscessation or cysts remain enlarged after antimicrobial and finasteride treatment, surgical drainage should be performed. The author prefers to combine prostate omentalization with castration in cases unresponsive to medical management. After surgery dogs should be evaluated at least every 2 months and selective antimicrobial drug therapy continued for at least 4 to 6 weeks.

References and Suggested Reading Freitag T et al: Surgical management of common canine prostatic conditions, Compend Contin Educ Vet 29:656, 660, 662, 2007. Johnston SD et al: Prostatic disorders in the dog, Anim Reprod Sci 60:405, 2000.

CHAPTER 

1015

Johnston SD, Root Kustritz MVR, Olson PNS: Disorders of the canine prostate. In Canine and feline theriogenology, Philadelphia, 2001, WB Saunders, p 337. Kamolpatana K et al: Effect of finasteride on serum concentrations of dihydrotestosterone and testosterone in three clinically normal sexually intact adult male dogs, Am J Vet Res 59:762, 1998. Kamolpatana K, Johnston GR, Johnston SD: Determination of canine prostatic volume using transabdominal ultrasonography, Vet Radiol Ultrasound 41:73, 2000. Limmanont C, Phawaphutanont J, Sirinarumitr K: Adverse effects of 5alpha-reductase inhibitor and GnRH-agonist and disease recurrence after cessation of treatment in dogs with benign prostatic prostatic hypertrophy: a clinical trial. The 36th World Small Animal Veterinary Association World Congress, Jeju, Korea, Oct 14-17, 2011, p 130. Limmanont C, Sirinarumitr K: A retrospective study of canine prostatitis. The 15th Veterinary Practitioner Association of Thailand Regional Congress, Bangkok, Thailand, April 26-29, 2009, p 258. Sirinarumitr K et al: Effects of finasteride on size of the prostate gland and semen quality in dogs with prostatic hypertrophy, J Am Vet Med Assoc 218:1275, 2001. Sirinarumitr K et al: Finasteride-induced prostatic involution by apoptosis in dogs with benign prostatic hypertrophy, Am J Vet Res 63:495, 2002. Weichselbaum RE et al: Imaging the reproductive tract in the male dog. In Kirk RW, Bonagura JD, editors: Kirk’s current veterinary therapy XII (small animal practice), Philadelphia, 1995, WB Saunders, p 1052.

221 

Methods and Availability of Tests for Hereditary Disorders of Dogs and Cats EDWARD E. (NED) PATTERSON, St. Paul, Minnesota

T

he study of the biochemical and physiologic bases of canine and feline heritable disorders over the last 10 to 20 years has identified mutations responsible for a number of diseases. The progress of the canine genome maps and the recent publication of the canine genome sequence, coupled with comparative data from human genome research, have led to the recent discovery of the molecular basis of additional canine inherited disorders. More than 570 inherited diseases and traits in dogs and more than 290 in cats are recognized, but in many the biochemical or molecular basis is not yet identified. More than 80 polymerase chain reaction (PCR) DNA tests are associated with canine diseases and more than 10

DNA tests are available for cats. With additional research and emerging technologies, the number of available tests will grow exponentially in the near future. A working knowledge of the basic methods and availability of such tests will be an increasingly important part of the knowledge base of the small animal veterinarian. Biochemical, direct mutation, and genetic marker tests are the three major categories of inherited disease diagnostic tests.

Scientific Basis of the Tests The basis, methods, techniques, and quality control of inherited disease testing are not standardized for small

1016

SECTION  X  Reproductive Diseases

animals. In addition, animal genetic testing laboratories and companies have no oversight or accreditation. Regulations and guidelines for small animal genetic testing are needed. Until these are enacted, veterinarians submitting samples for canine genetic disease testing must evaluate each test individually to determine its accuracy and reliability. A basic knowledge of the methods of the test and an evidence-based approach to its evaluation are important to guide decisions about when to use a specific test. Criteria for molecular genetic testing should be similar to those for any diagnostic medical test. Within a reasonable amount of time after development, the data and results of the test should be published in a peer-reviewed scientific journal. Ideally the test should be verified independently by an outside group. Any test, evidence, and data without the scrutiny of a peer review should be used cautiously or evaluated critically. For some of the currently available tests, only patent information is available; this information can be reviewed through the U.S. patent website (www.uspto.gov/main/patents.htm). In some cases companies offering tests are awaiting resolution of intellectual property issues.

Biochemical Tests Biochemical tests for inherited disorders in dogs and cats have been available for many years. They continue to play an important role in diagnosis of inherited disorders in which the chromosomal location or gene for the defect has not been identified. Most biochemical tests require only a simple blood or urine sample. Biochemical tests are also necessary to help evaluate newly developed molecular genetic tests, especially those lacking documentation or presenting controversy. Examples of some of the currently available biochemical tests include those for mucopolysaccharidosis, Fanconi syndrome, erythrocyte osmotic fragility, methylmalonic aciduria, cystinuria, urinary acids, urinary amino acids, urinary carbohydrates, urinary glycosaminoglycans, urinary oligosaccharides, cobalamin malabsorption, hypersarcosinemia, and other inborn errors of metabolism performed at the University of Pennsylvania School of Veterinary Medicine (PennGen) (Table 221-1). Factor assay tests for von Willebrand’s

disease and other inherited coagulopathies are performed at a number of veterinary diagnostic laboratories. In many cases biochemical tests are the best estimate of the genetic status of an individual (i.e., affected, carrier, or clear). However, test results can fall into overlapping categories, causing potential problems with classification and definition.

Deoxyribonucleic Acid–Based Tests Many genetic markers do not code for messenger ribonucleic acid or proteins (noncoding markers). These markers are interspersed throughout all chromosomes, and many noncoding markers are near every gene. The markers tend to be variable among individuals because changes in the nucleotides do not have any known functional effect. Many of the markers used in past canine genetic studies and marker tests are repeats of nucleotides (e.g., CA repeated 10 to 30 times). Restriction enzymes cut DNA at specific, short sequences. The resulting different lengths of DNA can be detected on a gel because the fragments migrate in an electrical field in inverse proportion to their size. The varying lengths of the marker are called different alleles, just as various blood types represent different alleles of a coding gene. Single nucleotide polymorphisms (SNPs), such as a C or T at the exact same chromosomal location (locus), are another type of genetic marker. Canine SNP arrays that can genotype thousands of SNP markers for one individual have been available for a number of years. Currently, most canine genetic disease research looks for association of SNP markers with the disease of interest for particular breed or a group of related breeds. A SNP array has just been developed and now is available for feline research. A genetic marker can be associated strongly or linked with a disease gene if it is close to a gene and the marker has more than one allele. The farther a marker is from a gene on the same chromosome, the more likely recombination is to have occurred during meiosis. The percentage of time a marker and gene have recombination between them is termed the recombination fraction. For a marker to be potentially useful as a screening genetic test, a recombination fraction of 5% or less typically is required. 

TABLE 221-1  Some Laboratories and Companies Offering Canine and Feline Genetic Testing in the United States and United Kingdom Name

Phone

Website

Animal Health Trust (AHT) (United Kingdom)

44-(0)1638-555621

www.aht.org.uk

DDC Animal DNA Testing

800-625-0874

http://www.vetdnacenter.com/

OptiGen LLC (Ithaca, NY)

607-257-0301

www.optigen.com

Orthopedic Foundation for Animals (OFA) (Columbia, MO)

573-442-0418

www.offa.org/dnatesting/

PennGen (University of Pennsylvania)

215-898-3375

www.vet.upenn.edu/penngen

Veterinary Genetics Laboratory (University of California, Davis)

530-752-2211

www.vgl.ucdavis.edu

VetGen LLC (Ann Arbor, MI)

800-483-8436

www.vetgen.com

CHAPTER  221  Methods and Availability of Tests for Hereditary Disorders of Dogs and Cats G A(2)

g A(1)

B(2)

B(1)

G A(2)

g A(1)

B(1)

Normal -

TCGGAT

100 bp

Mutation

TAGG AT

100 bp

1017

B(2) 100 bp

Figure 221-1  Genetic linkage of a marker A and gene G and

recombination between G and marker B. The left portion shows two homologous chromosomes with gene G and markers A and B. G refers to the normal gene allele and g refers to the mutated gene allele. A(2) is marker A allele 2, and A(1) is marker a allele 1. The left side shows the A(1) and B(1) marker alleles linked with the mutation g. The middle shows a recombination event during meiosis, and the right side shows that marker A, which is close to the gene, still has allele A(1) linked with the mutation g. However, marker B now has changed to allele B(2) linked with mutation g as a result of the recombination event. A marker must be close to the gene with a low recombination frequency and with specific population dynamics of the alleles to be a reliable screening test.

Figure 221-1 illustrates marker and gene linkage and recombination. A marker allele is linked to a disease; this is probably the most difficult concept pertaining to an understanding of published chromosomal locations of causative genes and molecular genetic disease testing. Direct mutation tests detect DNA sequence differences in the specific causative gene. A genetic marker test detects a marker allele linked to a mutation in a nearby, unknown gene. For either type of molecular genetic test only a small DNA sample obtained from a special cheek swab kit or an ethylenediaminetetraacetic acid (EDTA) whole-blood sample is needed. Instructions for the type of sample are found easily on the laboratory website or via phone contact. These tests can be performed at any age after weaning and are done only once in a lifetime. Laboratories always should run positive and negative controls for all molecular genetic tests to ensure accuracy and reliability. A list of the major canine and feline molecular genetic testing laboratories can be found in Table 221-1. This is not an inclusive list because new laboratories are established frequently.

Direct Mutation Tests The testing procedure for a direct mutation test is straightforward and relatively simple. Depending on the exact mutation, there are several different detection methods. For many of the tests the specific DNA in the area of the specific known mutation is PCR amplified and then cut with a restriction enzyme that differentially cuts or does not cut the normal and mutated sequences. The restriction enzyme products then are separated by size on a gel, and the different-sized products can be categorized into normal, heterozygous (carrier for a recessive disease or affected for a dominant disease), and homozygousaffected categories. A hypothetic example that illustrates direct mutation testing with a restriction enzyme for a recessive disease is given in Figure 221-2. Currently, using automated fluorescent SNP detection methods is common to find the normal and mutant allele for direct mutation testing. Each specific direct mutation test checks for only

60 bp 40 bp

Clear

Carrier

Affected

Figure 221-2  Gel electrophoresis results for a hypothetic direct

mutation test for a recessive disease. The normal and mutation polymerase chain reaction sequence products are both 100 base pairs (bp) long. They differ in a C to A substitution in the second nucleotide shown. A restriction enzyme cuts the mutation sequence between the G and A into a 60- and a 40-base pair fragment but does not cut the normal product. The fragments are size separated and visualized on a gel. The results unequivocally categorize individuals into clear, carrier, or affected for this one specific mutation. This does not test for other mutations in the same gene. Laboratories always should run positive and negative controls for all molecular genetic tests.

one mutation in the gene. Table 221-2 contains a list of some of the direct mutation tests currently available for dogs. Once a causative mutation for an inherited disorder has been well documented, a direct mutation test can be nearly 100% accurate if the disease in the breed has been passed on by a popular breeding animal. Many genetic diseases in the dog and cat are recessive because of this founder effect. In humans with recessive diseases, affected individuals often are compound heterozygotes (i.e., they have two different mutations of the same gene causing the disease). On the other hand, affected dogs and cats often have two identical copies of the same mutation passed on from the founding individual through both their sire and dam lines. If the founder effect is strong within a breed for a particular disease and no other similar forms of the disease are caused by a different mutation in the same gene or other genes, a direct mutation test is highly accurate. However, clinicians always must consider the possibility of a new (de novo) mutation occurring in the same gene or a similar gene and the possibility of heterogeneity of an identical-appearing disorder caused by a different mutation in the same gene or a mutation in a different gene. Among breeds the specific mutations are sometimes exactly the same, as in some instances of type I von Willebrand’s disease, in which the exact same mutation is shared by a number of breeds. In other instances the mutations are breed specific as with the three different mutations for narcolepsy in the hypocretin receptor gene of Doberman pinschers, Labrador retrievers, and dachshunds.

Genetic Marker Tests A genetic marker test is based on linkage and/or association between a genetic marker allele and a disease. There are two major ways to prove these associations. The first

1018

SECTION  X  Reproductive Diseases

TABLE 221-2  Some of the Common Direct Mutation Tests for Canine Inherited Disorders Disease

Breed(s)

Inheritance

Laboratory

Basis

Arrhythmogenic right ventricular cardiomyopathy

Boxer

Variable penetrance?

North Carolina State

Patent pending

Canine leukocyte adhesion deficiency

Irish setter

AR AR

OptiGen AHT

PBL PBL

Canine multifocal retinopathy

Bullmastiff Coton de tulear Great Pyrenees

AR? AR? AR?

OptiGen OptiGen OptiGen

NDY NDY NDY

Cataracts

Staffordshire bull terrier

AR

AHT

NDY

Centronuclear myopathy

Labrador retriever

AR

Alfort, France

PBL

Ceroid lipofuscinosis

American bulldog Border collie Dachshund English setter

AR AR AR AR

U of MO AHT U of MO U of MO

PBL PBL PBL PBL

Cobalamin malabsorption (methylmalonic aciduria)

Australian shepherd Giant schnauzer

AR AR

PennGenn PennGenn

PBL PBL

Collie eye anomaly

Australian shepherd Border collie Rough collie Shetland sheepdog Smooth collie

AR AR AR AR AR

OptiGen OptiGen OptiGen OptiGen OptiGen

Patent Patent Patent Patent Patent

Cone degeneration

German shorthaired pointer

AR

OptiGen

NDY

Congenital stationary night blindness

Briard

AR AR

OptiGen AHT

PBL PBL

Copper toxicosis

Bedlington terrier

AR AR

AHT VetGen

PBL PBL

Cystinuria

Newfoundland

AR AR AR

Penn OptiGen VetGen

PBL PBL PBL

Degenerative myelopathy

>15 breeds

AR(P)?

OFA

PBL

Dilated cardiomyopathy

Doberman pinscher

AR?

NCSU

Patent Pending

Exercise induced collapse (DNM1)*

Labrador retriever and 5 other breeds

AR

U of MN*

PBL

Familial nephropathy (hereditary nephritis)

English cocker spaniel

AR

OptiGen

PBL

Factor VII deficiency

Beagle Scottish deerhound

AR AR

Penn Penn

PBL PBL

Factor XI deficiency

Kerry blue terrier

AD(P)?

Penn

NDY

Fucosidosis

English springer spaniel

AR ARAHT

Penn PBL

PBL

Glanzmann’s thrombasthenia (I)

Great Pyrenees

AR

Auburn

PBL

Otter hound

AR

Auburn

PBL

Hemophilia B

German wirehaired pointer

XL

Cornell

PBL

Hyperuricosuria (SLC2A9)

Dalmatian and 11 other breeds

AR

UC Davis

PBL

Hyperparathyroidism

Keeshond

AD

Cornell

NDY

Hypothyroidism (congenital)

Rat and toy fox terrier

AR

MSU

PBL

Ivermectin toxicity

Australian shepherd Collie Longhaired whippet Old English sheepdog Shetland sheepdog

AR AR AR AR AR

Wash Wash Wash Wash Wash

L-2-hydroxyl glutaric aciduria

Staffordshire bull terriers

AR

AHT

PBL

Mucopolysaccharidosis IIIB

Schipperke

AR

Penn

PBL

State State State State State

PBL PBL PBL PBL PBL

pending pending pending pending pending

CHAPTER  221  Methods and Availability of Tests for Hereditary Disorders of Dogs and Cats

1019

TABLE 221-2 Some of the Common Direct Mutation Tests for Canine Inherited Disorders—cont’d Disease

Breed(s)

Inheritance

Laboratory

Basis

Mucopolysaccharidosis VI

Miniature pinscher

AR

Penn

PBL

Mucopolysaccharidosis VII

German shepherd

AR

Penn

PBL

Myotonia congenita

Miniature schnauzer

AR AR

Penn OptiGen

PBL PBL

Narcolepsy

Dachshund Doberman pinscher Labrador retriever

AR AR AR

OptiGen OptiGen OptiGen

PBL PBL PBL

Neuronal ceroid lipofuscinosis

American bulldog Dachshund English setter Tibetian terrier

AR AR AR AR

OFA U of MO U of MO OFA

PBL PBL PBL PBL

Neonatal encephalopathy

Standard poodle

AR

U of MO, OFA

PBL

Phosphofructokinase deficiency

American cocker spaniel

English springer spaniel

AR AR AR AR AR AR AR

OptiGen Penn VetGen OptiGen Penn VetGen AHT

PBL PBL PBL PBL PBL PBL PBL

Progressive retinal atrophy (PRA) type A

Miniature schnauzer

AD(P)

OptiGen

NDY

Progressive retinal atrophy (dominant)

Bullmastiff Old English mastiff

AD AD

OptiGen OptiGen

PBL PBL

Progressive retinal atrophy (X-linked)

Siberian husky Samoyed

XL XL

OptiGen OptiGen

PBL PBL

Progressive retinal atrophy (Rcd3)

Cardigan Welsh corgi

AR

OptiGen

PBL

Pyruvate kinase deficiency

Basenji

AR AR AR AR AR AR AR AR AR AR

OptiGen Penn Vetgen AHT Penn Penn Penn Penn Penn AHT

PBL PBL PBL PBL PBL PBL PBL PBL PBL PBL

Beagle Cairn terrier Dachshund Eskimo West Highland white terrier Rod cone dysplasia-1 (Rcd1)

Irish setter

AR AR AR

OptiGen VetGen AHT

PBL PBL PBL

Rod cone dysplasia-1 (Rcd1a)

Sloughi

AR AR

OptiGen AHT

PBL PBL

Rod cone dysplasia-3 (form of PRA)

Cardigan Welsh terrier

AR

OptiGen

PBL

Progressive rod cone degeneration (PRCD)

American Eskimo Australian cattle dog Australian shepherd Chesapeake Bay retriever Chinese crested English cocker spaniel Labrador retriever Nova Scotia duck tolling retriever. Miniature and toy poodle Portuguese water Dog

AR AR AR AR AR AR AR AR AR AR

OptiGen OptiGen OptiGen OptiGen OptiGen OptiGen OptiGen OptiGen OptiGen OptiGen

Patent Patent Patent Patent Patent Patent Patent Patent Patent Patent

Severe combined immunodeficiency

Bassett hound West Highland white terrier Cardigan Welsh corgi

XL XL XL

Penn Penn Penn

PBL PBL PBL Continued

1020

SECTION  X  Reproductive Diseases

TABLE 221-2 Some of the Common Direct Mutation Tests for Canine Inherited Disorders—cont’d Disease

Breed(s)

Inheritance

Laboratory

Basis

von Willebrand’s disease type I

Bernese mountain dog Doberman pinscher German pinscher Kerry blue terrier Manchester terrier Papillon Pembroke Welsh corgi Poodle (all varieties)

AR? AR? AR? AR? AR? AR? AR? AR?

VetGen VetGen VetGen VetGen VetGen VetGen VetGen VetGen

Patent Patent Patent Patent Patent Patent Patent Patent

von Willebrand’s disease type II

German shorthaired pointer

AR

VetGen

PBL

von Willebrand’s disease type III

Scottish terrier Shetland sheepdog

AR AR

VetGen VetGen

PBL Patent

AD, Autosomal-dominant; AD(P), autosomal-dominant with partial penetrance; AR, autosomal-recessive; NDY, no published data yet; Patent, patent that can be viewed on U.S. patent website; PBL, peer-reviewed publication; Un, unknown; XL, X-linked–recessive. Direct mutation tests can be virtually 100% accurate if there is a strong founder effect within the breed, but another mutation in the same gene or a different gene causing the disease is always a possibility in some percentage of the cases. *The author has a patent for the exercise induced collapse genetic test and receives a portion of the royalties for the genetic testing. (All information in this table is deemed reliable at the time of writing, but the author does not guarantee its accuracy or completeness; consult the individual laboratory for full details.)

is a family linkage study, in which marker alleles are tracked through generations of affected families in a breed to determine if the marker allele cosegregates with the disease. Statistically significant linkage found through a significant log of odds score of 3 or greater is direct evidence of the causative mutation residing on the chromosomal segment containing the marker. Association between a marker allele and a disease also is shown by a marker association study, which is done by testing markers on a group of affected individuals versus a matched group of normal control individuals. A statistically significant association by chi square or other similar statistical analysis can identify chromosomal regions that potentially contain the causative gene for an inherited disorder. This type of association of a marker allele and disease is termed linkage disequilibrium. It indicates that one allele of a marker is associated with a disease far more often than would be expected if the marker allele frequencies were in Hardy-Weinberg equilibrium. Statistical association in marker studies is not necessarily direct evidence that a gene is in a chromosomal segment close to the marker. Confounding variables and false positives caused by familial relationships of the dogs always are possible. A hypothetic example of a genetic marker test done on a family is illustrated in Figure 221-3. Genetic marker tests are never 100% accurate for all individuals in a breed; therefore they should be considered screening tests only. As previously discussed, depending on population dynamics and other factors, a direct mutation test can sometimes be close to 100% accurate and therefore is considered the definitive test. The accuracy of the genetic marker test depends on linkage disequilibrium, the recombination fraction between the marker and the gene, and the population dynamics of the breed. One specific allele of the marker most often is associated with the mutation because of a popular founding individual. However, often a few individuals have the

same specific allele but do not have the mutation because of a previous recombination event between the marker and the gene. This false association also can be caused by population dynamics in which some family lines always hold the same specific marker allele yet not associated with the mutated gene. The sensitivity, specificity, positive predictive value, and a negative predictive value can be calculated from sufficient data for a genetic marker test. Currently available genetic marker tests for canine inherited disorders are listed in Table 221-3. Some of the current major genetic testing laboratories are listed  in Table 221-1 and the Canine Health Foundations  keeps an updated online list of many of the laboratories (http://www.akcchf.org/canine-health/health-testing/ laboratory). Genetic marker tests are often temporary screening tests because once a genetic marker is documented, the nearby causative genetic mutation is likely to be identified by positional cloning. An example of this is copper toxicosis in Bedlington terriers, for which a linked marker and corresponding marker test were identified in 1997. The genetic linkage test was verified in a larger population shortly thereafter, and a number of years later the putative mutation was identified.

Future Test Development, Other Services, and Updated Test Lists The field of veterinary molecular genetics is evolving at a fast pace; therefore the list of available tests and services also is changing rapidly. Individual results for a direct mutation test generally have a straightforward interpretation. If direct mutation test results are used in a breeding program or if results of a genetic marker test are used for breeding decisions, a veterinary geneticist should be consulted for genetic counseling. Many of the listed laboratories (see Table 222-1) and some other laboratories offer

CHAPTER  221  Methods and Availability of Tests for Hereditary Disorders of Dogs and Cats

1

1021

8 2

3

4

5

6

7

Allele 3 - 104 base pairs Allele 2 - 102 base pairs Allele 1 - 100 base pairs

Carr

Clear

Carr

Aff

Aff

Carr

Clear

Carr

Figure 221-3  Gel electrophoresis results for a hypothetic genetic marker test in a family. Marker

A has three alleles that vary in size by two base pairs in size of a dinucleotide marker repeat such as CA. The marker is linked closely to the gene defect, with allele 1 usually associated with the disease allele and alleles 2 and 3 usually associated with the normal gene allele. The alleles from each individual can be separated and visualized on a gel by electrophoresis. Squares are males and circles are females. Individuals 1 and 8 are the parents and are both carriers. Individuals 4 and 5 are affected and have two copies of the 1 allele (only one band is visualized because the alleles from each parent are the same size). The status indicated below each set of gel band for each individual is the most likely genetic status for a hypothetic recessive disease (Clear = likely clear, Carr = likely carrier, Aff = likely affected). Genetic marker tests are never 100% accurate because of recombination events and/or population dynamics, but they can be good screening tests if there is a low recombination frequency and a strong founder effect. Eventually the actual mutation should be identified and a direct gene test developed. Laboratories always should run positive and negative controls for all molecular genetic tests.

TABLE 221-3  Genetic Marker Tests for Canine Inherited Disorders Disease

Breed(s)

Inheritance

Laboratory

Basis

Copper toxicosis

Bedlington terrier

AR

Vetgen

PBL

Dilated cardiomyopathy (juvenile)

Portuguese water dog

AR?

PennGen

NDY

AR, Autosomal-recessive; NDY, no published data yet; PBL, peer-reviewed publication. Refer to Table 221-1 for complete laboratory details. Genetic linkage tests are never 100% accurate and should be used as screening test only until the mutation is identified.

additional services such as individual DNA identification, parentage testing, DNA storage, coat color genetic testing, and/or karyotyping. The principles and details outlined here apply equally well to testing for inherited disorders of cats. Updated lists of the available tests for dogs and cats can be found at the website for the World Small Animal Veterinary Association (WSAVA) Genetic Database (http://research.vet  .upenn.edu/DNAGeneticsTestingLaboratorySearch/tabid  /7620/Default.aspx).

References and Suggested Reading Hungs M et al: Identification and functional analysis of mutations in the hypocretin (orexin) genes of narcoleptic canines, Genome Res 11(4):531, 2001. Lee YJ et al: Diagnosis of feline polycystic kidney disease by a combination of ultrasonographic examination and PKD1 gene analysis, Vet Rec 167:614, 2010.

Lindblad-Toh K et al: Genome sequence, comparative analysis and haplotype structure of the domestic dog, Nature 438(7069):803, 2005. Lyons LA: Feline genetics: clinical applications and genetic testing, Top Companion Anim Med 25:203, 2010. Mellersh C: DNA testing and domestic dogs, Mamm Genome 2011. DOI 10.1007/s00335-011-9365-z. Metallinos DL: Canine molecular genetic testing, Vet Clin North Am Small Anim Pract 31:421, 2001. Ostrander EA, Galibert F, Patterson D: Canine genetics comes of age, Trends Genet 16:117, 2000. Patterson DF: Companion animal medicine in the age of medical genetics, J Vet Intern Med 14:1, 2000. Shelton GD: Routine and specialized laboratory testing for the diagnosis of neuromuscular diseases in dogs and cats, Vet Clin Pathol 39:278, 2010. van de Sluis B et al: Identification of a new copper metabolism gene by positional cloning in a purebred dog population, Hum Mol Genet 11:165, 2002.

CHAPTER 

222 

Reproductive Oncology SHAY BRACHA, Corvallis, Oregon

R

eproductive tumors in the dog and cat are rare in comparison to other cancers because of the common practice of castration and ovariohysterectomy. However, some reproductive tumors have increased incidences in recent decades. Most reproductive tumors are benign and usually are an incidental finding. Therefore local clinical signs typically are seen in these patients, whereas systemic clinical signs may be present in cases of hormone-producing tumors. Treatments and prognosis vary according to the tumor type and invasiveness; however, through the use of surgery, chemotherapy, and radiation therapy, many types of reproductive tumors can be managed more easily.

Testicular Tumors Testicular tumors are among the most common malignancies in intact male dogs, whereas they are extremely rare in cats. Most of these tumors are undiagnosed and detected as a primarily incidental finding on either physical exam or abdominal ultrasound. In recent decades according to one study, incidences in intact dogs are increased. The prevalence of testicular tumors in the same study was 27%; interstitial cell tumors and seminomas are the most common, followed by Sertoli cell tumor. Although interstitial cell tumors and seminomas do not exhibit prominent clinical signs, Sertoli cell tumors are more likely to be detected because of the manifestation of obvious symptoms associated with hyperestrogenism. In the last decades, only a limited number of cases have been reported in the cat and included seminomas, interstitial cell tumors, teratomas, and Sertoli cell tumors. Many dogs present with bilateral tumors and occasionally have more than one tumor type. Intact older dogs and dogs of certain breeds such as boxers, German shepherds, and Afghan hounds present an increased risk for testicular tumors. Cryptorchidism significantly increases the risk for tumor manifestation in the dog, particularly for Sertoli cell tumor and seminomas. Cryptorchidism seems to increase the potential of a malignant testis in cats as well. Although studies in people showed an increased risk of testicular cancer after an exposure to environmental factors such as pesticides and radiation, it has yet to be determined in the dog. A possible association to chemical exposure was assumed in dogs that served in Vietnam. Testicular tumors can be classified into several categories by tissue of origin, such as germinal epithelium of the seminiferous tubules, sex cord stroma, mixed tumors, and tumors of different origin. Germinal epithelium cells give rise to seminoma, teratoma, embryonal carcinoma, 1022

and yolk sac carcinoma. Sertoli cell tumors as well as Leydig cell tumors arise from the sex cord stroma, and a mixed characters group of germ cell and sex-cord stromal tumors. Tumors of different origin, such as adenocarcinomas, sarcomas, and gonadoblastomas, rarely have been reported. The World Health Organization classification of seminomas in the dog labels the tumor histologic morphology as either intratubular (invasive or noninvasive) or diffuse. Further classification of classical seminoma and spermatocytic seminoma can be done and relates to the origin of the tumor cell. Spermatocytic seminomas originate from well-differentiated mature spermatocytes and therefore present a more benign nature in people. Classical seminomas, on the other hand, originate from undifferentiated gonocytes and therefore have a more malignant course. Immunohistochemistry can further differentiate between the two seminoma types. Classical seminomas typically stain positive to placental alkaline phosphatase and periodic acid stain, whereas spermatocytic seminomas are periodic acid stain negative. A recent study found that the expression of CKIT receptor is a sensitive marker for canine seminomas, whereas OCT 3/4, which is a sensitive marker in human seminomas, did not show the same sensitivity in the dog. The same study suggests that because CD30 was not expressed in seminomas it may be a good marker for distinguishing embryonal carcinoma from seminoma. Interstitial cell tumors are the least common to metastasize, and seminomas and Sertoli cell tumors rarely metastasize in the dog. Tumors that originate in a cryptorchid testicle show a higher metastatic risk in the dog. The most common sites of metastasis are the sublumbar lymph nodes, but metastasis to any organ is possible, including lungs, spleen, kidneys, skin, and central nervous system. In people, the rate of metastasis is much higher than in the dog, in which the incidence is less than 15%. A common finding of testicular tumors is a palpable mass on the affected testicle or, in the case of a cryptorchid dog, in the inguinal area. These may be accompanied with atrophy of the scrotum and the other testicle. Systemic clinical signs are not common, and when present, usually are associated with Sertoli cell tumor  and hyperestrogenism. Estrogen myelotoxicity may have fatal consequences and should be considered as a potentially life-threatening condition in dogs with testicular tumors. Clinical signs associated with myelotoxicity and pancytopenia may include hemorrhage, petechiation, lethargy, decreased appetite, ataxia, and fever. Other clinical signs associated with hyperestrogenism include feminization, symmetric bilateral alopecia, hyperpigmentation,

CHAPTER  222  Reproductive Oncology atrophied scrotum and penis, and metaplasia of the prostate. Although feminization was not reported in cats with testicular tumors, masculine behavior was observed in two cases and in one case was attributed to a potential increase in serum testosterone levels. Testosterone production may result in a perianal hernia in the dog, as well as hyperplasia of the prostate and of the perianal glands. Although a histologic sample is needed for a definitive diagnosis, a fine-needle aspirate has a relatively high sensitivity and high specificity. Generally, aspirates are performed with ultrasound guidance and typically are reserved for owners who resent castration. A thorough physical exam including rectal palpation should be  performed. A complete blood count (CBC) may reveal hematologic abnormalities associated with estrogen myelotoxicity, such as pancytopenia. In addition, plasma levels of estradiol-17β should be measured in dogs with feminization signs. However, clinical signs of feminization may exist in the absence of increased levels of estradiol-17β. Complete staging also should include an abdominal ultrasound and thoracic radiographs. The majority of dogs present with local disease and the preferred treatment is castration with en bloc scrotal ablation. Prevalence of metastasis in cats is increased; however, the number of reported cases is limited. For dogs with estrogen myelotoxicity, the prognosis is guarded even with intensive supportive treatment of broad-spectrum antibiotics and blood transfusions. Recovery of such an insult to the bone marrow may take several weeks to months. Bleomycin sulfate (Blenoxane) and cisplatin (Platinol-AQ) were reported for the treatment of metastatic disease but had mixed results. Cisplatin typically is administered at a dose of 60 mg/m2 IV over 20 minutes, generally every 3 weeks. However, an intravenous saline diuresis should be performed 4 hours before and 2 hours after the administration of cisplatin at a rate of 20 ml/kg/ hr. Although reports on radiation treatment are limited, it proved to be effective in the management of testicular tumors.

Penile and Preputial Tumors Penile and preputial tumors in dogs are rare and no reports exist in the cat. Multiple forms of skin cancer can affect the prepuce and penis; however, transmissible venereal tumor (dogs only) and squamous cell carcinoma are the most common. Transmissible venereal tumors are more common in younger dogs in tropical climate weather, whereas squamous cell carcinoma is more common in lightly pigmented dogs with history of exposure to solar radiation. Mast cell tumors have been reported on the prepuce and may involve the penis. Other tumors of the prepuce and penis include benign masses such as papilloma, hemangioma, fibroma, and sebaceous adenoma. Malignant tumors include lymphoma, hemangiosarcoma, and fibrosarcoma. Preputial and penile tumors are usually visible and palpable. Clinical signs may include paraphimosis, pineal prolapse, hematuria, hemorrhagic discharge from the prepuce or penis, and dysuria resulting from obstruction. Diagnosis can be determined with fine-needle aspirates  or impression smears. A histologic sample should be

1023

obtained for definite diagnosis. Further staging requires a CBC, blood chemistry panel, and urinalysis. Because of the potential metastasis of some of the tumors, such as hemangiosarcoma, mast cell tumor, squamous cell carcinoma, and fibrosarcoma, thoracic radiographs and an abdominal ultrasound are warranted. Although transmissible venereal tumors have a low risk to metastasize, such incidences were reported in up to 15% of the cases in one study and therefore complete staging is recommended. Surgical excision is the preferred treatment for most penile and preputial tumors, excluding transmissible venereal tumors, that typically show complete response with chemotherapy treatment. The extent of surgery and postsurgical therapy should be determined by the type of tumor. Vincristine (Oncovin or Vincasar PFS) is a common effective treatment for transmissible venereal tumors administered at a dosage of 0.5 to 0.70 mg/m2 IV once a week. Treatment with doxorubicin hydrochloride (Adriamycin) may be attempted in cases of resistance to vincristine. Transmissible venereal tumors are also sensitive to radiation, and in some cases a cure was reported with a single treatment of 1000 cGy. In one study, the entire cohort of 18 dogs achieved complete remission when 1 to 3 fractions of 1000 cGy were delivered.

Scrotal Tumors As in other locations of the dog’s skin, mast cell tumors are the most common on the scrotum. The aggressiveness of mast cell tumors in the inguinal area is debated. However, to date, survival seems to be equivalent for patients with the same grade disease regardless of the tumor location on the skin. Other possible tumors of the scrotum include squamous cell carcinoma, sweat gland carcinoma, hemangioma, myxoma, plasmacytoma, and melanoma. Scrotal tumors in the cat have not been reported. In most circumstances, scrotal tumors are obvious and easy to palpate. Squamous cell carcinomas usually have a nodular confined appearance and are more common in older dogs with lightly pigmented skin. Myxosarcoma may present as a nodular mass without defined borders, whereas mast cell tumors may present as a confined mass or more diffusive. Edema, bruising, and ulceration may be associated with mast cell tumors. Needle aspirates, impression smears, or tissue biopsies for a definite diagnosis should be obtained and ideally accompanied with complete staging. In cases of potential mast cell tumors, an injection of diphenhydramine hydrochloride (Benadryl) 20 minutes before the procedure may prevent possible complications associated with cell degranulation. The typical dose of diphenhydramine hydrochloride is 2 mg/ kg SC or IM. Surgical excision of the scrotum usually is curative. In the case of metastatic disease, chemotherapy may be necessary depending on the type of tumor.

Prostatic Cancer The prevalence of prostate cancer increases with the age of the dog. An epidemiologic study based on the

1024

SECTION  X  Reproductive Diseases

Veterinary Medical Data Base demonstrated an increased risk of prostate cancer in castrated male dogs. This study examined data from more than three decades and revealed a higher chance of metastatic disease in castrated males in comparison to those intact. Regardless of castration status, mixed-breed dogs and certain breeds such as Doberman pinschers, Shetland sheepdogs, Scottish terriers, beagles, German shorthaired pointers, Airedale terriers, and Norwegian elkhounds were reported to have a higher prevalence for prostate cancer. Prostatic tumors in the cat have not been reported. Dogs with prostate cancer often present with difficulties to defecate, hematuria, stranguria, and incontinence. The few reports in cats demonstrated similar clinical presentation. Metastasis to sublumbar lymph nodes and lungs are common. As in humans, skeletal metastasis is common as well, and younger dogs have an even increased risk for skeletal involvement. Neurologic deficits attributed to musculoskeletal disease were reported in about a third of dogs with prostate cancer. According to one study, the most common skeletal sites of metastasis were the lumbar vertebra, the pelvis, and the femur. A rectal examination may reveal enlarged prostate and sublumbar lymph nodes. Lameness and/or pain on spinal palpation may be evident in the case of skeletal involvement. Complete staging includes a CBC, blood chemistry, urinalysis, and urine culture. Thoracic radiographs and abdominal ultrasound may reveal metastatic disease to lymph nodes or other visceral organs. Fine-needle aspirates and biopsies ideally should be obtained with ultrasound guidance. Estrogen has a significant role in the differentiation of epithelial and stromal cells in the prostate. Expression of estrogen receptors was examined with immunohistochemistry (IHC) and IHC labeling in normal, hyperplastic, and neoplastic tissues. A marked nuclear expression was demonstrated in the normal and hyperplastic cells. However, neoplastic cells showed a reduced expression that was related to the cells’ poor differentiation. Immunohistochemistry staining for cytokeratin 7 can differentiate between tumors of epithelial origin or urothelium origin. Cytokeratin 7 stains positive in masses of urothelium origin and negative in prostate epithelium origin. A study of prostate carcinoma proteomics showed a significant overexpression of cytokeratin 7, GRP78, and endoplasmin when compared with the profile of normal prostate and normal urinary bladder. Protein profiling may help in the near future to develop a deeper understanding of prostate cancer type and origin and potential therapeutic targets. In one study a histological examination of prostatic cancer showed that about half of the tumors had a mixed morphology and about a third of the tumors were considered to be adenocarcinomas. The rest of the tumors were classified as squamous cell carcinomas and urothelial carcinomas. A more recent study indicated that canine prostate cancer can be classified as adenocarcinoma or poorly differentiated. The same study further classified prostatic adenocarcinoma and found that intraalveolar is the most common subtype in castrated dogs, whereas intact dogs had the small acinar type. Surgical methods that can be used are the total prostatectomy and subtotal

intracapsular prostatectomy. Total prostatectomy can be attempted but may result in serious postsurgical complications such as uncontrolled bleeding, sepsis, and acute renal failure. Less severe complications are urinary incontinence and urethral damage. Dogs that had subtotal intracapsular prostatectomy had fewer complications and longer survival times when compared with dogs that had total prostatectomy. In most instances, a prostatectomy is not performed because of the potential high morbidity involved with these procedures and the lack of evidence that it prolongs survival. In an advanced stage disease a partial or a complete obstruction of the urethra may take place. Possible palliative treatments include urethral stenting and tube cystostomy. Reports are limited regarding the treatments with chemotherapy. Prostate cancer in humans and dogs express COX-2. Although COX-2 could not be linked directly to disease progression in prostate cancer of the dog, treatment with nonsteroidal antiinflammatory drugs (NSAIDs) still may be valuable. The NSAID piroxicam (Feldene), with a dosage of 0.3 mg/kg q24h PO in a combination with mitoxantrone hydrochloride (Novantrone) at 5.0 mg/m2 IV once every 3 weeks, have proven to be effective in the treatment of transitional cell carcinoma and may be effective when the prostate is involved. Other potential treatments for metastatic disease may include carboplatin (Paraplatin) 300 mg/m2 IV once every 3 weeks and doxorubicin hydrochloride 30 mg/m2 IV once every 3 weeks. In humans, docetaxel is used commonly for the treatment of castration-resistant prostate cancer. Treatment with photodynamic therapy includes the administration of a photosensitizer (e.g., 5 aminolevulinic acid), a laser light source, and oxygen. Photodynamic therapy in dogs with prostatic cancer has had limited use; however, this therapeutic model may prove a good method for local disease control.

Ovarian Tumors Ovarian tumors are seldom seen in dogs, most probably because of the common practice of ovariohysterectomy. The prevalence of ovarian tumors is less than 1.2% in dogs, whereas in humans the incidence rate is 12.8 per 100,000 per year. Several breeds such as boxers, German shepherds, Yorkshire terriers, pointers, and bulldogs have a higher risk. Most affected dogs are older, except in the cases of granulosa cell tumors and teratomas, which are seen more commonly in younger dogs. According to one report the left ovary seems to be affected more frequently; however, not all studies support this observation. Classification is by the tissue of origin, including germ cell tumors, epithelial tumors, sex-cord stromal tumors, and mesenchymal tumors. Epithelial cell tumors typically are more common in older females and account for 40% to 50% of ovarian tumors. Epithelial tumors include papillary adenomas, cystadenoma, papillary adenocarcinomas, and undifferentiated carcinomas; of which papillary adenoma is the most common. Sex cord stromal tumors reported in the dog include thecomas, Sertoli-Leydig cell tumors (benign), and granulosa cell tumors (responsible for up to 50% of all ovarian tumors in the dog). Germ cell tumors account for a small percentage of the ovarian

CHAPTER  222  Reproductive Oncology tumors and include dysgerminoma tumors and teratomas. Mesenchymal tumors are rare and may include hemangioma, hemangiosarcoma, and leiomyoma. Sex cord tumors, germ cell tumors, and epithelial tumors have been reported in the cat. However, epithelial tumors are diagnosed much more often in the dog than in the cat. Cats most commonly have malignant granulosa cell tumors. Production of hormones may be associated with sex cord stromal tumors. These tumors are known to secrete inhibin, estrogen, progesterone, and, in some cases, testosterone. Production of estrogen may result in a pyometra, vaginal discharge, symmetric alopecia, polyuria, polydipsia, and abnormal estrous behavior. Estrogen myelotoxicity may result in severe anemia and sepsis, in which case the dog may become pyretic and lethargic. The production of progesterone can induce mammary hyperplasia. In the case of testosterone, behavioral changes (e.g., aggression) may be observed. Pulmonary metastasis or pleural effusion may cause coughing and dyspnea. A mass effect or ascites may result in a distended abdomen in dogs. In the dog about 30% of ovarian masses metastasize and hence a physical examination and complete staging are necessary for evaluation of the disease stage. A cytologic or histologic sample should be obtained for the determination of the nature of the tumor. Complete staging should follow any diagnosis of ovarian tumor. Cats may present with advanced disease because of the likelihood of malignant tumors. Breathing difficulties may point to lung metastasis or pleural effusion. Thoracic radiographs may show pulmonary metastasis or pleural fluid associated with carcinomatosis. Abdominal distention may be the result of a mass-occupying effect or malignant ascites. Abdominal ultrasound may reveal masses with or without free fluid. Scanning of the abdomen also may display bilateral ovary involvement, which can be associated with papillary adenomas and adenocarcinomas. Needle aspirates of ovarian tumors showed an accuracy of 94.7%; however, a histologic sample is warranted for a definitive diagnosis. Aspiration of free abdominal fluid that can accompany ovarian carcinomas may reveal malignant cells on cytologic evaluation. Ovariohysterectomy should follow a complete staging and is the treatment of choice for cases in which the tumors are confined to the ovaries. However, surgery should be reconsidered in the presence of metastatic disease. Chemotherapy can be considered specifically for metastatic disease. Systemic chemotherapy may be attempted, such as carboplatin (Paraplatin) 250 mg IV (for cats) or 300 mg/m2 IV (for dogs) once every 3 weeks; doxorubicin hydrochloride 30 mg/m2 IV (cats and dogs) once every 3 weeks; or mitoxantrone hydrochloride 5.0 to 5.5 mg/m2 IV (for cats) or 5.0 mg/m2 IV (for dogs) once every 3 weeks. The use of NSAIDs may be effective in the case of metastatic carcinoma; however, dosages should be calculated carefully when combined with other chemotherapies (e.g., carboplatin) to minimize the risk toward renal and gastrointestinal toxicities. Draining of pleural and abdominal effusion may provide a temporary relief for patients, but usually the procedure has a short-lived

1025

outcome. Intracavitary chemotherapy with carboplatin or mitoxantrone may yield temporary control in cases of carcinomatosis with abdominal or thoracic effusion. Immense supportive care should take place in the cases of dogs with myelotoxicity, which may include blood transfusions and broad-spectrum antibiotics. The prognosis is excellent for dogs with benign disease and fair for dogs with malignant tumors confined to the ovaries. However, metastatic disease presents a rather guarded prognosis even with chemotherapeutic treatment. Dogs with myelotoxicity may have a long recovery course that can take several weeks to months after the elimination of the myelotoxic insult.

Uterine Tumors Canine Uterine Tumors Uterine tumors are more likely to be diagnosed in older dogs and account for only 0.4% of all tumors. Two main uterine tumors are reported in the dog: the leiomyoma (benign) and leiomyosarcoma (malignant). Although not common in the dog, epithelial origin tumors are the most frequent uterine cancer in cats. Other tumors reported in the cat include müllerian tumor, hemangiosarcoma, fibroma, fibrosarcoma, leiomyoma, and leiomyosarcoma. In the dog, leiomyomas are diagnosed more commonly and usually are an incidental finding. In contrast, leiomyosarcomas are less commonly diagnosed and account for only 10% of uterine tumors. German shepherds may be predisposed to uterine leiomyomas because of a mutation on the BHD gene, which is inherited in an autosomal dominant manner. Along with the formation of uterine leiomyomas, German shepherds with a mutated BHD gene also may show multifocal renal cystadenocarcinomas and nodular dermatofibrosis. To date, no other breeds have been reported to have a predisposition to uterine tumors. Physical examination, CBC, and blood chemistry are part of a basic workup. Abdominal ultrasound and thoracic radiographs are desirable for complete staging,  especially in the case of leiomyosarcoma. Ovariohysterectomy is the treatment of choice for both types of tumors in dogs, with excellent prognosis for leiomyoma and good prognosis for leiomyosarcoma, considering there is no evidence of metastasis at time of diagnosis. Uterine and cervical carcinomas and adenocarcinomas were reported as a rare event in the dog. On one report, three of five dogs were described to have multiple tumors in the uterus and cervix accompanied with advanced metastasis. Common metastatic sites were the kidneys and lungs.

Feline Uterine Tumors Uterine neoplasia is rare in cats, making up 0.29% of all feline neoplasms. Uterine tumors are found more commonly in older, intact female cats between 4 and 16 years of age. Only one case of uterine adenocarcinoma has  been reported in an ovariohysterectomized cat. Types of uterine tumors reported in the cat include leiomyoma,

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SECTION  X  Reproductive Diseases

adenocarcinoma, leiomyosarcoma, adenoma, lymphosarcoma. squamous cell carcinoma, mixed müllerian tumor, mixed mesodermal tumor, paramesonephric carcinosarcoma, endothelioma, hemangioma, fibroadenoma, cystadenoma, and submucosal fibroma. Leiomyoma and adenocarcinoma are the most common in cats. Concurrent mammary adenocarcinoma may occur with uterine adenocarcinoma. The clinical signs of uterine tumors in cats vary but can include abdominal distention, weight loss, anorexia, pain, vaginal bleeding, and infertility. As with the dog, physical examination, CBC, and blood chemistry are part of the basic workup. Abdominal ultrasound and thoracic radiographs are desirable for complete staging, especially in the case of adenocarcinoma. Ovariohysterectomy is the preferred treatment for all uterine tumors in cats provided there is no evidence of metastasis at time of diagnosis. In the cat, carcinomas and adenocarcinomas frequently metastasize and hence carry a guarded prognosis.

References and Suggested Reading Bryan JN et al: A population study of neutering status as a risk factor for canine prostate cancer, Prostate 67:1174, 2007.

CHAPTER 

Fan TM, Lorimier LP: Tumors of the male reproductive system. In Withrow SJ, Vail DM, editors: Withrow and Macewen’s small animal clinical oncology, ed 4, St Louis, 2007, Saunders Elsevier, p 637. Grieco V et al: Canine testicular tumours: a study on 232 dogs, J Comp Pathol 138:86, 2008. Klein MK: Tumors of the female reproductive system. In Withrow SJ, Vail DM, editors: Withrow and Macewen’s small animal clinical oncology, ed 4, St Louis, 2007, Saunders Elsevier, p 610. LeRoy B et al: Protein expression profiling of normal and neoplastic canine prostate and bladder tissue, Vet Comp Oncol 5:119, 2007. Masserdotti C et al: Cytologic features of testicular tumours in dog, J Vet Med A Physiol Pathol Clin Med 52:339, 2005. Patnaik AK, Greenlee PG: Canine ovarian neoplasms: a clinicopathologic study of 71 cases, including histology of 12 granulosa cell tumors, Vet Pathol 24:509, 1987. Taylor KH: Female reproductive tumors. In Henry CJ, Higginbotham ML, editors: Cancer management in small animal practice. St Louis, 2010, Saunders, p 268. Taylor KH: Male reproductive tumors. In Henry CJ, Higginbotham ML, editors: Cancer management in small animal practice, St Louis, 2010, Saunders Elsevier, p 282. Yu CH et al: Comparative immunohistochemical characterization of canine seminomas and Sertoli cell tumors, J Vet Sci 10:1, 2009.

223 

Reproductive Toxicology and Teratogens MICHAEL E. PETERSON, Albany, Oregon

Reproductive Toxicity Sexually intact dogs and cats constitute a small percentage of patients in the average veterinary practice. Clinical focus on reproduction in small companion animals is a relatively new field, limited to breeding primarily purebred dogs and cats. Clients concerned about a reproductive disorder in their animals generally seek reproductive workups when the animals fail to conceive. Early ultrasonographic or hormonal diagnosis of pregnancy (within the first half of gestation) is of greatest benefit when dams fail to produce offspring from a breeding. The ability to distinguish between the failure to conceive and failure to carry a pregnancy to term defines the problem and correctly directs the workup between the dam, the sire, and the breeding management. The differential diagnosis of a reproductive toxicity usually does not result until a specific problem is

identified as the source of the infertility. At this point, the effect of exposure is apparent (e.g., ovulation failure as in the case of methanol exposure), but the underlying cause may never be known. In addition, some toxic effects may not become apparent until the next generation, as is the case of male offspring with decreased testosterone levels and low sperm counts whose dams were exposed to lindane while pregnant or lactating. Specific treatments for reproductive toxicities are limited to a number of conditions. For example, recovery of spermatogenesis after cyclophosphamide exposure may be improved with GnRH treatment. Reproductive problems in kennels or catteries in which multiple animals are housed are presented less commonly but are easier to work up with an epidemiologic approach. Diagnosing reproductive intoxications depends on a thorough history, physical examination, and appropriate laboratory testing. The history should include family

CHAPTER  223  Reproductive Toxicology and Teratogens reproductive history as well as past and current feeding and husbandry practices (Box 223-1). Industrial hygienists may be useful in site visits because these professionals are experienced in assessing sick building syndrome and workplace exposures to toxins. Assessing any exposure requires more than finding a suspect xenobiotic (Box  223-2). The Environmental Protection Agency (EPA)

BOX 223-1  Patient History Questions to Identify a Potential Case of Reproductive Toxicity Family Reproductive History • Have the sire and dam both produced offspring and if so, how long ago? • Did either parent receive any drug therapy in the days to months before conception? Feeding • Have there been any feed changes? • What feed supplements are used and how much? Housing • How are the animals housed? • Are the animals in a rural or urban setting? • What is used for pest control (both rodents and insects)? Cleaning • What disinfectants are used? • Are any fungicides or herbicides used? • Have any new shampoos been used?

BOX 223-2  A Partial List of Potential Reproductive Toxins Acrylonitrile Aniline Arsenic and its compounds Benzene Benzo(a)pyrene Beryllium Boric acid (Boron) Cadmium and its compounds Carbon monoxide Chlordecone (Kepone) Chloroform Chloroprene Dibromochloropropane (DBCP) Dichlorobenzene 1,1-Dichloroethane Dichloromethane Dioxane Epichlorohydrin Ethylene dibromide Ethylene dichloride Ethylene oxide Fluorocarbons Formaldehyde Formamides Lead (organic)

Manganese and its compounds Mercury and its compounds (Inorganic) Methyl n-butyl ketone Methyl chloroform Methyl ethyl ketone (MEK) Nitrogen dioxide Ozone Platinum and its compounds Polybrominated biphenyls (PBB) and polychlorinated biphenyls (PCB) Selenium and its compounds Styrene Tellurium and its compounds Tetrachloroethylene Thallium and its compounds Toluene and toluene-2,4-diisocyanate o-Toluidine Trichloroethylene Vinyl chloride Vinylidene chloride Xylene

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currently is assessing 87,000 compounds for their impact on the endocrine system. Issues relative to the total dose received, route of exposure, and length of exposure to a possible reproductive toxicant or teratogen are important in determining if the cause is sufficient to result in the particular disorder diagnosed. The level, timing, and nature of the exposure are paramount in assessing the possible reproductive risk to either the male or female breeding animal. It is not enough to determine exposure alone. In the case of the bitch or queen, was exposure preconception or postconception?

Target Sites Hypothalamus The hypothalamus produces gonadotropin-releasing hormone (GnRH), which is responsible for initiation of estrus and ovulation. The correct timing, amount, and frequency of GnRH release is controlled by positive and negative feedback responses. The primary action of GnRH is to induce the anterior pituitary gland to synthesize, store, and secrete gonadotropins (follicle-stimulating hormone [FSH] and luteinizing hormone [LH]). The hypothalamus responds to exposure to catecholamines, dopamine, serotonin, GABA, and endorphins by increasing or decreasing release of GnRH. These exposures can have significant negative reproductive effects. Anterior Pituitary The anterior pituitary is responsible for synthesis and release of FSH, LH, prolactin, growth hormone (GH), thyroid-stimulating hormone (TSH), and adrenocorticotropic hormone (ACTH). In the female, the primary function of FSH, LH, and prolactin is to control ovarian cyclicity, follicular recruitment/maturation, ovulation, and luteinization. In the male, the main function of FSH on testicular Sertoli cells is to stimulate spermatogenesis, whereas the primary function of LH on testicular Leydig cells is to stimulate steroidogenesis. Prolactin has synergistic action with LH in males. Generally these processes are controlled with positive or negative feedback from the gonads as well as by stimulation from hypothalamic GnRH. Gonads Ovaries.  The ovary is responsible for follicular development and maintenance of proper hormonal environment for correct growth and maturation of the oocyte. This process relies on endocrine stimulation and feedback. The ovary contains all the primordial eggs at birth, so any toxin exposure potentially affects all of the female’s eggs. Primordial follicle damage may take years to identify and may manifest as a decrease in reproductive life­ span. Environmental toxin exposure during estrus may damage preovulatory follicles, resulting in decreased litter size. Testes.  Testosterone produced by Leydig cells stimulates testicular Sertoli cells to induce spermatogenesis. It also regulates the hypothalamus and anterior pituitary to inhibit release of GnRH, LH, and FSH. Inhibin and estradiol are produced by the Sertoli cells, which also act to inhibit FSH secretion.

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The high rate of division of spermatic germ cells makes them particularly susceptible to toxic xenobiotics and environmental insults. The more primitive the germ cell affected by the toxin, the longer the effects will last on future spermatogenesis.

Diagnosis Stud or tom fertility workup is easier: sperm can be evaluated relative to count, motility, and morphology. Semen quality may be more reflective of xenobiotic exposures occurring during spermatogenesis 80 or more days previously. Any particular defect directs the clinician to specific locations or events in the male reproductive tract, helping to define the source of the problem. For example, abnormal motility usually is indicative of morphologic abnormalities of the midpiece or tail. Monthly serial semen collections over a span of 1 year can be used to monitor progress in returning to normal. Chromosomal testing can be performed. The endocrine axis can be evaluated by hormone-stimulating test. No response or poor response in serum testosterone levels after hormonal stimulation testing is an indicator for testicular biopsy to evaluate the spermatogenic germ cell population.

Treatment There are no general treatments for exposure to reproductive toxins. Patients should be treated with the same techniques employed for other potential toxic exposures. Once a diagnosis of toxicity is made, the patient should be removed from the source of the exposure and decontaminated if warranted. Any specific antidote (e.g., chelator for heavy metal intoxication) should be used. The patient then should be monitored for evidence of recovery and return to normal reproductive health. Serial testing of induced hormonal responses can be used to aid in the monitoring process. The prognosis always is guarded until the patient returns to normal reproductive health and function.

Endocrine Disruption Discussions about endocrine disruption often are clouded with political implications; therefore a precise definition is necessary. Common sources of endocrine disruptors are

pesticides, herbicides, plasticizers, and other industrial and agricultural waste products. In veterinary medicine, the most common source of endocrine disruptors is synthetic rather than natural and is generally from an environmental exposure. Endocrine disruptors may cause hormonal signal interference by disrupting communication between cells, organs, or animals. Endocrine disruptors bind to steroid hormone receptors (estrogenic, androgenic, and progestogenic). These compounds may have either inhibitory or stimulatory actions. Endocrine disruptors are capable of interfering with hormonal signaling, thereby inducing reproductive failure.

Teratogens Teratogenesis is defined as developmental defects induced by toxic exposures between conception and birth. Typically these defects are associated with embryonic or fetal death; morphologic, functional, and/or neurobehavioral anomalies; decreased birth weight; and decreased growth rates. Teratogenic defects occur not only because of exposure to a toxicant but also because this exposure happened at a specific time or developmental stage. Genetic damage may occur, inducing a variety of defects that can result in the loss of the pregnancy or birth of offspring with abnormalities. A particularly high-risk period for canine and feline fetuses is the first two thirds (approximately 40 days) of the pregnancy during organogenesis. Reproductive intoxicants and teratogens induce adverse effects on the physiologic processes, associated behaviors, and anatomic structures involved in normal reproduction and development. These xenobiotics usually act by inducing cellular dysregulation and alterations in normal cellular maintenance. Often the normal defensive mechanisms of the body allow the affected processes to be repaired.

References and Suggested Reading Ellington JE, Wilker CE: Reproductive toxicology of the male companion animal. In Peterson ME, Talcott TA, editors: Small animal toxicology, ed 2, St Louis, 2006, Elsevier, p 500. Evans T: Reproductive toxicity and endocrine disruption. In Gupta RC, editor: Veterinary toxicology—basic and clinical principles, New York, 2007, Academic Press. Wilker CE, Ellington JE: Reproductive toxicology of the female companion animal. In Peterson ME, Talcott TA, editors: Small animal toxicology, ed 2, St Louis, 2006, Elsevier, p 475.

CHAPTER 

224 

Acquired Nonneoplastic Disorders of the Male External Genitalia MICHELLE ANNE KUTZLER, Corvallis, Oregon

T

he subject of disorders of the male external genitalia is too vast to cover thoroughly in this concise chapter. Neoplastic disorders of the male genitalia are discussed in Chapter 222 in this text. Therefore the focus of this chapter is on acquired conditions affecting the male external genitalia. Congenital disorders (e.g., cryptorchidism, persistent frenulum, hypospadias) are not included.

Penis and Prepuce Paraphimosis and Phimosis Paraphimosis is the inability to withdraw completely the penis into the prepuce. Paraphimosis is the opposite of phimosis, which is the inability to extrude the penis from the prepuce. Paraphimosis occurs 14 times more frequently than phimosis. It is seen most commonly in young, intact male dogs (boxers and poodles are overrepresented in case reports), is uncommon in castrated male dogs, and is rare in cats. Although still uncommon, phimosis is reported in the literature more frequently in cats than dogs. The causes of paraphimosis are summarized in Box 224-1. The cranial preputial muscles normally draw the prepuce cranially about 1 cm in front of the tip of the penis. If the preputial musculature cannot retract effectively the penis into the prepuce because of muscular or neurologic deficits, then the prepuce may end at the tip of the penis or be shorter than the penis, allowing the  tip of the penis to remain exposed continuously. About 30% of paraphimosis cases are idiopathic (Papazoglou, 2001). Like paraphimosis, phimosis can have a number of developmental or acquired causes. The acquired causes of phimosis are summarized in Box 224-1. Paraphimosis The diagnosis of paraphimosis typically is made by visual inspection of the penis protruding from the prepuce.  The entire length of the penis and prepuce should be examined to determine if any other urogenital abnormalities exist. Chronic protrusion of the penis causes the penile mucosa to become dry, congested, erythematous, inflamed, edematous, ischemic, excoriated, and painful, which may lead to self-mutilation. Evidence or history of trauma or concurrent stranguria indicates the need for

radiographs of the penis to determine if the os penis has been fractured. The treatment goal is to replace the penis in the prepuce as soon as possible and prevent recurrence of the problem. Penile size (edema and inflammation) can be reduced using cold compression bandages, massage with topical hyperosmotic solutions, and systemic antiinflammatory therapy. Urine production should be monitored closely. If in doubt about urethral patency and/or bladder integrity, the clinician should place a urinary catheter. General anesthesia facilitates replacing the penis into the prepuce by reducing preputial muscle contraction. Before attempting manual replacement of the penis, the clinician should clip the hair around the preputial opening (in the dog) or pluck this hair (in the cat) and apply copious amounts of lubricant to the penile mucosa. If the penis cannot be replaced manually, surgery is required. If a preputiotomy is performed, the tissues should be closed carefully to the original state. Penile and preputial surgical repair requires a thorough understanding of normal anatomy and basic reconstruction principles. Castration often is performed in conjunction with surgical correction of paraphimosis, but castration alone is not successful in correcting paraphimosis. If the penis will not stay within the prepuce after replacement, additional surgery is needed. These techniques include a purse-string suture at the preputial orifice, preputial orifice narrowing, preputial lengthening (preputioplasty), cranial preputial advancement, preputial muscle myorrhaphy, and phallopexy. Phallopexy is the author’s preferred method for penile retention, which is a technique of creating a permanent adhesion between the dorsal surface of the penis and the preputial mucosa (Somerville and Anderson, 2001). If the penis cannot be returned to the prepuce or if it has been severely damaged, a complete or subtotal penile amputation with concurrent urethrostomy should be performed (Pavletic and O’Bell, 2007). The prognosis is good to guarded for resolution of paraphimosis, depending on the severity and duration of clinical signs. The owner must be informed that erection and ejaculation in the animal may be impaired after paraphimosis. Phimosis Common owner complaints for a patient with phimosis is that their pet may lick its prepuce excessively, may 1029

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BOX 224-1  Acquired Causes of Paraphimosis and Phimosis Paraphimosis Ineffective preputial musculature that cannot effectively retract the penis into the prepuce Neurologic deficits in dogs with posterior paresis (e.g., from intervertebral disk disease) Trauma (e.g., from os penis fracture) Constriction of preputial hair around the penis Hypoplastic prepuce resulting from early age castration Too large of preputial orifice Priapism Idiopathic

Phimosis Excessively thick penis from a penile tumor (which may be palpable through the preputial skin) Too small of preputial orifice (stenotic, fibrotic, or scarred) from excessive licking, previous wound, etc. Balanoposthitis Penis that is adhered to the preputial mucosa from trauma, chronic balanoposthitis, etc.

dribble urine from the preputial opening after urination, may suffer from an offensive or hemorrhagic preputial discharge, or may have a fluid-distended prepuce, stranguria, and pollakiuria. The diagnosis is often obvious once attempts are made to extend the penis for examination. In cases in which urine is voided into the preputial cavity, a secondary balanoposthitis may be evident as inflammation (reddening, swelling, and ulceration) of the tissues at the preputial opening. A bacterial culture and sensitivity must be submitted before treating balanoposthitis. Fluid (usually retained urine) may be palpable inside the preputial cavity; this also should be cultured. Other than direct examination, the diagnosis can be made using contrast radiography or ultrasonography. Contrast radiography is accomplished by filling the preputial cavity with saline and then taking radiographs of the penis and prepuce. Ultrasonographic examination largely can achieve the same results as contrast radiography. Ultrasonography allows for the detection of adhesions between the penis and preputial mucosa that were not detected by palpation through the preputial skin (Payan-Carreira and Bessa, 2008). Symptomatic cases of phimosis require surgical correction. Antimicrobial therapy targeted with sensitivity testing should be initiated 48 to 72 hours before surgery. The simplest corrective surgery involves widening an excessively narrow preputial opening. This can be accomplished by making a longitudinal, full-thickness incision through the dorsal aspect of the preputial ring. Making an incision through the ventral aspect of the preputial opening should be avoided because this results in the persistent exposure of the tip of the penis. In cases in which adhesions are present between the penile and preputial mucosa, the preputial cavity must be exposed through a ventral longitudinal incision in the middle of the prepuce. This allows adhesions to be broken by blunt and sharp dissection. Once separated, the penile and preputial mucosal defects should be closed with absorbable suture material. Leaving the defects open may result in

the formation of new adhesions and a recurrence of the problem. The prognosis for most phimosis cases that have been subjected to corrective surgery is good to excellent with appropriate postsurgical care to prevent self-trauma.

Balanoposthitis Balanoposthitis is an inflammation of the penis and the prepuce. In puppies, balanoposthitis can occur as a primary condition, similar to juvenile-onset vaginitis in the bitch. However, in most cases, balanoposthitis occurs as a sequela of another condition. In the cat, a case of balanoposthitis has been reported to occur secondary to chronic prostatitis, cystitis, and pyelonephritis (Pointer and Murray, 2011). Balanoposthitis may result after phallopexy if this procedure is performed too far caudally in the prepuce. Balanoposthitis occurs secondary to phimosis, especially if urine is accumulating within the prepuce, which can lead to urine scalding and eventually infection because of overgrowth of resident bacteria. Balanoposthitis may cause ulceration of the preputial and penile mucosa that over time leads to adhesion formation, creating a vicious cycle until corrected.

Trauma Injury to the prepuce and penis may occur from blunt force trauma (e.g., vehicular accidents); bite wounds; breeding; or self-mutilation (e.g., secondary to separation anxiety) (Ghaffari et al, 2007). The degree of trauma varies widely from superficial lacerations of the prepuce to penile amputation. The need for surgical intervention depends on the existence of or potential for urethral obstruction or uncontrolled hemorrhage. Lacerations of the Prepuce and Penis Although lacerations of the external prepuce are readily apparent, injuries to the penis may be less obvious. Small volumes of blood may drip slowly and continuously from the preputial orifice, or large amounts may be released intermittently as the preputial cavity fills and overflows. Hemorrhage from a lacerated penis may be exacerbated by penile erection, particularly when wounds are deep and penetrate the cavernous spaces. Minor injuries to the penis (e.g., punctures) should be managed as open wounds, treated with topical and systemic antimicrobials, and allowed to heal by second intention. For lacerations demonstrating significant hemorrhage, surgical debridement, ligation of compromised vasculature, and a double layer closure of the tunica albuginea and penile mucosa using absorbable suture must be performed. In cases in which urethral integrity may be compromised, placement of an indwelling urinary catheter for the first several days after repair may reduce self-trauma and deter stricture formation. Traumatic Penile Amputation Traumatic penile truncation or amputation has been reported in the dog. The injury site should be cleaned and débrided, and a new urethral opening fashioned through apposition of the urethral mucosa to the penile mucosa

CHAPTER  224  Acquired Nonneoplastic Disorders of the Male External Genitalia using an indwelling urinary catheter as a guide. In cases in which a large proportion of the penis has been lost or in which the os penis is exposed, partial penile amputation with preputial urethrostomy or complete penile amputation with scrotal or perineal urethrostomy are indicated. Fracture of the Os Penis The function of the os penis is to stiffen the penis to assist in intromission. It has a lower mineral density than long bones (e.g., radius), which may be a mechanism designed to decrease the stiffness and thus reduce the risk of fracture during copulation (Sharir et al, 2011). Males suffering from an acute fracture of the os penis may present with concurrent preputial or penile laceration, penile deviation, hemorrhagic preputial discharge, and/or dysuria. However, chronic os penis fractures tend to present with histories of hematuria and/or dysuria for months to years, possibly after a traumatic event. Urinary obstruction is associated with callus formation resulting from healing fracture. Although clinical signs of hematuria and/or dysuria in the presence of penile deviation, crepitus, and pain on palpation of the penis are suggestive of a fracture of the os penis, radiography confirms the diagnosis. The feline os penis can be visualized on radiographs (especially computed versus analog) and should not be mistaken for a pathologic finding (e.g., urolithiasis or dystrophic mineralization) (Piola et al, 2011). Urinary catheter placement before radiography or retrograde contrast urethrography aids in determining the degree of urethral canal impingement. Fractures of the os penis are most often simple and may be managed conservatively with placement of an indwelling urinary catheter to impart stability during healing. The catheter is positioned proximal to the fracture site and left in place for 5 to 7 days, during which time systemic antimicrobial and antiinflammatory medications are administered. Fractures of the os penis may be reduced openly and stabilized through internal fixation using a titanium or stainless steel finger plate. Progressive dysuria with or without hematuria is the hallmark of urinary outflow compromise secondary to bone callus formation in healing os penis fractures. Surgical callus removal may be accomplished through resection of the lateral wall of the urethral groove of the os penis (partial ostectomy), complete removal of the os penis (total ostectomy), or penile amputation and urethrostomy, depending upon the size and location of the callus. Penile amputation generally is favored by surgeons over total ostectomy of the os penis because removal of the os penis in its entirety is technically challenging, may precipitate profuse hemorrhage, and may injure the urethra, resulting in stricture formation and urinary obstruction. As mentioned previously, penile and preputial surgical repair requires a thorough understanding of normal anatomy and basic reconstruction principles.

Scrotum Lesions of the scrotum and the scrotal contents are not uncommon in intact males. Clinical problems involving the scrotum typically present as the presence of fluid in

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the scrotum, pain and discomfort with or without discoloration of the scrotum, or changes in size, shape, or consistency of the scrotal contents. Scrotal dermatitis may accompany any of the above signs. Pyoderma, dermatophytes, keratinization defects, immune-mediated skin disease, or food allergy can result in scrotal lesions. A common client complaint is that the patient repeatedly is licking his scrotum. Episodic scrotal mutilation has been reported.

Trauma Lacerations of the scrotum may be caused by blunt force trauma (e.g., vehicular accidents) and bite wounds. Most scrotal injuries should be treated as open wounds with the goal to minimize inflammation and resulting pressure necrosis. Systemic antibiotics should be administered in all cases of scrotal trauma.

Hernia When a scrotal hernia occurs, abdominal contents move through the inguinal canal into the vaginal process within the scrotum. Scrotal hernias can cause acute onset of severe pain and swelling. Strangulation of the abdominal contents within the hernia is a surgical emergency. Severe damage to the scrotal wall and testes often requires surgical removal of the affected tissue (e.g., unilateral or bilateral orchidectomy). Ultrasound and nuclear imaging are valuable tools in identification of a scrotal hernia. Ultrasonographic examination of a scrotal hernia reveals a normal-appearing testis amid fluid and portions of omentum. Nuclear imaging is useful in ruling out a concurrent testicular torsion.

Dermatitis Scrotal skin is thinner than most of the skin on the body with few hair follicles and is irritated readily. Temperature extremes, insect bites, allergic eruption, and trauma may result in rapid progression from a minor scrape to a lesion resembling pyotraumatic dermatitis. The affected area rapidly becomes firm, thickened, warm to the touch, and exquisitely painful. Treatment must be aggressive to avoid injury to the testicles. Topical therapy is usually successful and includes corticosteroids, antihistamines, and judicious use of tranquilizers (to prevent self-trauma). The scrotum is also exquisitely sensitive to contact dermatitis from a large range of substances and chemical irritants. The diagnosis of contact dermatitis is made by results of avoidance and/or provocation testing or patch testing. Avoidance testing is against floor detergents, bleach, cement, laundry detergent, and plastic. Once an etiologic agent is identified, treatment is straightforward, consisting of agent avoidance.

Testes Trauma Testicles are not traumatized commonly in dogs and cats because of their mobile nature within the scrotum. 

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Clinical signs of testicular trauma include pain and swelling of the affected testicle with possible corresponding hind limb lameness. In more severe cases scrotal swelling and bruising may be seen. Severe blunt trauma may result in local hemorrhage and rupture of the tunica albuginea, the fibrous covering of the testis. Sperm granulomas are possible sequelae of testicular rupture. Diagnosis of testicular trauma is by careful physical examination. Rupture of the tunica albuginea may be difficult to detect because of local swelling. Severe testicular trauma may require unilateral or bilateral castration. Castration should be delayed until the extent of testicular damage is evaluated completely using ultrasonography.

References and Suggested Reading May LR, Hauptman JG: Phimosis in cats: 10 cases (2000-2008),  J Am Anim Hosp Assoc 45:277, 2009. Ghaffari MS et al: Penile self-mutilation as an unusual sign of a separation-related problem in a crossbreed dog, J Small Anim Pract 48:651, 2007.

Papazoglou LG: Idiopathic chronic penile protrusion in the dog: a report of six cases, J Small Anim Pract 42:510, 2001. Pavletic MM, O’Bell SA: Subtotal penile amputation and  preputial urethrostomy in a dog, J Am Vet Med Assoc 230:375, 2007. Payan-Carreira R, Bessa AC: Application of B-mode ultrasonography in the assessment of the dog penis, Anim Reprod Sci 106:174, 2008. Piola V et al: Radiographic characterization of the os penis in the cat, Vet Radiol Ultrasound 52:270, 2011. Pointer E, Murray L: Chronic prostatitis, cystitis, pyelonephritis, and balanoposthitis in a cat, J Am Anim Hosp Assoc 47:258, 2011. Sharir A et al: The canine baculum: the structure and mechanical properties of an unusual bone, J Struct Biol 175:451, 2011. Somerville ME, Anderson SM: Phallopexy for treatment of  paraphimosis in the dog, J Am Anim Hosp Assoc 37:397, 2001. Trenti D et al: Suspected contact scrotal dermatitis in the dog: a retrospective study of 13 cases (1987 to 2003), J Small Anim Pract 52:295, 2011.

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WEB CHAPTER 

72 

Aspermia/Oligospermia Caused by Retrograde Ejaculation in Dogs STEFANO ROMAGNOLI, Legnaro, Italy GIOVANNI MAJOLINO, Collecchio, Italy

A

retrograde flow of small quantities of spermatozoa into the bladder is a normal event. This may occur during ejaculation or sexual rest and has been documented in many species, including the bull, ram, cat, dog, and human. Because testicular sperm production is a continuous event, sperm leave the testis at a constant rate and move through the caput and corpus epididymis as a result of rhythmic contractions of the smooth-muscle epididymal wall. Although the cauda epididymis is normally quiescent, occasional smooth-muscle contractions at this level promote voiding of spermatozoa and epididymal fluids into the urethra during periods of sexual rest, which explains the common finding of spermatozoa in the urine sediment of humans and domestic male animals. In dogs examination of the urine sediment has been suggested as a way to establish occurrence of spermatogenesis. A retrograde flow of large quantities of spermatozoa into the bladder is an abnormal event, which may occur during ejaculation as a result of a partial or complete absence of bladder neck contraction during semen expulsion. When this happens, the bladder becomes the least resistant pathway for seminal fluids coming from the urethra. The ejaculate is scant or absent, and spermatozoa can be retrieved in large quantities from the bladder. After erection and pelvic thrusting, a normal dog produces an ejaculate composed of 0.5 to 2.5 ml of presperm and sperm-rich fraction and 4 to 45 ml of prostatic fluid fraction, depending on testicular volume. A complete lack of

ejaculate or production of minute quantities of ejaculate may indicate that semen was diverted totally or almost totally from its normal ejaculatory path and flowed into the bladder. Retrograde ejaculation is defined as a retrograde flow of the majority of or all the semen into the bladder, resulting in no semen (aspermia) or minute quantities of semen (oligospermia) ejaculated antegrade. Aspermia in the dog may be caused by sexual immaturity, pain, psychologic factors; drug therapy; diseases of the reproductive tract, such as Brucella canis and Pseudomonas aeruginosa infection; or sympathetic neuropathy either idiopathic or secondary to diabetes mellitus or spinal cord injury. Oligospermia in the dog may be idiopathic or caused by season; unilateral Sertoli cell tumor; prostate disease, orchitis, and epididymitis caused by B. canis, Escherichia coli mycoplasma, and other aerobic organisms; immune-mediated orchitis; or use of drugs such as steroids, chemotherapeutic agents, ketoconazole, and gonadotropin-releasing hormone agonists/ antagonists. An oligospermic ejaculate is characterized by a low number of spermatozoa diluted in a small quantity or in a normal quantity of prostatic fluid. However, presence of a normal quantity of prostatic fluid in the ejaculate generally rules out failure of bladder neck closure. Therefore retrograde ejaculation should be suspected whenever an aspermic or oligospermic (0.1 to 0.3 ml total volume) ejaculate is produced after normal erection and pelvic thrusting.

WEB CHAPTER  72  Aspermia/Oligospermia Caused by Retrograde Ejaculation in Dogs

Normal Antegrade Ejaculation The ejaculatory process consists of three distinct events: seminal emission (the deposition of seminal fluid originating from the vasa deferentia and the prostate into the prostatic urethra), bladder neck closure (caused by contraction of the dorsal segment of the bladder neck), and seminal expulsion or ejaculation (the passage of seminal fluids through the urethra followed by their expulsion through the external urethral orifice). Once erection is achieved, peristaltic contractions in the epididymis and vas deferens caused or increased by oxytocin start to convey spermatozoa and seminal plasma into the prostatic urethra, causing an increase in urethral pressure. Such an increase (helped by contraction of the smooth muscle cell component of prostatic lobules) forces prostatic fluid into the prostatic urethra, which in the adult male dog has a rich elastic layer in the submucosa and is almost devoid of smooth muscle. Further increase in intraurethral pressure occurs when the erectile tissue of the urethra expands, thereby reducing the urethral lumen. When the intraluminal pressure of the vasa deferentia and prostatic urethra reaches maximum, the striated musculature of the pelvic urethra relaxes, which allows expulsion of seminal fluid outside through the pelvic and penile urethra. Seminal emission is powered by recoil of elastic fibers in the prostatic urethra. At this point a striated urethral muscle peristaltic wave cycle sets in motion, which completes the ejaculatory process. The bladder neck plays an important role during seminal emission and seminal expulsion, preventing a retrograde flow of semen into the urinary bladder. During the ejaculatory process the canine bladder neck shows periods of intense contractile activity followed by phases of relaxation. The duration of each relaxation phase decreases gradually until a continuous contractile momentum of the dorsal segment of the bladder neck (the ventral segment of the canine bladder neck is involved primarily with continence and voiding) occurs toward the end of the ejaculatory process. When the dorsal segment of the bladder neck is relaxed (during sexual rest and in between urethral muscle peristaltic contractions early in the ejaculatory process), semen may flow back into the urinary bladder following the least resistant pathway. If the bladder neck contracts at ejaculation, the urethra becomes the least resistant pathway through which semen is propelled outside. The ejaculatory process is coordinated by sympathetic and parasympathetic neural activity. The brain facilitates or inhibits sexual function by mediating and integrating reproductive motivation and reproductive behavior with other types of social behavior, whereas the spinal cord integrates visceral and somatic stimuli, evoking the reflexes of erection and ejaculation. Spinal reflexes occurring during the ejaculatory process in the dog are listed in Web Table 72-1.

Treatment of Retrograde Ejaculation The fact that the canine vas deferens, epididymis, prostate, and bladder neck are primarily under sympathetic nervous system control gives sympathomimetic agents a

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WEB TABLE 72-1  Spinal Reflexes Occurring in the Dog During the Ejaculatory Process Reflex Type

Visible Response

Type 1

A very intense ejaculatory reflex occurring soon after intromission and lasting 15 to 30 seconds characterized by pelvic thrusting, alternate stepping of the hind legs, rapid engorgement of the erectile penile tissue, and expulsion of the sperm-rich fraction of semen

Type 2

A less intense ejaculatory reflex lasting 10 to 45 minutes characterized by rhythmic contractions of the bulbospongiosus muscle and ejaculation of prostatic fluid accompanied by rhythmic contractions of the anal sphincter

Type 3

Pelvic thrusting provoked by manual stimulation of the glans penis, often accompanied by partial erection without ejaculation

Type 4

Lordosis and strong extension of the hind legs when the distal end of the penis is touched

From Hart BL: Vet Clin North Am Small Anim Pract 4:557, 1974.

pivotal role in the pharmacologic treatment of retrograde ejaculation. After administration of sympathomimetic drugs, the canine epididymal and prostatic tissue displays phases of rhythmic contractions. Contraction and relaxation of the vas deferens are mediated by α- and β-adrenoceptors, respectively. The use of an α-adrenoceptor agonist together with a β-adrenoceptor antagonist has been proposed to increase spermatozoal output in the dog. Administration of xylazine (an α2-adrenoceptor agonist) in the dog increases contractility of the vas deferens and epididymis and decreases urethral pressure, inducing nonejaculatory displacement of canine spermatozoa in the bladder. Selective α2-adrenoceptor antagonists such as yohimbine or rauwolscine have a stimulatory effect on ejaculation in dogs when administered at low doses (both drugs have been used at 0.01 to 0.1 mg/kg, IP). When used at this dose in the dog, yohimbine can prevent a decrease in the amount of ejaculate produced demonstrated by repeated semen collections (up to eight times a day), whereas a high dose (1 mg/kg) decreases the amount of ejaculate produced. The canine bladder neck has a rich cholinergic and adrenergic innervation. Cholinergic stimulation produces gradual contraction of the neck, as well as of the whole bladder (occurring during micturition), whereas adrenergic stimulation occurring at ejaculation causes contraction of the neck and relaxation of the body of the bladder. Administration of the α-adrenoceptor antagonist phentolamine 5 to 10 minutes before semen collection may increase the retrograde flow of canine spermatozoa into the bladder up to 2.5% of the total ejaculate. Administration of the β-receptor agonist clenbuterol before semen collection increased the number of spermatozoa found in the bladder of two of three dogs, whereas administration

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of the α-receptor agonist midodrine was able to counteract the effect of clenbuterol. Sympathomimetic agents such as ephedrine, pseudoephedrine hydrochloride, phenylpropanolamine, and imipramine generally are used (alone or in combination) to treat human retrograde ejaculation. Treatment protocols using sympathomimetic drugs reported in the dog include phenylpropanolamine (3 mg/kg q12h PO) and pseudoephedrine hydrochloride (3 to 5 mg/kg q8h PO or given 3 hours followed by 1 hour before breeding/semen collection). Success of treatment depends on cause. Retrograde ejaculation can be the result of anatomic causes (iatrogenic defects after bladder or prostate surgery), neuropathic causes (diabetes; prolonged treatment with ganglionic or adrenergic blocking drugs such as methyldopa, phenoxybenzamine, guanethidine, reserpine, and phentolamine; or following retroperitoneal lymph node dissection for testicular cancer), or psychologic factors (pain, fear of new environment, uneasiness when a manual semen collection is attempted for the first time, or lack of interest in the bitch). Treatment of retrograde ejaculation from anatomic causes generally is unsuccessful. Humans with lack of antegrade ejaculation caused by diabetes or retroperitoneal lymph node dissection for testicular cancer are treated successfully with sympathomimetic drugs, whereas in the case of chronic therapy with ganglionic or adrenergic-blocking drugs, cessation of treatment reestablishes an antegrade ejaculation. In men the use of drugs influencing libido such as human chorionic gonadotropin is reported as effective in the case of retrograde ejaculation caused by psychologic factors.

Clinical Examples of Retrograde Ejaculation In the dog, retrograde ejaculation has been observed by researchers while doing experiments on male reproductive physiology. In addition, spontaneous (non–druginduced) retrograde ejaculation causing aspermia has been reported in a 4-year-old German shepherd (Meinecke, 1976) and in a 7-year-old English cocker spaniel (Romagnoli, 1992), and oligospermia has been reported in a 19-month-old Labrador retriever (Root, Johnston, and Olson, 1994). The German shepherd had never fathered a litter of pups before referral, and its libido was normal; it showed a complete lack of ejaculate, and a high number of 30% progressively motile sperm were found in the bladder after an attempt at semen collection. Pharmacologic treatment was not attempted in this dog (Meinecke, 1976). The English cocker spaniel previously had fathered two litters of six and five puppies and had been treated with megestrol acetate because of behavioral problems for about 8 months, during which time it progressively lost its libido. Several months after cessation of therapy the dog was examined for breeding soundness because of infertility. The blood glucose and libido were normal. However, semen collection performed at various times over a 2-month period consistently failed to produce any ejaculate, whereas large numbers of 50% to 70% motile spermatozoa were retrieved in voided urine samples (Web

Web Figure 72-1  Smear of the sediment of a voided urine sample of a 7-year-old English cocker spaniel dog after an aspermic ejaculation. A cross-section hyaline cylinder can be observed in the upper half of the picture (Harris-Schorr, 400×).

Figure 72-1). Pseudoephedrine (5 mg/kg q8h PO) failed to induce an antegrade ejaculation, but a normal antegrade ejaculation was obtained when pseudoephedrine was administered at a dose of 3 mg/kg given 3 and 2 hours before semen collection. During this time the dog produced a litter of three normal pups using semen collected with a pseudoephedrine pretreatment, and several months later it regained its capability to ejaculate antegradely without pseudoephedrine pretreatment (Romagnoli, 1992). A Labrador retriever had bred two bitches, neither of which had produced a litter. On semen collection with an estrous teaser bitch it ejaculated 1 ml of semen containing 1 million spermatozoa with 50% progressive motility. Hypothyroidism was diagnosed based on decreased resting serum levels of triiodothyronine and thyroxine. Pseudoephedrine (4 mg/kg PO) given to the dog 1 and 3 hours before semen collection resulted in the production of 1.5 ml of semen with 250 million spermatozoa with 60% to 70% progressive motility. The hypothyroidism had been resolved 1 month later, but the dog would ejaculate normally only after a pseudoephedrine treatment. This dosage allowed collection of a goodquality semen sample with which a litter of five puppies was produced. A cause-and-effect relationship between hypothyroidism and retrograde ejaculation could not be established in this case (Root, Johnston, and Olson, 1994). These authors have observed retrograde ejaculation causing oligospermia in one English setter and aspermia in one German shepherd (data not published). An 8-yearold previously fertile English setter was referred with a history of infertility observed over the last 2 years. On the first two semen collections with estrous teaser bitches the dog showed good libido, displaying pelvic thrusting, alternate stepping on the hind limbs, and anal contractions and lordosis but produced no semen on the first collection and 0.1 ml of semen with 70% progressively motile spermatozoa on the second. A 15-ml voided urine sample collected at the second semen evaluation showed a total count of 45 million 70% progressively motile

WEB CHAPTER  72  Aspermia/Oligospermia Caused by Retrograde Ejaculation in Dogs spermatozoa. The dog was treated with pseudoephedrine (5 mg/kg PO) 4, 1, and 1 2 hour before semen collection and produced on two different occasions 1 week apart 0.3 and 1 ml of normal semen with 70% progressively motile spermatozoa, respectively. The owner was instructed to administer pseudoephedrine at home using this dosage before natural breeding, and the dog produced a normal litter. A 4-year-old German shepherd was referred to the authors for never producing a litter of puppies. The referring veterinarian had attempted semen collection on two different occasions, always in the presence of estrous teaser bitches: on both instances the dog showed normal libido, pelvic thrusting, alternate stepping of the hind limb, and anal contractions but produced no ejaculate; a voided urine sample collected at the second semen evaluation performed by the referring veterinarian showed a low concentration of dead spermatozoa. When semen was collected subsequently in the presence of an estrous bitch, the dog again showed a normal libido and produced no semen; a voided urine sample showed large numbers of live and progressively normal spermatozoa. The owner was instructed to administer pseudoephedrine before a natural breeding at home, but the dog died of trauma shortly thereafter.

Clinical Considerations When performing a breeding soundness evaluation in the dog, clinicians must observe carefully behavior during semen collection or natural breeding. A normal dog in a comfortable environment consistently displays types 1 and 2 spinal reflexes, indicative of ejaculation, such as pelvic thrusting and alternate stepping on the hind legs, followed by rhythmic anal contractions. Pelvic thrusting generally is displayed during natural breeding and semen collection, whereas alternate stepping on the hind legs often is observed only during natural breeding. If rhythmic contractions of the anal sphincter (indicating contractions of bulbospongiosus muscle causing ejaculation of prostatic fluid) are not preceded by pelvic thrusting, ejaculation may be incomplete (only prostatic fluid) or absent. If types 1 and 2 spinal reflexes are displayed and no semen is collected or no spermatozoa are observed in a vaginal smear after breeding, evaluation of a urine sample (voided or cystocentesis) looking for large numbers of live, normal spermatozoa is warranted. Although considered a rare event, retrograde ejaculation in the dog could be more frequent than expected. Inadequate penile manipulation during canine semen collection may increase the percentage of retrograde flowing spermatozoa from 0 to 60%. Also, lack of interest in the bitch or fear of a new environment could be responsible for lack of or insufficient spinal reflexes, leading to insufficient activation of the sympathetic system, thereby causing retrograde ejaculation. The role of diabetes mellitus, urinary/prostatic surgery, or

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retroperitoneal lymph node dissection in the pathogenesis of canine retrograde ejaculation has not been investigated. When diagnosing oligospermia (with minute quantities of semen) or aspermia, clinicians should rule out retrograde ejaculation by collecting a urine sample (voided or cystocentesis) and looking for large numbers of live, normal spermatozoa. Human spermatozoa ejaculated retrogradely into the bladder can be retrieved and used for artificial insemination provided that the urinary environment is alkaline (pH >7.0) and with a low osmolality (200 to 300 mOsm/ kg of water). This is achieved by having the man drink large amounts of water and take sodium bicarbonate on the day before and the day of semen collection. Voided or catheterized urine is centrifuged at 300 to 500 g, the sperm pellet resuspended in a semen extender, and inseminated. Although such a procedure has been attempted in the dog without success (Post et al, 1992), more clinical research is needed on this topic. Sympathomimetic agents deserve more attention from clinicians because of their specific action on sperm production and output in the dog. Yohimbine appears able to increase sperm output in the dog, a claim that, if substantiated by clinical reports, could open new avenues for the treatment of oligospermic dogs. In the treatment of human retrograde ejaculation the use of some of the sympathomimetic agents is characterized by development of tachyphylaxis (caused by depletion of norepinephrine stores at the terminal nerve endings), a feature that is less common when using the α-sympathomimetic drug phenylpropanolamine. The occurrence of tachyphylaxis after treatment with sympathomimetic drugs has not been studied extensively in small animals; however, tachyphylaxis resulting from ephedrine and phenylpropanolamine is reported to occur in the cat and dog, respectively. Adverse effects of sympathomimetics on heart rhythm and blood pressure should be appreciated.

References and Suggested Reading Beaufays F, Onclin K, Verstegen J: Retrograde ejaculation occurs in the dog, but can be prevented by pre-treatment with phenylpropanolamine: a urodynamic study, Theriogenology 70:1057, 2008. Hart BL: Physiology of sexual function, Vet Clin North Am 4:557, 1974. Meinecke B: Retrograde ejaculation in the dog, Zuchthygiene 11(3):122, 1976. Noguchi Y et al: In vivo study on the effects of alpha1adrenoceptor antagonists on intraurethral pressure in the prostatic urethra and intraluminal pressure in the vas deferens in male dogs, Eur J Pharmacol 580:256, 2008. Post K et al: Retrograde ejaculation in a Shetland sheepdog, Can Vet J 33:53, 1992. Romagnoli S: Retrograde ejaculation in the dog. In Proc XVII Congress World Small Anim Vet Assoc (Rome) 1435, 1992. Root MV, Johnston SD, Olson PN: Concurrent retrograde ejaculation and hypothyroidism in a dog: case report, Theriogenology 41:593, 1994.

WEB CHAPTER 

73 

Priapism in Dogs JAMES A. LAVELY, Rohnert Park, California

P

riapism is a persistent penile erection lasting longer than 4 hours without sexual stimulation. Priapism easily can be confused with paraphimosis. Paraphimosis occurs when the nonerect penis cannot be ensheathed in the prepuce and can result secondarily in edema. However, the penis is not erect as with priapism. Paraphimosis can result from inadequate length of the prepuce, weakened preputial muscles, too small of a preputial orifice, or trauma (Web Figures 73-1 and 73-2). Priapism is reported infrequently in dogs and cats. Idiopathic, neurologic, and traumatic injuries have been reported causes in dogs and cats. Priapism in humans is categorized as either ischemic (venoocclusive, low flow) or nonischemic (arterial, high flow). Nonischemic priapism is caused by increased arterial inflow through the corpus cavernosa. It often is caused by trauma but also can result from neurologic conditions and vasoactive drugs. Ischemic priapism is caused by venous congestion to the penis and enhanced blood viscosity. In humans, ischemic priapism often is associated with sickle cell disease, hematologic dyscrasias, neoplasia, vasoactive drugs, parenteral nutrition, heparin therapy, hemodialysis, anesthesia, and neurologic conditions such as spinal cord injury. Stuttering priapism is a subset of ischemic priapism. It is a pattern of recurrent events with intermittent periods of tumescence. Stuttering priapism typically lasts less than 3 hours. Clinically ischemic priapism often is painful, whereas nonischemic priapism is not.

Physiology of Erection The canine erection is mediated through the pelvic nerve, a parasympathetic nerve, arising primarily from the first and second sacral nerves (S1-S2). Stimulation of the pelvic nerve dilates penile arteries, partially inhibits venous drainage, and increases penile blood pressure, causing an erection. Initially blood flow to cavernous bodies increases, as the muscles in the helicine branches of the deep arteries and the arteries of the urethral bulb relax. The corpus spongiosum receives a larger share of blood from the artery of the bulb of the penis. Arterial blood then is shunted to the corpus cavernosum from the artery of the bulb (Web Figure 73-3). The deep vein of the penis becomes unable to drain the increased arterial blood flow into the cavernous spaces from the helicine arteries. Internal pressure against the tunica albuginea results in the corpus cavernosum becoming stiff. The intrinsic veins subsequently become compressed. A second stage occurs after intromission when partial venous occlusion is a factor in the erection of the glans penis. Contraction of e354

the female’s constrictor vestibulae muscles stimulates reflexive contraction of the male’s ischiourethralis muscle. Arterial flow increases and is directed into the dorsal artery of the penis. The pudendal nerve, arising from S1-S3, also is involved by stimulating contraction of the extrinsic penile muscles. Ischiourethralis muscle contraction decreases venous blood flow through the dorsal veins. Venous blood is shunted from the corpus cavernosum toward the bulbus glandis. The relatively thick muscular-walled arteries prevent arterial flow from being occluded by the extrinsic muscle contraction. Venous connections with the corpus spongiosum and valves in the deep veins of the glans prevent blood from exiting the bulbus except through the currently inefficient dorsal penile veins. Relaxation of the intersinusoidal trabecular smooth muscles facilitates pars longa glandis and bulbus glandis engorgement, increasing penile stiffness. The hypogastric nerve, a sympathetic nerve that originates from L1-L4, also may have a regulatory role in the canine erection. Hypogastric nerve stimulation in the dog causes increased blood flow into the cavernous space secondary to vasodilation of the inflow blood vessels. However, an inhibitory effect also may occur because of relaxation of the outflow blood vessels, increasing cavernous blood outflow. The hypogastric nerve is responsible for prostatic secretion and ejaculation. Sympathetic chain fiber stimulation inhibits erection via increasing arterial resistance, decreasing venous resistance and decreasing corpus cavernosal pressure. The sympathetic inhibition of the erectile process is regulated by the α1-adrenergic system.

Pathophysiology Neurologic disease has been reported as a cause of ischemic and nonischemic priapism in humans. However, it is a rare cause. In a series of 105 people with priapism, no cases were caused by neurologic disease. Priapism was reported secondary to rabies infection in a person. In dogs neurologic diseases associated with priapism include spinal injury, canine distemper virus, acute disk herniation after T12-T13 hemilaminectomy and were seen in a dog with a meningomyelocele in the cauda equina and syringohydromyelia in the lumbar spine. A dysregulatory hypothesis for the pathophysiology of priapism has been postulated. Dyssynergic neurostimulations of inflow and outflow penile blood vessels cause prolonged spasms of vascular or smooth muscle. This dysregulation may occur at the level of the penis or at other regulatory levels of penile erection, including the peripheral or central nervous system.

WEB CHAPTER  73  Priapism in Dogs

Web Figure 73-1  Priapism in a 4 12-year-old Savannah cat.

Web Figure 73-2  Paraphimosis in an 11-month-old Cane Corso mastiff. The penis is swollen markedly and cannot be ensheathed in the prepuce.

Deep vein and artery of the penis

Vein and artery of the bulbus penis Dorsal artery and vein of the penis Deep vein of the glans

Corpus spongiosum

Corpus cavernosum

Bulbus glandis

Web Figure 73-3  Anatomy and vascular supply of the canine penis. (Illustration courtesy Alex Frederick.)

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Perioperative medications or anesthesia also can result in priapism; phenothiazine drugs and α-adrenergic antagonists have been reported to cause priapism in humans and in horses. It occurs in horses because the retractor penis muscle is under control of solely α-adrenergic fibers. In dogs, intracorporeal injection of chlorpromazine was shown to cause consistent erections, but intravenous injections of chlorpromazine did not cause or facilitate erection. Nonischemic priapism often is caused by trauma in humans. It results from fistula formation within cavernous tissue. Blood bypasses the typically high resistance helicine arteriolar bed. No ultrastructural tissue damage or detrimental homeostatic changes occur even after years of nonischemic priapism in humans. Therefore nonischemic priapism initially is treated conservatively, and if the condition persists arterial embolization is often successful. Ischemic priapism is considered an emergency in humans. Hypoxia, glucopenia, and acidosis impair corpus cavernosal smooth muscle tone and contractile responses to physiologic and pharmacologic stimuli within 4 hours after the onset of priapism. The acidotic and hypoxic conditions decrease α-receptor affinity. Trabecular interstitial edema develops 12 hours after onset. Thrombi form in sinusoidal spaces and fibrosis and necrosis of smooth muscle cells occur within 24 hours after onset in humans. Endothelial defects, loss of plasma membrane integrity, and potential development of fibrin-like deposits have been identified in dogs. These changes occur quickly and suggest that early therapeutic intervention for ischemic priapism is warranted in the dog. Ischemic priapism has been reported in cats. A traumatic cause is common with priapism often developing during mating or after castration. Ischemic priapism occurred in a cat with FIP and an idiopathic cause has been suspected in other cats. Thus far, Siamese cats have been overrepresented. Penile damage and infection have led to most cats being treated via penile amputation and perineal urethrostomy. Successful surgical treatment has been reported in a cat via small incisions made bilaterally in the tunica albuginea of the corpora cavernosa penis and in some parts of the corpora cavernosa itself. Heparinized saline was used to irrigate the corpora cavernosa. Skin sutures were placed, but the tunica albuginea was not sutured. Ischemic priapism also has been reported secondary to trauma in the dog. Successful surgical treatment was achieved via bilateral incisions to the longa glandis and the tunica albuginea. Blood then was pressed out. Irrigation with heparinized saline was done until red blood flow returned and the tunica albuginea was sutured. History and clinical signs may help differentiate between nonischemic and ischemic priapism. Nonischemic priapism in humans typically is not painful and the entire penis is partially rigid, whereas ischemic priapism often is painful, with a rigid penile shaft and a soft glans. Color-flow Doppler ultrasonography can detect high systolic flow into the cavernosal artery or can help evaluate for an arterial to cavernosum fistula. Ultrasonography also may detect anatomic abnormalities. Ultrasonography is done in the perineum and then

SECTION  X  Reproductive Diseases

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B

A

Web Figure 73-4  A, Transverse ultrasound image of a dog with priapism. Note the engorged vessels in the corpus cavernosum (arrows). B, Transverse ultrasound image of a normal nonerect canine penis. (Image courtesy Tomas Baker.) the entire penile shaft because perineal portions of the corpora cavernosa may be abnormal in trauma. Ultrasound can help rule out causes such as emboli, neoplasia, and other obstructive causes (Web Figure 73-4). Retrograde urethrography also can be used to evaluate for urethral obstruction that may be related to the priapism. Aspiration of blood from the corpus cavernosum may be diagnostic and therapeutic. Cavernous blood gas evaluation may differentiate nonischemic and ischemic priapism. Nonischemic priapism typically results in a pH of 7.4, a PO2 of more than 90 mm Hg, and a PCO2 of less than 40 mm Hg, whereas ischemic priapism typically results in a pH of less than 7.25, a PO2 of less than 30 mm Hg, and a PCO2 of more than 60 mm Hg.

Treatment Various medical therapies have been used to treat priapism. However, few controlled data exist regarding the use of systemic drugs in humans, dogs, or cats. Pseudoephedrine, an α-adrenergic drug, appeared to resolve nonischemic priapism in one dog and gabapentin successfully resolved nonischemic priapism in a cat. The cat first failed ephedrine and then failed terbutaline therapies. Studies in humans suggested a possible beneficial trend with terbutaline usage but were not statistically significant. Systemic therapies are not recommended in treatment of ischemic priapism in humans because of the limited data and a consensus panel review. The management goal in stuttering priapism is to prevent future episodes. Therefore systemic therapies such as gabapentin, terbutaline, baclofen, estrogen, gonadotropin-releasing hormones, anti-androgens, hydroxyurea, and PDE-5 inhibitors have been used for prevention but are not recommended for individual episodes of stuttering priapism. Human therapeutic guidelines have been established. Initial aspiration is done to obtain blood gas analysis and to relieve pain. If ischemic priapism is present, then irrigation may be done after aspiration. Aspiration with or

without irrigation is about 30% successful in humans. Either initially or if initial aspiration with or without irrigation has failed an intracavernous injection of an α-adrenergic sympathomimetic agent is recommended in ischemic priapism. Phenylephrine is the preferred drug because of its limited cardiovascular risks compared with other sympathomimetic drugs with greater β- adrenergic activity. The phenylephrine is diluted with saline to 100 to 500 µg/ml and 100 to 200 µg every 5 to 10 minutes is injected until detumescence is achieved with a maximal dose of 1000 µg in adults. Children and patients with higher risk profiles are given smaller doses. Resolution rates with aspiration and use of sympathomimetic agents range from 43% to 81%. Patients are monitored closely for cardiovascular adverse effects during and after sympathomimetic injections. It is recommended to treat concurrently any underlying cause for priapism. Surgical shunting is recommended in humans if intracavernous therapy is not successful within 48 to 72 hours. Evaluation of treatment options in dogs and cats is difficult because of infrequent canine and feline reports of priapism. Given the similar histopathology and pathophysiology a similar algorithm as that in humans is likely reasonable for dogs and cats. Distinguishing nonischemic priapism versus ischemic and identifying and treating the underlying cause are important. If determined to be ischemic, then aspiration under sedation or anesthesia with or without irrigation is warranted. Intracavernosal injections of phenylephrine should be considered. However, this may carry some risk because appropriate dosages have not been determined in dogs and cats. Starting with low dosages (1 to 3 µg/kg) and cardiovascular monitoring is therefore important. Dogs and cats may have a longer duration of priapism before initial presentation compared with humans. Prolonged exposure of the penis makes lubrication important to mitigate tissue damage secondary to exposure and excoriation. An Elizabethan collar may be needed to prevent self-mutilation and further damage. If intracavernosal drainage and injections are unsuccessful or significant tissue damage is present, then

penile amputation and perineal urethrostomy may become necessary. The smaller size of dogs and cats compared with humans and the relative lack of experience with embolization procedures make treatment of nonischemic priapism more difficult. Therefore conservative treatment, protecting penile tissue integrity with lubrication, and preventing excoriation are recommended. If detumescence is not achieved and a fistula can be identified, then embolization, cauterization, or ligation may be a consideration. The benefit of systemic therapy for priapism is anecdotal at this time. Systemic therapy could be considered if the priapism is not considered an emergency, and if intracavernous injections or if surgical treatment are declined.

References and Suggested Reading Burnett AL, Bivalacqua TJ: Priapism: current principles and practice, Urol Clin North Am 34:631, 2007. Evans HE, Christensen GC: The urogenital system. In Evans HE, editor: Miller’s anatomy of the dog, vol 1, ed 3, Philadelphia, 1993, Saunders, p 494. Lavely JA: Priapism in dogs, Top Companion Anim Med 24:49, 2009. Montague DK et al: American urological association guideline to the management of priapism, J Urol 170:1318, 2003. Orima H et al: Surgical treatment of priapism observed in a dog and a cat, Nippon Juigaku Zasshi 51:1227, 1989. Winter CC, McDowell G: Experience with 105 patients with priapism: update review of all aspects, J Urol 140:980, 1988. Yuan J et al: Insights of priapism mechanism and rationale treatment for recurrent priapism, Asian J Androl 1:88, 2008.

SECTION XI Neurologic Diseases Chapter Chapter Chapter Chapter Chapter

225: 226: 227: 228: 229:

Chapter 230: Chapter 231: Chapter 232: Chapter Chapter Chapter Chapter

233: 234: 235: 236:

Chapter 237: Chapter 238: Chapter 239: Chapter 240: Chapter 241:

Congenital Hydrocephalus Intracranial Arachnoid Cysts in Dogs Treatment of Intracranial Tumors Metabolic Brain Disorders New Maintenance Anticonvulsant Therapies for Dogs and Cats Treatment of Cluster Seizures and Status Epilepticus Treatment of Noninfectious Inflammatory Diseases of the Central Nervous System Peripheral and Central Vestibular Disorders in Dogs and Cats Canine Intervertebral Disk Herniation Canine Degenerative Myelopathy Diagnosis and Treatment of Atlantoaxial Subluxation Diagnosis and Treatment of Cervical Spondylomyelopathy Craniocervical Junction Abnormalities in Dogs Diagnosis and Treatment of Degenerative Lumbosacral Stenosis Treatment of Autoimmune Myasthenia Gravis Treatment of Myopathies and Neuropathies Vascular Disease of the Central Nervous System

1034 1038 1039 1047 1054 1058 1063 1066 1070 1075 1082 1090 1098 1105 1109 1113 1119

The following web chapters can be found on the companion website at www.currentveterinarytherapy.com Web Chapter 74:

Physical Therapy and Rehabilitation of Neurologic Patients

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CHAPTER 

225 

Congenital Hydrocephalus WILLIAM B. THOMAS, Knoxville, Tennessee

Causes Hydrocephalus is active distention of the ventricular system of the brain caused by obstruction of the flow of cerebrospinal fluid (CSF) from its point of production to its point of absorption (Rekate, 2009). CSF is produced at a constant rate by the choroid plexuses of the lateral, third, and fourth ventricles; the ependymal lining of the ventricular system; and blood vessels in the subarachnoid space. The CSF circulates through the ventricular system into the subarachnoid space, where it is absorbed by arachnoid villi. Obstruction can be caused by developmental abnormalities or acquired lesions such as neoplasia or inflammatory lesions. A number of conditions such as infarction and necrosis can result in decreased volume of brain parenchyma that leaves a vacant space filled passively with CSF. Although this situation previously was referred to as hydrocephalus ex vacuo, it does not cause active distention of the ventricles and therefore is not classified as hydrocephalus. Early hydrocephalus initially damages the ependymal lining of the ventricles. This allows water and larger  molecules to leak into the adjacent white matter, causing periventricular edema. Further enlargement of the ventricles compresses the white matter, which leads to  demyelination and axonal degeneration. The septum pellucidum separating the lateral ventricles can become fenestrated or completely destroyed, so that one single, large ventricle is created (Figure 225-1). In some cases, the cerebral cortex is preserved. In more severe cases, the cortex becomes thin, with neuronal vacuolation and loss of neurons. This affects the prognosis after surgical shunting. If the cortex is preserved, shunting results in reexpansion of the white matter and regeneration of remaining axons. However, if the cortex is damaged, the neuronal damage persists even after shunting. With severe obstruction to CSF flow, the volume of CSF can increase so fast that it causes an increase in intracranial pressure, which leads to further brain damage and impairs blood flow to the brain.

Clinical Features Based on the age of onset, hydrocephalus can be classified broadly as pediatric or acquired. Pediatric hydrocephalus is caused by developmental abnormalities, and clinical signs often are noticed by several months of age. Toy and brachycephalic dogs are at increased risk, including the Maltese terrier, Yorkshire terrier, English bulldog, Chihuahua, Lhasa apso, Pomeranian, toy poodle, cairn terrier, Boston terrier, pug, and Pekingese. The most commonly 1034

identified cause in these breeds is stenosis of the mesencephalic aqueduct associated with fusion of the rostral colliculi. In many cases, however, an obvious site of obstruction is not apparent. These cases may be due to obstruction at the level of the subarachnoid space or arachnoid villi, which is difficult to detect. Another  possibility is the occurrence of intraventricular obstruction during a critical stage of development with later  resolution of the obstructive lesion so that only the ventricular enlargement remains. Pediatric hydrocephalus also may be associated with other malformations such  as meningomyelocele, Chiari’s malformation, DandyWalker syndrome, and cerebellar hypoplasia. Many toy and brachycephalic dogs have enlarged ventricles with no apparent neurologic dysfunction. Hydrocephalus is seen sporadically in kittens, and although a genetic basis has been suggested in the Siamese, this has not been confirmed with genetic studies. Clinical signs of pediatric hydrocephalus include an enlarged, dome-shaped head with persistent fontanelles and open cranial sutures. However, not all patients with a persistent fontanelle have hydrocephalus, and not all patients with pediatric hydrocephalus have a persistent fontanelle. Enlargement of the calvaria can be assessed subjectively by noticing whether the most lateral aspect of the parietal bone extends laterally beyond the level of the zygomatic arch. There may be ventral or ventrolateral strabismus due to either malformation of the orbit or brainstem dysfunction. Affected patients often are unthrifty and smaller than normal. Common neurologic deficits include abnormal behavior and cognitive dysfunction, such as inability to become house trained. Visual deficits include unilateral or bilateral blindness with normal pupillary function. (One should remember that the menace response may not develop until at least 4 weeks of age in normal puppies and kittens.) Ataxia, seizures, circling, and vestibular dysfunction also are possible. The clinical course is variable and difficult to predict. Neurologic deficits can progress over time, remain static, or even improve after 1 to 2 years of age. The condition of affected patients often is fragile and can worsen later in life coincident with other diseases. Patients with very large lateral ventricles and a thin cerebral cortex are at risk of intracranial hemorrhage from relatively trivial head trauma that results in tearing of bridging veins. This can result in chronic subclinical hematomas or sudden neurologic deterioration due to intracranial bleeding. Acquired hydrocephalus can develop at any age and can be caused by neoplasia, head trauma, and meningoencephalitis. Neurologic deficits are similar to those in

CHAPTER  225  Congenital Hydrocephalus

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Figure 225-2  Transverse ultrasound performed through the

fontanelle. The lateral ventricles are evident as a single large anechoic structure.

Figure 225-1  MRI of a golden retriever puppy with pediatric

hydrocephalus. The septum pellucidum separating the lateral ventricles is completely destroyed, giving rise to one single large ventricle.

young animals, but if hydrocephalus develops after the cranial sutures have closed, malformation of the skull does not develop. Clinical signs also may reflect the underlying cause of the hydrocephalus.

Diagnosis Diagnosis is based on the clinical features and brain imaging to assess ventricular size and identify any specific causes. Ventricular size usually is assessed subjectively by noting the progressively greater proportion of the intracranial volume occupied by the lateral, third, or fourth ventricles. However, there is poor correlation between clinical signs and ventricular size. Also, symmetric or asymmetric enlargement of the lateral ventricles is relatively common in normal animals. Therefore diagnosis of hydrocephalus is based on clinical features, not just ventricular size. In pediatric patients with persistent fontanelles, ultrasonography allows easy detection of obviously enlarged ventricles. Normal-sized ventricles appear as paired, slitlike anechoic structures just ventral to the longitudinal fissure on either side of the midline. Enlarged ventricles are seen easily as paired anechoic regions. With marked ventricular enlargement, the septum pellucidum that normally separates the lateral ventricles is absent and the ventricles appear as a single, large anechoic structure (Figure 225-2). Computed tomography (CT) and magnetic resonance imaging (MRI) enable accurate determination of ventricular size, extent of cortical atrophy, and the presence of any focal lesions that may account for the hydrocephalus. Imaging also is useful for monitoring patients after surgical placement of ventriculoperitoneal shunts. Obstructing masses such as tumors, granulomas, and cysts may be

Figure 225-3  Transverse T2-weighted fluid-attenuated inver-

sion recovery (FLAIR) MRI. The lateral ventricles are seen as hypointense (dark) structures. Periventricular edema is evident as hyperintensity (bright) regions (arrows) adjacent to the ventricles.

identified. MRI is more sensitive than CT in demonstrating small focal lesions, especially those in the caudal fossa. Periventricular edema may be identified on CT as blurring or loss of the normally sharp ventricular margins. On MRI, this edema is best appreciated on T2-weighted images as increased intensity compared with normal white matter. Heavily T2-weighted FLAIR (fluid-attenuated inversion recovery) sequences are useful in detecting subtle periventricular lesions (Figure 225-3). Periventricular edema usually is associated with acute hydrocephalus and increased intraventricular pressure, rather than chronic, relatively compensated hydrocephalus with normal intraventricular pressure.

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SECTION  XI  Neurologic Diseases

It is critical to differentiate between hydrocephalus and ventricular enlargement secondary to brain atrophy. Atrophy is characterized by widening of the cerebral sulci and subarachnoid space. On the other hand, effacement of sulci, periventricular edema, and rounding of the frontal portion of the lateral ventricles and ventral displacement of the third ventricle suggest hydrocephalus with increased intraventricular pressure. Analysis of CSF is helpful in cases of suspected meningoencephalitis. CT or MRI is performed first to identify any shifting of brain tissue, such as caudal cerebellar herniation, or other abnormalities that may increase  the risk of CSF collection from the cerebellomedullary cistern. In some cases, it may be safer to collect CSF  from an enlarged lateral ventricle through a persistent fontanelle.

Treatment Medical Therapy Medical therapy is used when surgery is not an option or is not indicated and for short-term management of acute deterioration. Several medications have been shown to decrease CSF production and may provide temporary relief of clinical signs. Acetazolamide (10 mg/kg q8h PO) is a carbonic anhydrase inhibitor that decreases CSF production. Furosemide (1 mg/kg q24h PO) inhibits CSF formation to a lesser degree by partial inhibition of carbonic anhydrase. The proton pump blocker omeprazole (0.5 mg/ kg q24h PO) decreases CSF production in normal dogs (Javaheri et al, 1997). Glucocorticoids also are commonly used to treat hydrocephalus in veterinary patients. One protocol is prednisone given at a dosage of 0.25 to 0.5 mg/ kg q12h PO until signs improve, followed by a dose  reduction at weekly intervals until 0.1 mg/kg q48h PO is reached. Removal of CSF sometimes is performed to provide temporary relief and to help predict which patients will benefit from surgical shunting. In pediatric patients with a fontanelle, an enlarged lateral ventricle can be punctured with a 25-gauge needle inserted at the lateral aspect of the fontanelle, with care taken to avoid the sagittal sinus on the midline. Ultrasonography is helpful in determining the depth of the center of the ventricle; optimally this procedure should be performed by a specialist with experience in the technique. Approximately 2 ml of CSF can be removed safely in most patients.

Ventriculoperitoneal Shunt Definitive treatment is insertion of a shunt to divert CSF from the ventricular system to another body cavity, typically the peritoneal space. The presence of enlarged ventricles alone does not indicate the need for surgery. The key findings in recommending surgery are progressive neurologic deficits, progressive enlargement of the ventricles on repeated imaging, or image features indicating increased intraventricular pressure, such as periventricular edema. A variety of shunt systems designed for human patients are available and have been used in dogs and cats. All of

the shunt manufacturers make pediatric or low-profile versions designed for small infants, and these work well in small dogs and cats. Several trials in human pediatric patients failed to demonstrate any difference in outcome among various systems (Kestle et al, 2000; Pollack et al, 1999). A shunt consists of three components: a ventricular catheter that is inserted into the ventricle, a valve, and a peritoneal catheter placed in the abdomen. Most valves are differential pressure valves that open when the pressure across the valve exceeds a certain threshold and close when the pressure drops below that level. The most common design is a diaphragm valve, in which a silicone membrane is deflected in response to pressure to allow the flow of CSF. Some shunts employ a slit valve consisting of one or more slits in the distal tubing that open and close at certain pressures. Valves are available in low-, medium-, and high-pressure versions, which roughly correlate with pressures of 5, 10, and 15 cm H2O. Several manufacturers provide externally adjustable valves that enable the clinician to regulate the opening pressure after the shunt is implanted using a device that emits a magnetic field. An advantage of this type of valve is that the function of the shunt can be adjusted noninvasively based on the individual patient’s clinical response without the need for surgery to change the valve. Because these valves contain ferromagnetic material, they create an artifact on MRI scans. Another disadvantage is the additional cost of the shunt and the programming device compared with that of nonadjustable valves. Surgical Technique Surgical technique is similar for all ventriculoperitoneal shunts, although details vary slightly based on the specific system. Aseptic technique and meticulous hemostasis are critical to minimize the chance of shunt infection and obstruction. The site of the incision over the skull is determined using preoperative brain imaging so that the catheter tip is placed in the center of the occipital horn or frontal horn, caudal or rostral to the choroid plexus. The abdominal incision is located 2 to 3 cm caudal to the last rib, about halfway between the lumbar spine and the ventral aspect of the abdomen. The patient is measured to determine the proper shunt length so that approximately one third to one half the shunt is placed in the abdomen. The patient is clipped and prepared from the head to the side of the abdomen. The skin and subcutaneous tissues are incised over the skull and abdomen. A subcutaneous tunnel is created connecting the two  incisions, and the catheter is pulled from the cranial incision through subcutaneous tissues to the abdominal  incision. The ventricular catheter is placed into the ventricle through a burr hole in the skull and secured with sutures placed through one or two small holes in the bone. Securely anchoring the catheter to the skull is important to prevent dislodgement of the catheter. The abdominal muscles and peritoneum are incised to allow the distal end of the shunt to be placed into the peritoneal cavity. The shunt tubing is secured to the abdominal wall using nonabsorbable suture tied to an anchoring clip or tied in a finger-trap fashion to the tubing and the abdominal muscle is apposed with absorbable suture. The

CHAPTER  225  Congenital Hydrocephalus

1037

Other postoperative complications are migration of an intact shunt, fracture or disconnection of shunt components, and infection. These adverse events usually require replacement of the shunt. Securely anchoring the shunt at the skull and the abdomen decreases the risk of migration. Infection is manifested as wound infection, fever, or obstruction. Cytologic analysis and culture of CSF collected percutaneously from the shunt reservoir is helpful in the diagnosis of shunt infection. The infection may resolve after 4 weeks of antibiotic therapy guided by culture and sensitivity testing; obstruction or persistent infection indicates the need to replace the shunt. Perioperative antibiotic administration and meticulous aseptic technique are important to decrease the risk of infection. Antibiotic-impregnated shunts are available and decrease the risk of infection in human patients, but veterinary trials are lacking.

Prognosis

Figure 225-4  Radiographs after insertion of a ventriculoperito-

Some patients can be managed successfully with medication, especially when the hydrocephalus is not progressive. But in many cases medical therapy provides only temporary benefit. Approximately 85% of dogs treated with shunting have long-term improvement. Fifteen percent of patients require shunt revision, usually due to shunt obstruction, fracture, or migration (de Stefani et al, 2011; Shihab et al, 2011).

subcutaneous and skin incisions are closed routinely. A postoperative radiograph is obtained to document adequate shunt placement (Figure 225-4).

References and Suggested Reading

neal shunt. 1, Ventricular catheter. 2, Valve. 3, Peritoneal catheter.

Complications Ventriculoperitoneal shunting is prone to several complications. Most common is obstruction of flow through an intact shunt as a result of scarring or ingrowth of the choroid plexus at the ventricular catheter tip, valve occlusion by blood or proteinaceous debris, or scarring or adhesions around the peritoneal tubing. Lower-pressure valves are more prone to obstruction by proximal occlusion because they allow slightly more drainage of CSF and smaller ventricles (Robinson et al, 2002). Distal slit valves are more prone to obstruction with omentum or debris than are valve of other designs (Cozzens et al, 1997). Therefore the author generally uses medium- or highpressure valves and avoids slit-valve designs. Obstruction can occur at any time after implantation and is accompanied by recurrence of signs of hydrocephalus. Shunt obstruction is suspected in any patient that initially improves after surgery and then develops lethargy, ataxia, or abnormal behavior. An imaging finding of ventricles that are larger than on a previous scan is a strong indication of obstruction.

Cozzens JW, Chandler JP: Increased risk of distal ventriculoperitoneal shunt obstruction associated with slit valves or distal slits in the peritoneal catheter, J Neurosurg 87:682, 1997. De Stefani A et al: Surgical technique, postoperative complications and outcome in 14 dogs treated for hydrocephalus by ventriculoperitoneal shunting, Vet Surg 40:183, 2011. Javaheri S et al: Different effects of omeprazole and Sch 28080 on canine cerebrospinal fluid production, Brain Res 754:321, 1997. Kestle J et al: Long-term follow-up data from the Shunt Design Trial, Pediatr Neurosurg 33:230, 2000. Klimo P Jr et al: Antibiotic-impregnated shunt systems versus standard shunt systems: a meta- and cost-savings analysis,  J Neurosurg Pediatr 8:600, 2011. Pollack IF, Albright AL, Adelson PD: A randomized, controlled study of a programmable shunt valve versus a conventional valve for patients with hydrocephalus. Hakim-Medos Investigator Group, Neurosurgery 45:1399, 1999. Rekate HL: A contemporary definition and classification of hydrocephalus, Semin Pediatr Neurol 16:9, 2009. Robinson S, Kaufman BA, Park TS: Outcome analysis of initial neonatal shunts: does the valve make a difference? Pediatr Neurosurg 37:287, 2002. Shihab N et al: Treatment of hydrocephalus with ventriculoperitoneal shunting in twelve dogs, Vet Surg 40:477, 2011.

CHAPTER 

226 

Intracranial Arachnoid Cysts in Dogs CURTIS W. DEWEY, Ithaca, New York

I

ntracranial arachnoid cyst (IAC), also termed intraarachnoid cyst and quadrigeminal cyst, is a developmental brain disorder in which cerebrospinal fluid (CSF) is believed to accumulate within a split of the arachnoid membrane during embryogenesis. The developing neural tube is surrounded by a loose layer of mesenchymal tissue called the perimedullary mesh; this tissue eventually becomes the pia and arachnoid layers of the meninges. In normal development, pulsatile CSF flow from the choroid plexuses is thought to divide the perimedullary mesh into pia and arachnoid layers, effectively creating the subarachnoid space. It is postulated that some aberration of CSF flow from the choroid plexuses during this stage of development forces a separation within the forming arachnoid layer that eventually leads to the creation of an IAC. The intraarachnoid location of IACs has been demonstrated via light and electron microscopy in people. The mechanisms by which an IAC continues to expand with fluid are unknown, but several theories have been proposed. Fluid may be secreted by the arachnoid cells lining the cyst cavity. There is evidence that cells lining the IAC may have secretory capacity. There also may be fluid movement into the cyst via an osmotic pressure gradient. Considering that the fluid within the IAC is nearly identical to CSF, this latter theory is unlikely. In addition, there have been documented cases in people in which the IAC and the subarachnoid space communicate via small slits. These slits act as one-way valves, diverting CSF into the cyst during systole but preventing return to the subarachnoid space during diastole. Although IAC has been reported to occur in several locations in humans, all reported canine cases have been in the caudal fossa. Because IAC typically is associated with the quadrigeminal cistern in dogs, these accumulations of fluid often are called quadrigeminal cysts in this species. Also termed intracranial intraarachnoid cyst, IAC accounts for 1% of all intracranial masses in people and has been sporadically reported in dogs. IAC often is an incidental finding in humans; it has been suggested recently that this also may be the case in dogs.

Clinical Findings In the veterinary literature, there have been nine clinical reports of IAC in dogs, with a total of 53 cases described. The IAC was suspected to be an incidental finding in 1038

approximately one third to over one half of the reported cases. The likelihood of clinical signs probably relates to the extent to which the cyst compresses the occipital lobe. The vast majority of reported IAC cases in dogs have involved small breeds, with a predominance of brachycephalic dogs. The breeds and numbers reported to date include the Shih Tzu (12), Maltese (4), pug (4), cavalier King Charles spaniel (4), Yorkshire terrier (4), Lhasa apso (4), Chihuahua (3), Staffordshire bull terrier (3), bulldog (3), Pekingese (2), West Highland white terrier (2), and one each of bichon frise, Pomeranian, cairn terrier, Jack Russell terrier, terrier mix, beagle, miniature schnauzer, and German shorthaired pointer. There is a wide range in age at the time of clinical presentation (2 months to 10 years), with an approximate average age of 4 years. The most common clinical signs are attributed to forebrain dysfunction (including seizure activity), central vestibular (cerebellovestibular) disease, or both. Dogs also may be brought in with a primary complaint of neck pain. Diagnosis of IAC typically is made via computed tomography or (preferably) magnetic resonance imaging (Figure 226-1). IACs also can be visualized using ultrasound imaging (via the foramen magnum, a temporal window, or a persistent bregmatic fontanelle), especially in younger dogs. The characteristic appearance of IAC is that of a large, well-demarcated fluid-filled structure that is isointense with the CSF spaces and is located between the caudal cerebrum and rostral cerebellum. Because IAC may be an incidental finding, it is important to rule out concurrent inflammatory disease (i.e., by CSF examination). In the author’s opinion, it is often difficult or impossible to discern whether IAC in the presence of another brain disorder is purely an incidental finding. Since the presence of a large fluid-filled structure within the cranial vault likely decreases intracranial compliance, some IACs may contribute to clinical signs rather than being simply an incidental finding. Because this disorder is believed to represent a developmental abnormality  of the intracranial ventricular CSF system, it may occur concurrently with other fluid abnormalities (including congenital hydrocephalus). The cyst may or may not communicate with the remainder of the ventricular system. When one is faced with evidence of IAC and another disease (e.g., granulomatous meningoencephalitis) in the same patient, obtaining an optimal response to treatment may entail treating both conditions.

CHAPTER  227  Treatment of Intracranial Tumors

1039

or cystoperitoneal shunt placement. Both procedures have been reported in dogs with IAC. Five cases have been reported in which IAC was considered the primary disease and was treated by fenestration. In three cases reimaging was performed after surgery; two of the three dogs had evidence of cyst persistence on magnetic resonance imaging. However, only one of these two dogs required reoperation. The author has reported successful cystoperitoneal shunting in four dogs with IAC. The success rate for surgical management of IAC appears to be high in humans and dogs, and whether fenestration or cystoperitoneal shunting is the preferred procedure remains controversial in both species.

References and Suggested Reading Figure 226-1  Sagittal T2-weighted brain image of a dog with a large intracranial arachnoid cyst.

Treatment Medical treatment for IAC is identical to that described for congenital hydrocephalus; namely, corticosteroids, diuretics, and anticonvulsants if indicated. Dogs with IAC tend to respond initially to medical therapy, but the response often is temporary. Surgical management of IAC in people typically is achieved via either cyst fenestration

CHAPTER 

Dewey CW et al: Craniotomy with cystoperitoneal shunting for treatment of intracranial arachnoid cysts in dogs, Vet Surg 36:416, 2007. Dewey CW et al: Intracranial arachnoid cysts in dogs, Compend Contin Educ Vet 31(4):160, 2009. Duque C et al: Intracranial arachnoid cysts: are they clinically significant? J Vet Intern Med 19:772, 2005. Matiasek LA et al: Clinical and magnetic resonance imaging characteristics of quadrigeminal cysts in dogs, J Vet Intern Med 21:1021, 2007. Vernau KM et al: Magnetic resonance imaging and computed tomography characteristics of intracranial arachnoid cysts in 6 dogs, Vet Radiol Ultrasound 38:171, 1997. Vernau KM et al: Intracranial arachnoid cysts with intracystic hemorrhage in two dogs, Vet Radiol Ultrasound 43:449, 2002.

227 

Treatment of Intracranial Tumors ERIN N. WARREN, Knoxville, Tennessee JILL NARAK, Knoxville, Tennessee TODD W. AXLUND, Akron, Ohio ANNETTE N. SMITH, Auburn, Alabama

I

ntracranial tumors cause a devastating clinical picture, with signs that may include seizures, behavioral changes, proprioceptive deficits, altered mentation, vestibular disease, and other cranial nerve abnormalities. Clinical signs are caused in part by destruction of normal brain tissue by the neoplasm, but patients also deteriorate due to secondary lesions. These include peritumoral edema and hemorrhage that lead to increased intracranial pressure and potentially brain herniation. Intracranial neoplasia affecting dogs and cats can  arise from primary or secondary sources. Primary tumors originate from intracranial structures and include

meningioma, glial tumors, neuroepithelial tumors, neural tumors, pituitary gland tumors, pineal gland tumors, and germ cell tumors. Secondary tumors arise from extracranial structures and include extension of nasal or skull tumors and metastatic neoplasia. All intracranial tumors carry a poor prognosis; however, often it is difficult to discuss prognosis because treatment sometimes is initiated without a definitive diagnosis. Definitive treatment relies on an accurate histopathologic tumor diagnosis, although correlations between tumor appearance on magnetic resonance imaging (MRI) and histopathologic diagnoses have been reported (Kraft et al,

1040

SECTION  XI  Neurologic Diseases

1997; Snyder et al, 2006). The patient’s prognosis is related to tumor biologic behavior, as well as severity and progression of clinical signs. Without treatment intracranial tumors offer a grave prognosis.

Definitive Therapies Definitive treatments include surgical excision, irradiation, and chemotherapy. These therapies aim to reduce or eradicate the tumor mass and decrease its secondary effects, such as peritumoral edema, hemorrhage, and intracranial hypertension.

Surgical Excision Surgical Approaches and Considerations Surgical removal of an intracranial tumor achieves many treatment goals. There is decompression and reduction of intracranial pressure. Moreover, a histopathologic diagnosis can be obtained, which allows for accurate prognostication and additional treatment planning in the case of subtotal resection. Surgical approaches include rostrotentorial, caudotentorial, transfrontal, and suboccipital craniotomies or craniectomies, and combinations of these approaches may be used. The tumor size, degree of invasiveness, and location determine whether or not surgical removal is a viable option; these also guide the neurosurgical approach. Intraaxial tumors, which are located within the brain parenchyma, are more difficult to remove than extraaxial tumors. In addition, approaches to the caudal fossa are difficult and seldom attempted because of the possibility of inducing iatrogenic trauma to the brainstem, which can result in severe clinical signs. However, one recent case report describes a novel basiooccipital surgical approach to relieve compression of the caudal brainstem and cranial cervical spinal cord caused by a meningioma in a canine patient (Barreau et al, 2010). In most cases the goal of surgery is removal of the entire mass. Tumor removal can be achieved using a combination of sharp and blunt dissection, or an ultrasonic aspirator can be used. Adequate dissection can be difficult because many tumors are not well delineated from normal tissue, and adjacent normal brain tissue may be compromised because of peritumoral edema or hemorrhage. Endoscopy has been used to assist in removal of residual intracranial tumor after a debulking procedure (Klopp et al, 2009). This is particularly useful when removing  a tumor from the olfactory and frontal regions of the brain as well as the cerebellum. In these procedures, an endoscope increases the visibility of regions that otherwise receive inadequate exposure in routine surgical approaches. The dura mater must be incised or removed to obtain adequate visualization of the underlying brain structures. The defect can be closed using a graft (synthetic or fascial), or it may be left open. In dogs and cats cerebrospinal fluid (CSF) typically does not cause complications when leaked into the surrounding tissues (Niebauer et al, 1991). To protect the underlying brain, the skull defect generally is replaced when using a transfrontal or radical rostrotentorial approach; replacement is not necessary when other approaches are used.

To assess the completeness of resection, the neurosurgeon can check the gross surgical margins intraoperatively using a sterile ultrasonographic technique or after surgery using advanced brain imaging (most commonly computed tomography [CT] or MRI). However, in certain instances it may be difficult to distinguish between residual tumor and inflammation secondary to the surgical procedure itself via MRI. If it is indicated, the surgeon can reoperate immediately to remove more tumor tissue or address life-threatening postoperative hemorrhage or cerebral swelling. Microscopic surgical margins can be assessed intraoperatively by histopathologic analysis using cryosectioned biopsy samples. A tissue diagnosis also may be obtained using the  less-invasive CT- or MRI-guided biopsy; stereotactic or freehand image-guided biopsy may be performed. Both techniques may induce iatrogenic hemorrhage, and a  craniotomy may have to be performed to manage hemostasis. Anesthetic Considerations Intracranial tumor patients typically are older animals, and concurrent disease may be present. Preanesthetic screening, including complete blood count (CBC), serum biochemistry profile, urinalysis, thoracic radiography, and abdominal ultrasonography, is indicated both to ensure the general health of the patient and to identify potential metastatic or other systemic disease, which could change the management approach. In addition, these patients often have elevated intracranial pressure; thus the anesthetist should take measures to avoid or reduce intracranial hypertension, including maintaining normotension (systolic blood pressure of 110 to 160 mm Hg or mean arterial pressure of 80 to 110 mm Hg), eucarbia (35 to 45 mm Hg), and analgesia. Inhalant anesthetics increase cerebral blood flow (see Chapter 13), which can lead to or potentiate intracranial hypertension; injectable agents such as propofol and fentanyl can be used to decrease the requirement of inhalant anesthetics. Diuretics and glucocorticoids may be given to decrease brain edema (Table 227-1). Intracranial surgery can be associated with intraoperative hemorrhage; thus one should be prepared for a blood transfusion. After surgery the patient should be allowed to recover gradually from anesthesia. It is critically important to avoid excitement on recovery, and additional sedation may be required. Analgesia should be continued and titrated to the patient’s needs. Intraoperative and Postoperative Considerations Intraoperative complications include hemorrhage, hypotension, intracranial hypertension, and air embolism. Postoperative infection may be of concern after transfrontal craniotomy because the approach involves incision through the contaminated frontal sinus. However, postoperative infection is not a typical complication after intracranial surgery, possibly because of the routine use of perioperative antibiotics (see Table 227-1). Intracranial hypertension is a concern following surgery, and patient positioning can aid in maintaining intracranial pressure within the normal range. Intracranial pressure can be measured directly, or it can be monitored indirectly by

CHAPTER  227  Treatment of Intracranial Tumors

1041

TABLE 227-1  Medications Used in the Treatment of Intracranial Tumors Drug

Dosage

Use/Indication

Carmustine

50 mg/ml q6wk IV (over 15-20 min)

Nitrosourea chemotherapeutic agent; may be used to treat meningioma and glioma

Cefazolin

22 mg/kg q90min IV 2

Perioperative antibiotic 2

Cytarabine (cytosine arabinoside)

20-100 mg/m q1wk intrathecally; 50 mg/m SC for 2 days. Repeat every 3 weeks

Chemotherapeutic agent used to treat CNS lymphoma

Diazepam and midazolam

0.5 mg/kg as needed IV; or 2 mg/kg as needed per rectum

Anticonvulsant used in emergency management of status epilepticus or cluster seizures

Dimenhydrinate

Dog: 25-50 mg q8-24h PO Cat: 12.5 mg q8-24h PO

Antihistamine used as antiemetic in vestibular disease

Hydroxyurea

Dog: 50 mg/kg once daily, 3 days per week PO Cat: 25 mg/kg once daily, 3 days per week PO

Chemotherapeutic agent; may be used to treat meningioma

Levetiracetam

20 mg/kg q8h PO 20-60 mg/kg IV for status epilepticus

Anticonvulsant

Lomustine

Dog: 60-90 mg/m2 q3-6wk PO Cat: 50-60 mg/m2 q6wk PO

Nitrosourea chemotherapeutic agent; may be used to treat meningioma and glioma

Mannitol

0.5-1 g/kg q4h or as needed IV

Osmotic diuretic used to decrease brain edema and lower intracranial pressure

Meclizine

25 mg/dog and 12.5 mg/cat q24h PO

Antihistamine used as antiemetic in vestibular disease

Methylprednisolone sodium succinate

30 mg/kg once IV; or 100 mg/kg given over 24 hr IV

Glucocorticoid used to decrease peritumoral brain edema and lower intracranial pressure

7.5% NaCl

5-20 ml/kg as needed IV

Osmotic diuretic used to decrease brain edema and lower intracranial pressure

Phenobarbital

Loading dosage: 5 mg/kg as needed IV (up to 20 mg/kg total) Maintenance dosage: 2-8 mg/kg q12h PO (Adjust dose by monitoring blood concentrations)

Anticonvulsant

Potassium bromide

Loading dosage: 200 mg/kg per day every 3-5 days Maintenance dosage: 30-40 mg/kg q24h PO

Anticonvulsant

Prednisone

0.5-1 mg/kg q12h PO

Glucocorticoid used for supportive treatment of intracranial tumors

Zonisamide

10 mg/kg q12h PO

Anticonvulsant

CNS, Central nervous system; IV, intravenously; PO, orally.

observing for changes associated with intracranial hypertension, including Cushing’s response (systemic hypertension with reflex bradycardia) and changes in pupil size and symmetry. The patient’s head should be elevated (approximately 30 degrees), jugular occlusion should be avoided (e.g., no jugular venipuncture or neck leads), and pain and excitement should be prevented. If necessary, diuretics with or without glucocorticoids can be continued in the postoperative period. If the patient is recumbent, urinary catheterization may be necessary. Care should be taken to keep the patient clean and dry, and appropriate bedding with frequent rotation or placement in a sling to prevent the formation of decubital ulcers is required. To avoid aspiration pneumonia the patient should be given nothing by mouth for 24 hours postoperatively. Nutritional and intravenous fluid support is indicated in a patient who cannot maintain adequate nutrition orally.

Meningioma Meningiomas usually are easily accessible to the neurosurgeon since they are often extraaxial masses. However, meningiomas located along the brainstem and those located on the falx cerebri, tentorium cerebelli, or along the lateral ventricles may be more difficult to access. Surgical removal of feline meningiomas may be curative since the entire mass often can be removed in total. Accordingly, surgical excision is the treatment of choice for feline meningiomas. Troxel and associates (2003) reported that cats treated by surgical removal of meningiomas had a significantly longer survival time than cats treated by any other modality (Table 227-2). Niebauer and colleagues (1991) reported that 50% of cats were alive 2 years after surgery. Canine meningiomas are more difficult to remove totally. Histologically these tumors tend to be more aggressive and invasive in dogs than in cats. Thus surgical

1042

SECTION  XI  Neurologic Diseases

TABLE 227-2  Comparison of Median Survival Times in Dogs and Cats with Intracranial Tumors Treated with Surgical Excision and/or Irradiation Study

Tumor Type

Number of Patients

Treatment

Results/Median Survival Time (Days)

Troxel et al

Meningioma

34 cats

Surgical excision

685

Greco et al

Meningioma

17 dogs

Surgical excision

1254

Axlund et al

Meningioma Meningioma

14 dogs 12 dogs

Surgical excision Surgical excision followed by irradiation

210 495

Brearley et al

Extraaxial tumor Intraaxial tumor Pituitary tumor

41 dogs 34 dogs 8 dogs

Irradiation Irradiation Irradiation

347 282 147

Turrel et al

Meningioma Undifferentiated sarcoma Astrocytoma

2 dogs 1 dog 1 dog

Irradiation

322

Heidner et al

Meningioma Other tumor types Unknown tumor types

9 dogs 8 dogs 8 dogs

Irradiation (some dogs + hyperthermia, some dogs + surgery)

137

Evans et al

Meningioma Lymphoma Pituitary adenoma Metastatic anaplastic carcinoma Oligodendroglioma Granulomatous meningoencephalitis Unknown tumor type

4 1 1 1 1 1 5

dogs dog dog dog dog dog dogs

Irradiation

9 dogs (39 Gy): 1545 dogs (45 Gy): 519

Iwamoto et al

Meningioma Glioma Pituitary tumor (presumed)

18 dogs 6 dogs 1 dog

Irradiation

Clinical improvement and decrease in tumor size

LaRue et al

Unknown tumor type

65 dogs

Irradiation (some dogs + surgery)

405

Spugnini et al

Meningioma Glioma Choroid plexus tumor

21 dogs 4 dogs 3 dogs

Irradiation

250

Kent et al

Pituitary tumor

19 dogs

Irradiation

1405

Mayer et al

Pituitary tumor

8 cats

Irradiation

522

Bley et al

Extraaxial tumor Intraaxial tumor Pituitary

22 dogs 13 dogs 13 dogs

Irradiation

1174

removal often leaves behind microscopic disease, and further treatment with follow-up radiation therapy or chemotherapy is necessary. Greco and colleagues (2006) reported that histopathologic tumor subtype influenced prognosis: transitional and meningothelial meningiomas were associated with higher median survival times than fibroblastic, anaplastic, and psammomatous meningiomas. Théon and associates (2000) found that a high tumor proliferative index, noted on immunohistochemical analysis of histologic tumor sections, was a significant prognostic indicator for tumor progression in dogs with meningioma. Glioma Surgical removal of gliomas can be helpful for debulking and histopathologic confirmation of the diagnosis of glioma. However, gliomas are invasive tumors, and it is

difficult to obtain clean margins. These tumors typically are highly vascular, and because of their deep location, surgical resection may damage normal brain parenchyma. Tumor location also may make visualization difficult during surgery. Intraoperative ultrasonography may help to delineate tumor margins. For these reasons surgical removal of gliomas usually is followed by radiation therapy. Other Neoplasms Pituitary microadenomas may be amenable to surgical removal, but macroadenomas typically are too large for excision. Radiation therapy is the treatment of choice for those tumors, although the prognosis is worse if neurologic signs are present. The ratio of pituitary height to brain area is used to discriminate between pituitary microadenoma and macroadenoma and to determine the

CHAPTER  227  Treatment of Intracranial Tumors feasibility of surgical removal. Traditionally a macroadenoma may be defined as a pituitary gland that is greater than 1 cm in height, although Meij and associates (1998) describe that in veterinary medicine a pituitary tumor is classified as a macroadenoma when the ratio of pituitary height to brain area is more than 0.31. Techniques described for pituitary microadenoma removal include use of the transsphenoidal and transcranial approaches. Neuroepithelial tumors such as choroid plexus papillomas and ependymomas may be removed surgically; however, they often are situated in difficult locations within the ventricular system. As a result, obstructive hydrocephalus may occur and exacerbate clinical signs. To relieve hydrocephalus, a viable palliative option is the placement of a ventriculoperitoneal shunt. This procedure may be combined with tumor removal in selected cases.

Radiation Therapy Radiation therapy may be used as adjunct treatment to surgical excision. In fact, it may be most effective when combined with surgical tumor removal (Table 227-3). Radiation therapy also can be used as sole therapy for intracranial tumors. Because of the potential morbidity associated with surgical removal of brainstem masses, the use of radiation as sole therapy is the treatment of choice for tumors in those locations. The use of radiation as sole

1043

therapy is justified if a qualified surgeon is not available; however, radiation therapy typically requires referral to a specialty center. Megavoltage radiation is recommended, but orthovoltage also has been used. Radiation oncologists base treatment planning on the known or suspected tumor type and location, keeping in mind the acute and late adverse effects that may be induced by radiation therapy. The goal of radiation therapy is to deliver a tumoricidal dose of radiation while sparing normal brain tissue. High doses of radiation improve control of brain tumors but put the patient at risk of radiation-induced brain necrosis; thus the risk : benefit ratio needs to be considered for each patient. Radiation-induced brain damage is the result of focal necrosis and local hemorrhage. Fractionation is a strategy used to avoid radiation-induced brain necrosis. This approach relies on the ability of normal tissue to repair itself between doses of radiation. Tumor cells have lost this ability for repair; thus the radiation doses are lethal to the tumor mass. Typical fractionation schedules call for three to five anesthetic episodes per week, which can be stressful to the typical geriatric brain tumor patient. Ideally, to avoid radiation-induced brain necrosis, treatments are delivered in fractions of less than 300 cGy to reach a total dose of 45 to 50 Gy. Therapy may fail as a result of tumor recurrence or radiation-induced brain necrosis. Advanced imaging cannot distinguish between these processes, and both

TABLE 227-3  Comparison of Treatment Results in Dogs with Intracranial Tumors Treated Using Various   Chemotherapy Protocols Study

Protocol

Tumor Type

Number of Patients

Couto et al

Cyclophosphamide, vincristine, cytosine arabinoside, prednisone, chlorambucil

CNS lymphoma

2 dogs

1 dog: 63 days 1 dog: complete remission after 90 days

Cook et al

BCNU 50 mg/m2 IV q4-6wk

Glioma 1 benign vascular tumor and 1 unidentified tumor Meningioma Pituitary tumor

3 dogs 2 dogs

9-11 mo >12 mo

Unknown Unknown

4-6 mo Little to no response

Survival Time

Dimski et al

BCNU 50 mg/m2 IV q6wk + Phenobarbital + Oxacillin + Prednisone

Astrocytoma

1 dog

7 mo

Jeffery et al

CCNU 60-80 mg/m2 PO q4wk

Glioblastoma multiforme Meningioma

1 dog 1 dog

4 mo 11 mo

Tamura et al

Hydroxyurea 30 mg/kg 3 times per wk PO × 5 mo then increased to 45 mg/kg 3 times per wk × 2 mo then discontinued + Dexamethasone

Meningioma

1 dog

14 mo

Jung et al

Lomustine 60 mg/m2 PO × q6wk + Prednisone 1 mg/kg BID PO

Meningioma

1 dog

13 mo

Adapted from Van Meervenne SAE et al: Therapy of brain tumors in dogs and cats, Vlaams Diergen Tijds 76:165, 2007. BCNU, Carmustine; BID, twice daily; CCNU, lomustine; CNS, central nervous system; IV, intravenously; PO, orally.

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SECTION  XI  Neurologic Diseases

conditions present with similar clinical signs. It can be difficult to know if a patient is deteriorating as a result of tumor progression or brain necrosis. A severe and rapid neurologic decline may be the result of radiation-induced brain necrosis, whereas a slowly progressive decline in neurologic status may represent tumor regrowth (Brearley et al, 1999). Ultimately, this differentiation can be  made only at postmortem examination. Brain is a lateresponding tissue; thus these radiation adverse effects may not be noted until months to years after treatment, and Spugnini and associates (2000) reported that only  5% to 20% of veterinary patients with brain tumors survive to be at risk of these effects. Another late adverse effect to consider is new tumor growth induced by radiation, as noted in one report by Théon and colleagues (2000). Acute adverse effects of radiation therapy in the brain can be seen weeks to months after therapy and include transient demyelination, which usually responds to antiinflammatory dosages of corticosteroids (see Table 227-1). Other acute adverse effects of radiation therapy depend on the normal tissues included in the treatment portal. These may include keratoconjunctivitis, corneal ulcers, mucositis, otitis externa, and dermatitis. Although these effects are not life threatening, they may cause debilitation in the short or long term and require management. Stereotactic radiosurgery is a technique that allows for the precise delivery of radiation to the tumor while sparing adjacent normal brain tissue. Fewer anesthetic episodes are required because a sufficient dose of radiation is delivered to the tumor at once or over a few treatment sessions, whereas only a fraction is delivered to normal brain tissue. This technique can be used to treat tumors of relatively small diameter and requires referral to an adequately equipped specialty center. Other techniques such as boron neutron capture therapy and brachytherapy have been attempted to deliver a precise dose of radiation to the tumor tissue.

Chemotherapy Chemotherapy has been largely ineffective in the treatment of brain tumors, but certain therapeutic agents deserve consideration (see Table 227-3). The blood-brain barrier is impermeable to large hydrophilic compounds. Consequently most drugs are unable to penetrate the blood-brain barrier and exert tumoricidal effects. However, in the face of significant lesions, the blood-brain barrier may not be completely impenetrable, and some drugs may gain limited access to the tumor. Agents that increase the permeability of the bloodbrain barrier (e.g., mannitol) may be given to enhance the effectiveness of a chemotherapeutic agent; however, this technique may increase the toxic effects of the drug, so the approach generally is not advised. To achieve maximum delivery into the central nervous system (CNS), agents can be injected directly into the subarachnoid space (intrathecal injection). Alternatively, intratumoral injections of chemotherapeutic agents have been used in humans and may deliver a precise dose of the drug directly into the tumor; however, this technique is limited by the invasiveness of the procedure.

Certain tumors are considered to be relatively chemoresponsive, including CNS lymphoma, medulloblastoma, and oligodendroglioma, but chemotherapy may be considered for any patient with an intracranial tumor. In particular, lymphoma of the CNS is considered a nonsurgical disease and is treated with systemic and sometimes intrathecal chemotherapy. Chemotherapy is also used  to treat metastatic brain neoplasia; the protocol used depends on the primary tumor. Surgical debulking and radiation therapy may not be advised for metastatic brain neoplasia because of the poor prognosis; however, these modalities can be offered as palliative therapy. Standard protocols for chemotherapy for the treatment of intracranial tumors have not yet been developed, but certain chemotherapeutic agents are discussed here. Nitrosoureas Nitrosoureas are highly lipophilic and obtain rapid passage across the blood-brain barrier. Lomustine (CeeNU) and carmustine (BiCNU) are used as adjunct therapy for brain tumors (see Table 227-1). These agents have been used to treat glioma and meningioma with varying degrees of success. Adverse effects of the nitrosoureas include myelosuppression; thus CBCs should be monitored weekly, beginning after the first week of treatment. Maximum myelosuppression may not occur until 4 to 6 weeks after treatment, and the effects (neutropenia and thrombocytopenia) may be cumulative. If the patient becomes neutropenic with a count of less than 1000 × 103 neutrophils/µl but otherwise appears to be healthy, administration of broad-spectrum oral antibiotics may be advised; if the patient is neutropenic with less than 1000 × 103 neutrophils/µl and displays signs of sepsis or systemic illness (lethargy, vomiting, diarrhea, or fever), the patient should be hospitalized and given broad-spectrum intravenous antibiotics with monitoring for progression of sepsis. Lomustine also can cause hepatotoxicity and nephrotoxicity; thus it is important to monitor the results of serial serum biochemical tests. Prophylactic administration of Denamarin (S-adenosylmethionine and silybin) has been used to prevent liver toxicity (Skorupski et al, 2011). If evidence of toxicity is present, hepatic and renal function tests and/or abdominal ultrasonography should be performed. Hydroxyurea Hydroxyurea is a chemotherapeutic agent that also crosses the blood-brain barrier and may be useful in the treatment of intracranial tumors (see Table 227-1). Hydroxyurea has shown promise in treating humans with unresectable or recurrent meningioma, but there is no evidence demonstrating its efficacy in dogs or cats. The most serious adverse effect of hydroxyurea is myelosuppression; serial CBCs should be monitored. Cytarabine Intrathecal delivery of cytarabine (cytosine arabinoside, Cytosar) has been used in the treatment of CNS lymphoma when malignant cells are found in the CSF. Cytosine arabinoside may be delivered intrathecally (see Table 227-1).  The chemotherapy is continued until 1 week beyond a finding of no atypical lymphocytes on CSF tap; three to six

CHAPTER  227  Treatment of Intracranial Tumors treatments usually are necessary. Intrathecal delivery of chemotherapy requires general anesthesia and the technical expertise to perform a CSF tap. Systemic chemotherapy is recommended in conjunction with intrathecal chemotherapy. An oncologist or neurologist should be consulted regarding protocols. Response to treatment usually occurs in weeks to months. Other Chemotherapeutic Drugs The combination of procarbazine, lomustine, and vincristine has been used to treat certain types of human glioma. Temozolomide is an alkylating agent that also has been used with varying success in humans with glioma. Methotrexate has been used intrathecally to treat humans with CNS lymphoma. Studies are needed in veterinary medicine to address the efficacy and safety of these drugs.

Supportive Therapies Supportive therapy is aimed at seizure control and reduction in intracranial pressure and is often instituted regardless of whether or not definitive treatments are undertaken. When used in combination with definitive therapy such as surgery or radiation, these treatments aid in reducing the patient’s clinical signs in the short term during the wait for definitive treatments to take effect. Supportive therapies can be used as the sole means of treatment, but owners should be made aware that the patient’s prognosis is poor; these therapies treat only the symptoms of the intracranial tumor and do not affect the tumor itself. The usefulness of supportive therapies as the sole means of treatment is short-lived because eventually the tumor mass enlarges and exacerbates the patient’s clinical signs. However, supportive care can extend a patient’s life in the short term and temporarily alleviate clinical signs associated with the intracranial tumor.

Treatment of Acute Intracranial Hypertension Intracranial hypertension can develop because of the presence of the brain tumor or because of secondary complications such as edema and hemorrhage. Left untreated, intracranial hypertension can cause brain herniation and death. Intravenous fluid support is implemented to maintain normotension and support blood flow to the brain since cerebral perfusion pressure relies on adequate mean arterial blood pressure. Methylprednisolone sodium  succinate (Solu-Medrol) is a glucocorticoid effective in decreasing peritumoral edema (see Table 227-1). Diuretics also may be given to decrease brain edema. Mannitol and hypertonic saline are osmotic diuretics effective in decreasing intracranial pressure (see Table 227-1). It is important to monitor the patient’s hydration status when using diuretics since therapy can lead to hypovolemia and hypotension, which can exacerbate cerebral ischemia caused by hypoxia.

Anticonvulsants Phenobarbital and potassium bromide are the typical first-line anticonvulsants used in veterinary patients, but recently other drugs such as levetiracetam and zonisamide

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have become popular (see Table 227-1). Serum phenobarbital concentrations should be measured 2 weeks after maintenance therapy is initiated; the therapeutic range is 15 to 45 µg/ml when phenobarbital is used as monotherapy. High levels of phenobarbital may be associated with hepatotoxicity. Increased alkaline phosphatase levels may be noted in the serum biochemistry profile, although this is associated with hepatic enzyme induction rather than hepatotoxicity. Bone marrow hypoplasia is an uncommon adverse effect of phenobarbital therapy. Additional adverse effects are polydipsia and polyuria, polyphagia, sedation, ataxia, and paraparesis. These adverse effects often resolve within 1 to 2 weeks of therapy initiation. In patients receiving phenobarbital, serial serum biochemistry profiles should be measured and serum phenobarbital concentration should be monitored regularly to aid in dose adjustments if needed. Potassium bromide may be used as monotherapy to suppress seizures or it may be added to phenobarbital therapy in refractory cases. Because it takes a long time to reach steady state, patients usually are given a loading dose for 5 days, followed by a maintenance dosage. Serum concentrations of potassium bromide should be measured in 3 weeks, and the dosage adjusted accordingly. Adverse effects of potassium bromide are similar to those of phenobarbital. Potassium bromide is not known to cause hepatotoxicity, although it may be associated with pancreatitis. Potassium bromide is not recommended for use in cats because it has been linked with the development of inflammatory pneumonitis. It is important to keep the salt content of the patient’s diet consistent during bromide therapy since increased dietary chloride can reduce the serum levels of bromide and affect seizure control. The appearance of cluster seizures or status epilepticus is an emergency, and treatment includes the administration of diazepam (Valium) or midazolam (Versed). Phenobarbital may be given as a loading dose (see Table 227-1). If these anticonvulsants cannot control the patient’s seizures, anesthetics such as pentobarbital, propofol, and inhalant anesthetics should be considered, with recognition that the patient may require ventilatory support.

Corticosteroids Glucocorticoids may be given to reduce peritumoral edema and decrease CSF production. An antiinflammatory dosage of prednisone is recommended (see Table 227-1). This dosage can be adjusted based on the patient’s response to therapy.

Antihistamines Meclizine and dimenhydrinate are antihistamines with antiemetic effects that are useful to alleviate nausea in patients with vestibular disease (see Table 227-1).

Emerging Therapies Emerging molecular therapies such as immunotherapy, gene therapy, and oncolytic viral therapy have been used

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SECTION  XI  Neurologic Diseases

with varying success in humans, and these approaches represent future directions for research in veterinary patients. Both gene therapy and vaccination have been tested for treatment of malignant gliomas in dogs and have shown promising results as an adjunctive therapy to surgery or radiation. Gene therapy is the insertion, alteration, or deletion of genes within an individual’s cells to treat disease. Vaccination, on the other hand, is the administration of antigenic material to stimulate the immune system of an individual to develop adaptive immunity to a disease. One recent study (Xiong et al, 2010) demonstrated the usefulness of an adenoviral vector for delivery of genes encoding an immunostimulatory cytokine (human soluble fms-like tyrosine kinase 3 ligand, or hsFlt3L) to leukocytes in a peripheral canine blood culture. The study showed that this therapy triggers an antitumor immune response which leads to increased production of antigen-presenting cells (dendritic cells) demonstrating antitumor activity (phagocytic activity, increased secretion of antitumor cytokines). Vaccination against tumor cells also has been used in conjunction with gene therapy and surgery to improve outcomes in dogs with malignant gliomas. In one canine case study (Pluhar et al, 2010), a dog with spontaneous glioma was treated using a combination of surgery, gene transfer, and vaccination. In this study, an adenovirus vector was used to deliver the gene for intratumoral interferon-γ into the brain resection cavity following debulking surgery for the glioma. Interferon-γ has been shown to increase recruitment of lymphocytes to brain tumor sites in murine models but has extended survival times only modestly when used as a single agent. The vaccine used in this study consisted of a glioma cell  lysate with a potent vaccine adjuvant that promotes  signaling through toll-like receptor 9 in dendritic cells and B cells to induce an adaptive, antitumor immune response. The adjunctive use of these treatment modalities resulted in complete resolution of clinical signs in the dog and tumor-free survival for at least 450 days following surgery. Nonthermal irreversible electroporation (N-TIRE) is a promising new modality for treatment of intracranial tumors. N-TIRE is a novel, minimally invasive technique that involves placing electrodes in or around a targeted area and delivering a series of short, intense electrical pulses that destabilizes the cellular membranes within tissues and leads to increased membrane permeability. This increased membrane permeability ultimately leads to cell death due to loss of cell homeostasis and thus ablation of tumor cells within the treated area. One advantage of N-TIRE over other focal ablation techniques is that the electrical pulses do not cause the thermal damage associated with resistive heating; therefore major blood vessels, extracellular matrix, and other surrounding tissue structures are spared.

References and Suggested Reading Axlund TW, McGlasson ML, Smith AN: Surgery alone or in combination with radiation therapy for treatment of intracranial meningiomas in dogs: 31 cases (1989-2002), J Am Vet Med Assoc 221:1597, 2002.

Barreau P et al: Canine meningioma: a case report of a rare subtype and novel atlanto basioccipital surgical approach, Vet Comp Orthop Traumatol 23(5):372, 2010. Bley CR et al: Irradiation of brain tumors in dogs with neurologic disease, J Vet Intern Med 19(6):849, 2005. Brearley MJ et al: Hypofractionated radiation therapy of brain masses in dogs: a retrospective analysis of survival of 83 cases (1991-1996), J Vet Intern Med 13:408, 1999. Couto CG et al: Central nervous system lymphosarcoma in the dog, J Am Vet Med Assoc 184(7):809, 1984. Dimski DS et al: Carmustine-induced partial remission of  an astrocytoma in a dog, J Am Anim Hosp Assoc 26:179, 1990. Evans SM et al: Radiation therapy of canine brain masses, J Vet Intern Med 7(4):216, 1993. Greco JJ et al: Evaluation of intracranial meningioma resection with a surgical aspirator in dogs: 17 cases (1996-2004), J Am Vet Med Assoc 229:394, 2006. Heidner GL et al: Analysis of survival in a retrospective study  of 86 dogs with brain tumors, J Vet Intern Med 5(4):219, 1991. Iwamoto KS et al: Diagnosis and treatment of spontaneous canine brain tumors with a CT scanner, Radiother Oncol 26(1):76, 1993. Jeffery N et al: Brain tumours in the dog: treatment of 10 cases and review of recent literature, J Small Anim Pract 34:367, 1993. Jung DI et al: Long-term chemotherapy with lomustine of intracranial meningioma occurring in a miniature schnauzer, J Vet Med Sci 68(4):383, 2006. Kent MS et al: Survival, neurologic response, and prognostic factors in dogs with pituitary masses treated with radiation therapy and untreated dogs, J Vet Intern Med 21(5):1027, 2007. Klopp LS, Ridgway M: Use of an endoscope in minimally invasive lesion biopsy and removal within the skull and cranial vault in two dogs and one cat, J Am Vet Med Assoc 234(12):1573, 2009. Kraft SL et al: Retrospective review of 50 canine intracranial tumors evaluated by magnetic resonance imaging, J Vet Intern Med 11:218, 1997. LaRue SM et al: Recent advances in radiation oncology, Comp Contin Educ Pract 16:795, 1993. Mayer MN et al: Outcomes of pituitary tumor irradiation in cats, J Vet Intern Med 20(5):1151, 2006. Meij BP et al: Results of transsphenoidal hypophysectomy in 52 dogs with pituitary-dependent hyperadrenocorticism, Vet Surg 27:246, 1998. Nakaichi M et al: Primary brain tumors in two dogs treated by surgical resection in combination with postoperative radiation therapy, J Vet Med Sci 58(8):773, 1996. Niebauer GW, Dayrell-Hart BL, Speciale J: Evaluation of  craniotomy in dogs and cats, J Am Vet Med Assoc 198:89, 1991. Pluhar GE et al: Anti-tumor immune response correlates with neurological symptoms in a dog with spontaneous astrocytoma treated by gene and vaccine therapy, Vaccine 28(19):3371, 2010. Skorupski KA et al: Prospective randomized clinical trial assessing the efficacy of Denamarin for prevention of CCNU-induced hepatopathy in tumor-bearing dogs, J Vet Intern Med 25:838, 2011. Snyder JM et al: Canine intracranial primary neoplasia: 173 cases (1986-2003), J Vet Intern Med 20:669, 2006. Spugnini EP et al: Primary irradiation of canine intracranial masses, Vet Radiol Ultrasound 41:377, 2000. Tamura S et al: A canine case of skull base meningioma treated with hydroxyurea, J Vet Med Sci 69(12):1313, 2007.

CHAPTER  228  Metabolic Brain Disorders Théon AP et al: Influence of tumor cell proliferation and sexhormone receptors on effectiveness of radiation therapy for dogs with incompletely resected meningiomas, J Am Vet Med Assoc 216:701, 2000. Troxel MT et al: Feline intracranial neoplasia: retrospective review of 160 cases (1985-2001), J Vet Intern Med 17:850, 2003.

CHAPTER 

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Turrel JM et al: Radiotherapy of brain tumors in dogs, J Am Vet Med Assoc 184(1):82, 1984. Van Meervenne SAE et al: Therapy of brain tumors in dogs and cats, Vlaams Diergen Tijds 76:165, 2007. Xiong W et al: Human Flt3L generates dendritic cells from canine peripheral blood precursors: implications for a dog glioma clinical trial, PLoS One 5(6):e11074, 2010.

228 

Metabolic Brain Disorders CRISTIAN FALZONE, Zugliano, Italy

M

etabolic disorders affecting the brain are relatively common, and clinical signs can range from subtle to severe. This chapter considers selected primary disorders of the brain associated with disturbances of energy metabolism including mitochondrial encephalopathies, inborn errors of metabolism, and methylmalonic aciduria and malonic aciduria.

Energy Metabolism in the Brain Although the brain represents only 2% of the body weight, it performs many vital functions, even during sleep. Constant high energy production is needed, and any metabolic disorder potentially can have dramatic effects on brain function. Almost all the energy produced and used by the brain is derived from the metabolism of glucose, which is mostly oxidized to CO2 and H2O, with concurrent production of high-energy compounds (see later). Approximately 25% of total body glucose and 20% of total body oxygen consumption (at rest) occurs in the brain. Because glucose is produced or stored only minimally in the brain, the majority must be delivered via the arterial blood flow, with the brain receiving about 15% of the cardiac output. Brain energy metabolism therefore represents an equilibrium between blood flow, glucose utilization, and oxygen consumption. Cerebral blood flow (CBF), glucose metabolism, and oxygen consumption are closely related. CBF is influenced and regulated by a number of factors, including arterial blood pressure, intracranial pressure, venous outflow, blood viscosity, arterial partial pressures of carbon dioxide (PaCO2) and oxygen (PaO2), collateral flow, vasoreactivity and the status of cerebral autoregulation. Chemical mediators such as K+, Ca2+, H+, and adenosine also may play a role in regulation of CBF. However, cerebral metabolism is the major determinant of regional

blood flow. The distribution of capillaries is organized functionally throughout the central nervous system (CNS); hence capillary density may provide an anatomic indicator of oxidative and glucose metabolism. Areas with the greatest capillary density are most commonly located in the gray matter, but regional heterogeneity can be identified. CBF increases with increased neuronal activity. Hemodynamically, CBF is determined by the ratio of cerebral perfusion pressure to cerebral vascular resistance, where cerebral perfusion pressure is the difference between mean arterial blood pressure (MABP) and intracranial pressure (ICP). High-energy phosphates, predominantly adenosine triphosphate (ATP), are the most important energy source for the brain. ATP is produced almost entirely by oxidative metabolism of glucose. Glucose is derived from the diet and is transported into the brain by transmembrane proteins known as glucose transporters. There glucose undergoes metabolic degradation via glycolysis or the Krebs cycle (tricarboxylic acid cycle); these processes  generate 2 and 36 molecules of ATP, respectively. Glycolysis also leads to the production of pyruvate, which  can follow three different pathways: (1) it can be metabolized to ethanol (alcoholic fermentation); (2) it can be reduced to lactate (lactic fermentation); or (3) it can be transferred to the mitochondria, where it is used in the tricarboxylic acid cycle. Most of the energy obtained from the tricarboxylic acid cycle is captured by the oxidized form of nicotinamide adenine dinucleotide and flavin adenine dinucleotide, and later converted to ATP via an electron transport chain in mitochondria, known as oxidative phosphorylation. Most of the ATP (~65%) is used to maintain energydependent ion transport—in particular, the Na+,K+-ATPase pump—which represents the main energy-consuming process in neural cells. The remaining energy is used for

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SECTION  XI  Neurologic Diseases

axonal transport and for the synthesis of neurotransmitters, proteins, lipids, and glycogen. Despite that only small quantities of neurotransmitters are stored in the brain, neurotransmitter synthesis actually can account for about 5% of the energy consumption, and it takes place almost entirely in the glial cells. Although brain energy metabolism often is considered to reflect predominantly neuronal energy metabolism, it is now clear that other cell types—namely, neuroglial and vascular endothelial cells—not only consume energy but also can play an active role in the flux of energy substrates to neurons. Glial cells, which make up almost 50% of the brain volume, have a much lower metabolic rate than neurons and account for less than 10% of total cerebral metabolism. Among the glial cells, astrocytes seem mainly to contribute to brain energy metabolism. Moreover, other energy substrates such as lactate and pyruvate can be released by astrocytes, and they can potentially be used to a lesser degree to support the metabolism of neurons. Brain function and tissue integrity also are highly dependent on a continuous supply of oxygen. Changes in local brain energy metabolism now can be studied in humans using functional magnetic resonance imaging (MRI) and positron emission tomography (PET). These studies can monitor alterations in the relationships between blood flow, glucose utilization, and oxygen consumption during activation of specific brain areas. In addition to oxygen supply, clearance of carbon dioxide also is very important. Minimal changes in PaCO2 can have a marked impact on cerebral blood flow by changing the hydrogen ion concentration and then modulating extracellular pH. This can modify the cerebrovascular resistance and blood flow. Of importance to clinicians, hypercapnia relaxes vascular smooth muscles, whereas hypocapnia produces vasoconstriction and reduces flow. Disruption of blood flow, glucose utilization, oxygen supply, and clearance of metabolites all potentially can lead to metabolic encephalopathy. Metabolic encephalopathies can be divided into either primary or secondary, depending on whether the encephalopathy is due to a local metabolic disorder or a systemic disease, respectively. Systemic diseases that can cause a secondary metabolic encephalopathy, including those associated with hepatic, renal, and cardiovascular diseases as well as hypoglycemia, electrolyte disorders, and acid-base disturbances, are beyond the scope of this chapter. The focus here is on those brain diseases that are caused primarily by abnormal cellular metabolism or abnormal function of the mitochondrial respiratory chain.

Primary Metabolic Brain Diseases Primary metabolic brain disorders are the direct result of a defect in cellular metabolism, caused by deficiencies of either mitochondrial respiratory chain enzymes or, less commonly, cytosolic enzymes. This group of diseases usually is referred to as mitochondrial encephalopathy. In addition, encephalopathies due to an abnormal metabolism of organic and amino acids are discussed briefly at the end of the chapter.

Mitochondrial Encephalopathies Mitochondria are organelles located in the cytoplasm of almost all mammalian cells and they are inherited maternally. Because several important biochemical functions take place in mitochondria, such as the tricarboxylic acid cycle and oxidative phosphorylation as described earlier, defects in the respiratory chain complexes can lead to different metabolic disorders. Most of these defects are heritable and are the result of either a nuclear DNA or a mitochondrial DNA mutation (with mitochondrial DNA being of maternal inheritance). The clinical expression of a mitochondrial DNA mutation is heterogeneous. Tissues with high metabolic demand such as brain, heart, and muscle are more prone to develop dysfunction. Although pure neurologic syndromes involving either the central nervous system (CNS) or peripheral nervous system (PNS) are possible, multisystemic disorders are not uncommon. Different syndromes can be associated with the same mutation, and a single syndrome can be associated with different mutations. In humans, many mitochondrial encephalopathies, myelopathies, and myopathies have been reported. Recently, several inherited myopathies, mitochondrial encephalopathies, and encephalomyelopathies have been reported in dogs. Clinical Signs In humans with mitochondrial encephalopathy, severity can vary from acute life-threatening disease to a subacute progressive degenerative disorder. Progression may be unrelenting with rapid deterioration over hours, episodic with intermittent decompensations and asymptomatic intervals, or insidious with slow degeneration over decades. The presenting clinical signs of these neurometabolic diseases often are very non specific and are caused by progressive destruction of motor, mental, and perceptual functions potentially associated with seizures and with earlier death, often before adulthood. As in people, relatively nonspecific, progressive or episodic, classically life-threatening signs of CNS dysfunction related to neurometabolic diseases have been reported in isolated cases or families of dogs (Table 228-1). Since the neurons have the highest metabolic demand of the different brain cells, the cerebral cortex is the most  susceptible to energy metabolism disorders. Thus the overwhelming majority of animals with metabolic encephalopathies initially experience neurologic signs referable to forebrain dysfunction; these signs then can progress to more generalized brain involvement (brainstem or cerebellar signs may develop later on) and eventually death. The neurologic signs usually develop in the first year of life; however, the age of onset may vary from as young as 4 months to 6 years or older. Clinical signs usually are compatible with a generalized bilateral and symmetric encephalopathy or a multifocal CNS disease (e.g., cerebrum and cerebellum, or cerebrum and spinal cord). Clinical signs generally correlate well with the location of structural lesions observed on gross and microscopic examination of the CNS. However, the abnormalities  also may reflect a functional disturbance of neuronal

CHAPTER  228  Metabolic Brain Disorders

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TABLE 228-1  Clinical Signs and Imaging Findings in Dogs with Mitochondrial Encephalopathy Breed

Clinical Signs

Imaging Findings

Alaskan husky

Ataxia, seizures, behavioral abnormalities, blindness, facial hypalgesia and difficulty in prehension of food

MRI: Bilateral lesions in center of brainstem, extending from midthalamus to medulla; to a lesser degree, lesions in putamen, caudate nucleus, and claustrum. Lesions were hyperintense with T2 weighting and isointense/ hypointense nonenhancing with T1 weighting.

Yorkshire terrier

Behavioral changes with or without seizures, visual deficits, generalized ataxia

Well-circumscribed, noncontiguous, bilateral, oblique areas within basal nuclei, midthalamus and brainstem that appeared hypodense on CT and on MRI images; hyperintense with T2 weighting and hypointense nonenhancing with T1 weighting.

Jack Russell terrier

Ataxia/hypermetria, fine head tremor, bilateral blindness and deafness

Imaging not performed.

English springer spaniel

Ataxia/hypermetria, visual deficits, positional nystagmus, delayed postural reactions in all four limbs

Imaging not performed.

Shih Tzu

Progressive bilateral brachial plexus/caudal cervical spinal cord disorder; later, brain signs (behavioral changes such as aggressiveness and vocalization)

MRI: Two well-demarcated, intraaxial lesions into cervical spinal cord, caudal colliculi, vestibular nuclei, medulla of cerebellum; hyperintense with T2 weighting and FLAIR, and hypointense nonenhancing with T1 weighting.

Australian cattle dog

Seizures, followed by progressive ataxia and tetraparesis

MRI: Multiple ovoid, bilaterally symmetric, T2 hyperintense, T1 isointense/hypointense nonenhancing lesions on interposital nuclei, vestibular nuclei, pontine nuclei, and caudal colliculi.

Shetland sheepdog and Australian cattle dog

Seizures, followed by depressed mental status, hypermetric gait, intention head and neck tremor, and eventually inability to walk with extensor spasticity of all four limbs

CT: Diffuse hypomyelination (i.e., hypodense areas) and dilated lateral and fourth ventricles.

CT, Computed tomography; FLAIR, fluid attenuated inversion recovery; MRI, magnetic resonance imaging.

populations not visible by light microscopy, and this is relatively common in metabolic disorders. In cases of forebrain localization, mental obtundation, blindness, and behavioral changes with or without seizures have been reported most commonly. Brainstem-cerebellar signs such as generalized ataxia, dysmetria, and a widebased stance also have been reported with a relatively high frequency. A combination of these signs is seen with a diffuse or multifocal problem. Encephalopathies proved or suspected to be due to a mitochondrial disorder have been reported sporadically in Alaskan huskies, Yorkshire terriers, Jack Russell terriers, springer spaniels, Shih Tzus, Australian cattle dogs, and Shetland sheepdogs. However, other dogs previously reported to have vacuolar or spongiform encephalopathy of idiopathic origin currently are suspected to have an underlying mitochondrial dysfunction. The encephalopathy described in the Alaskan husky shares many similarities with that reported in the Yorkshire terrier, springer spaniel, and, to a lesser degree, the Jack Russell terrier and resembles subacute necrotizing encephalomyelopathy, or Leigh’s syndrome, in humans. This syndrome includes a heterogeneous group of heritable neurodegenerative diseases. Currently, most of the diseases reported are known

to be caused by diverse defects of the mitochondrial respiratory chain. In dogs with changes similar to those in Leigh’s syndrome, the clinical signs usually include ataxia (mostly cerebellar-quality ataxia), seizures, behavioral abnormalities (including obtundation and propulsive pacing), and visual deficits. Moreover, the neurologic examination commonly reveals delayed postural reactions and some other cerebellovestibular signs like nystagmus and head tremor. Varying degrees of tetraparesis, facial hypalgesia, and difficulty in prehending food also have been reported in Alaskan huskies. In Australian cattle dogs, after an initial presentation of psychomotor seizures (episodes of running in circles, vocalizing, and urinating), usually progressive fatigue and thoracic limb stiffness, and eventually spastic tetraparesis occur over a 6- to 12-month period (Harkin et al, 1999; Brenner et al, 1997b). In one dog, the thoracic limb stiffness was exacerbated while the dog was placed in lateral recumbency; the thoracic limbs were in fact rigidly extended in a tetanic posture with persistent contraction of extensor muscles (Harkin et al, 1999). In the single Shih Tzu recently reported in which a mitochondrial CNS disease was suspected, the signs initially were compatible

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SECTION  XI  Neurologic Diseases

with a progressive bilateral brachial plexus–caudal cervical spinal cord disorder that mostly spared the back  legs; only later did the dog develop concurrent brain  signs consisting of behavioral changes such as aggressiveness and vocalization (Kent et al, 2009). In the Shetland sheepdogs the clinical signs were intermittent, present from puppyhood, and composed mainly of seizures. As the disease progressed, depressed mental status, hypermetric gait, and intention head and neck tremor developed, and ultimately these dogs became unable to walk, with extensor spasticity of all four limbs (Wood et al, 2001). Diagnostic Tests Results of urinalysis and routine blood tests, including a serum biochemistry profile, usually are within normal limits. In humans with Leigh’s syndrome serum lactate and pyruvate levels can be elevated. Lactate and pyruvate levels were elevated in the cerebrospinal fluid (CSF) of the affected Australian cattle dogs, and in one of them, mild CSF pleocytosis and increase in protein content were detected (Brenner et al, 1997b). The remaining dogs had normal CSF findings. Advanced imaging such as computed tomography (CT) and MRI has been performed in a small number of canine cases, and as with humans, lesions associated with the diagnosis seem to be evident using magnetic resonance imaging. Some of the key features identified in dogs are summarized in Table 228-1. When CT examination was performed (Yorkshire terriers and Alaskan husky), changes were the same in distribution as those reported on MRI scans, and they were compatible with bilateral and symmetric cavitary lesions. In Shetland sheepdogs, in which the major histopathologic finding is the spongy degeneration of the white matter of the cerebrum and spinal cord (see next section), CT changes compatible with diffuse hypomyelination (i.e., hypodense areas) and dilated lateral and fourth ventricles were reported. However, MRI or CT findings reported in dogs with mitochondrial encephalomyelopathy are not pathognomonic and may be encountered to varying degrees in other brain diseases, including nutritional disorders (e.g., thiamine deficiency), toxicosis, and degenerative diseases (e.g., spongy degeneration of the CNS). Pathologic Findings The definitive diagnosis of Leigh’s syndrome in people is based on gross and histopathologic demonstration of characteristic lesions in the brain and spinal cord. Lesions usually are bilateral and symmetric and show a tendency to be noncontiguous. Characteristic features of acute lesions are loosening and spongiosis of the neuropil followed by necrosis. There is capillary proliferation, macrophage infiltration, gliosis, and occasional perivascular cuffs. An important feature is the relative preservation of neurons. Findings may vary in different regions in the same individual: although some areas may have end-stage lesions, others may show florid changes. The destructive process is episodic, and total tissue damage is cumulative. These lesions in humans with Leigh’s syndrome bear a considerable resemblance in their distribution and quality to those observed in the dog, the characteristics of which

are summarized in Table 228-2. There are differences between the canine and human disorders mainly in the topography of the lesions; the thalamus is the most severely affected region in dogs, whereas it is involved in fewer than half of Leigh’s syndrome cases. In the single springer spaniel with mitochondrial encephalopathy reported, no gross abnormalities were noted. Microscopically, the lesions were bilateral and symmetric throughout the brain and spinal cord. Other findings identified in affected canine breeds are summarized in Table 228-2. Interestingly, the histopathologic changes in Shetland sheepdogs delineated a leukodystrophy or leukoencephalomyelopathy resembling human Canavan’s disease, but amino acid and organic acid metabolism abnormalities were not detected. Diminished aspartoacylase enzyme activity in tissue and excessive N-acetylasparticaciduria, which are the hallmark abnormalities in Canavan’s disease, were not found in the affected dogs. The relative sparing of the neurons in all these forms except for the generalized involvement of astrocytes indicates an active role for the latter cells in brain metabolism, and this is further supported by histochemical studies that showed an abundance of enzymes in astrocytes that take part in different metabolic pathways. Astrocytic compromise is presumed to be diffuse throughout the neuraxis, whereas the multifocal involvement is believed to reflect regional variations in neuronal metabolism. Increased neuronal activity presumably increases the workload of adjacent astrocytes. Thus lesion topography as seen on histologic and MRI examinations may reflect glial sensitivity to the metabolic disturbance as well as regional neuronal functional activity. Ultrastructurally, mitochondrial abnormalities of either morphology or number in neuronal cells and more commonly astrocytes have been reported in Australian cattle dogs, Yorkshire terriers, English springer spaniels, Jack Russell terriers, and Shih Tzus (see Table 228-2). The lack of mitochondrial structural abnormalities cannot rule out the diagnosis of mitochondrial disease, and such abnormalities are identified in only a small percentage of people with mitochondrial disorders. In Yorkshire terriers an abnormal mitochondrial respiratory chain activity has been demonstrated. Moreover, in two families of dogs with the spongiform leukoencephalomyelopathy (Australian cattle dogs and Shetland sheepdogs) a maternally inherited missense mutation in mitochondrial DNA was identified that was related to respiratory chain dysfunction, but no overt changes in the mitochondria were apparent. The disorder in dogs initially was thought to resemble Canavan’s disease in people; however, these canine findings are more similar to a mitochondrial disorder known as Kearns-Sayre syndrome, in which the major pathologic finding is the spongy change of the white matter caused by the splitting of the myelin sheath, as is reported in the affected dogs. Treatment and Prognosis Treatments for mitochondrial encephalopathies in human patients have been unrewarding despite major advances in the understanding of mitochondrial diseases. Pharmacologic therapies have been reported to be of some isolated benefit, but for the vast majority of patients, the

CHAPTER  228  Metabolic Brain Disorders

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TABLE 228-2  Pathologic Changes and Related Mitochondrial Abnormalities in Dogs with   Mitochondrial Encephalopathy Breed

Pathologic Changes

Mitochondrial Abnormality

Alaskan husky

Bilateral and symmetric V-shaped cavitated foci in thalamus and basal nuclei, and sometimes extending into caudal brainstem. Microscopic lesions: varying degree of neuronal loss, spongiosis, gliosis, and cavitation. Minor multifocal lesions at base of sulci in cerebral cortex and in ventral vermis of cerebellum.

Not reported.

Yorkshire terrier

Changes similar to those reported in Alaskan husky.

Increased number of dysmorphic mitochondria. Abnormal mitochondrial respiratory chain activity.

Jack Russell terrier

Bilateral, symmetric neuronal degeneration and mineralization in cochlear and cerebellar nuclei, dorsal areas of medulla oblongata, vestibulocochlear nerve, and plexus choroideus, and within granule cell layer of ventral cerebellar hemispheres.

Mitochondria that were increased in number and enlarged.

English springer spaniel

Astrogliosis, mild focal spongiosis, and mild neuronal, mostly Purkinje cell, loss. Diffuse neuropil spongiosis in brain and spinal cord.

Giant and bizarre mitochondria within neuronal perikarya and axons.

Shih Tzu

Spongiosis of neuropil with reactive astrocytes in cervical spinal cord, caudal colliculi, and vestibular and cerebellar nuclei (polioencephalomyelopathy).

Mitochondria that were increased in number and swollen, mainly in astrocytes.

Australian cattle dog

Bilateral and symmetric foci of malacia in nuclei of cerebellum, caudal colliculi, lateral vestibular nuclei, lateral cuneate nuclei, lateral reticular nuclei, and gray matter of spinal cord associated with cervical and lumbosacral intumescences. Minor lesions in interposital nucleus and spinal nuclei of trigeminal nerve (polioencephalomyelopathy).

Marked mitochondrial accumulation and swelling in astrocytes.

Shetland sheepdog and Australian cattle dog

Spongiosis of white matter in cerebellar medulla and folia, in cerebral white matter, and in dorsal funiculi of spinal cord. Purkinje cells were slightly swollen.

Missense mutation in mitochondrial DNA but no changes in morphology or number.

current emphasis primarily is supportive. In many situations, supportive care for mitochondrial disease is no different from that for any other progressive illness. Reports of treatment efficacy thus far primarily are anecdotal or are based on small clinical trials using surrogate (as opposed to major clinical) end points. Dietary change and supplementation with various quantities of B vitamins, vitamin E, and other ergogenic aids such as coenzyme Q10 (CoQ10) have been used. CoQ10 is an essential component of the respiratory chain, and in a few well-documented cases of isolated CoQ10 deficiency its use has been highly effective. However, results were inconclusive in the only published double-blind, multicenter study of CoQ10 supplementation in humans with mitochondrial myopathies (Bresolin et al, 1990). Riboflavin and thiamine (B2 and B1 vitamins, respectively) are cofactors in respiratory chain complexes or enzymes. However, their therapeutic effects seem minimal at best. L-Carnitine often is used in conjunction with CoQ10 in patients with respiratory chain disease. Although only a minority of human patients with respiratory chain defects have a secondary carnitine deficiency, many individuals have reported an improvement in symptoms with L-carnitine treatment. However, the precise mechanism of benefit remains obscure. Corticosteroids also have been

TABLE 228-3  Recommended Dosages of Supplements in Canine Mitochondrial Myopathies Supplement

Dosage

L-Carnitine

50 mg/kg q12h PO

Coenzyme Q10

100 mg q24h PO

Riboflavin

100 mg q24h PO

PO, Orally.

used in patients with MELAS (mitochondrial myopathy, encephalopathy, lactic acidosis, and strokelike episodes) and other mitochondrial encephalomyopathies, but again there have been conflicting results. Thus far, reported canine cases have not been treated systematically, and all dogs have died or have been euthanized. Empiric therapy can be considered (Table 228-3). The inadequacy of these current biochemical therapeutic strategies has led to the consideration of gene therapy, which is still investigational.

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SECTION  XI  Neurologic Diseases

Encephalomyelopathy and Organic Acidopathies Inborn errors of metabolism, distinct from mitochondrial encephalopathies, rarely are reported in the veterinary medical literature. Several inherited diseases in people that involve abnormal metabolism of organic and amino acids leading to neurologic dysfunction have been reported in dogs, including L-2-Hydroxyglutaricaciduria, methylmalonic aciduria, and malonic aciduria with  progressive encephalopathy or encephalomyelopathy. Hexanoylglycineaciduria, similar to medium-chain acylcoenzyme A dehydrogenase deficiency in humans, was reported recently in a 2-month-old cavalier King Charles spaniel with refractory seizures that seemed to respond positively to levetiracetam therapy (Platt et al, 2007).

L-2-Hydroxyglutaricaciduria L-2-Hydroxyglutaricaciduria is the best characterized of the inborn errors of metabolism associated with encephalomyelopathy, and it is attributed to a mutation in the canine homolog of the L-2-hydroxyglutarate dehydrogenase (L2HGDH) gene. Although the specific metabolism of L-2-hydroxyglutaric acid and its physiologic and pathologic role are unknown, it is thought that a link may exist between L-2-hydroxyglutaric acid and lysine catabolism or oxidative stress from L-2-hydroxyglutaric acid buildup in the brain, and possibly interference with creatine kinase activity in the cerebellum. Clinical Signs In humans the clinical signs usually start during childhood and are characterized by progressive psychomotor delay with intellectual impairment, ataxia, and occasionally seizures. In dogs the disease first was reported in Staffordshire bull terriers and subsequently in a West Highland white terrier and a Yorkshire terrier. Although the development of clinical signs generally is thought  to be insidious and progressive, cases also have been reported with acute manifestations, especially in dogs with seizures. Signs usually occur within the first few years of life. Forebrain signs are common clinical findings in affected dogs, with behavioral changes, visual deficits, tonic-clonic seizures, and postural reaction deficits. Generalized ataxia, hypermetria, and head-neck tremors  also have been documented as a result of cerebellar involvement. Diagnostic Tests and Pathologic Findings Results of laboratory studies (including hematologic testing, biochemistry studies, and urinalysis) are normal in affected dogs. As in humans, MRI can reveal typical changes in dogs. Specific MRI characteristics of human L-2-hydroxyglutaricaciduria consist of prominent hyperintensities of the subcortical white matter tracts and hyperintensities in the gray matter regions of the basal ganglia and dentate nucleus with T2-weighted imaging. The areas of hyperintensity on T2-weighted images often correlate with regions of non-enhancing hypointensity on T1-weighted images. The cerebellum is prominently involved in most cases. In dogs, as in the mitochondrial

encephalopathies previously described, T2-weighted MRI reveals bilaterally symmetric and hyperintense lesions. These generally involve the cerebral and cerebellar cortices, thalamus, dorsal portion of the brainstem, and basal and cerebellar nuclei. The same areas are isointense to hypointense on T1-weighted images, with no evidence of contrast enhancement after intravenous injection of gadolinium. Results of routine CSF analysis are unremarkable. In humans, the diagnosis of the disorder is based on urinary organic acid screening with demonstration of a high concentration of L-2-hydroxyglutaric acid, which, however, also is consistently high in the CSF and plasma. High levels of L-2-hydroxyglutaric acid have been detected consistently in the CSF, plasma, and urine of affected dogs by means of gas chromatography and mass spectroscopy. The reported urine concentration ranges from 2223 mmol/ mol of creatinine to 3922 mmol/mol creatinine. High levels of methylmalonic acid, lysine, or arginine also have occasionally been reported, although their significance is unknown. Since L-2-hydroxyglutaricaciduria is inherited in both people and dogs as an autosomal-recessive disease, diagnosis may be confirmed through DNA testing for the mutation of the gene encoding L2HGDH. In one Staffordshire bull terrier a histopathologic examination of brain tissue was performed (Abramson et al, 2003). No gross lesions were identified in the brain. Microscopy of the brain mainly revealed clear or empty vacuoles in the gray matter astrocytes around neurons and blood vessels; changes extended into the adjacent white matter, with vacuoles found in astrocytes and myelin sheaths. Most of these changes were compatible with cytotoxic edema mainly affecting the gray matter (polioencephalopathy), although differences between gray and white matter lesions in dogs and those in humans were identified. Treatment and Prognosis Currently there is no known treatment for L-2-hydroxyglutaricaciduria, and as previously described for mitochondrial encephalopathy, metabolic disorders may require dietary manipulation to compensate for altered metabolic pathways. Thus supportive treatment and antioxidant diet supplementation with L-carnitine, CoQ10, and riboflavin have been attempted. The long-term prognosis is guarded. In dogs with seizure activity, phenobarbital has controlled clinical signs adequately. Cobalamin supplementation has been implemented in cases of concurrent methylmalonicaciduria, with uncertain results (see later). As with mitochondrial encephalopathies, gene therapy represents a possible future treatment option.

Methylmalonic Aciduria and Malonic Aciduria A progressive encephalomyelopathy has been reported in a 12-week-old Labrador retriever with a variety of forebrain and brainstem signs (Podell et al, 1996). Clinical findings included stiffness and ataxia that progressed to tetraparesis, nystagmus, decreased menace response, anisocoria, ventrolateral strabismus, diminished gag

CHAPTER  228  Metabolic Brain Disorders reflex, and apparent dysphonia. Significant biochemical abnormalities included methylmalonic aciduria and malonic aciduria, mild lactic aciduria, and pyruvic aciduria. Disordered cobalamin metabolism was suspected, although serum cobalamin levels were normal. The condition was considered an inborn error of metabolism resulting in abnormal organic acid accumulation with similarities to methylmalonicacidemia in neonatal humans (an autosomal-recessive disorder). Many human patients respond to large doses of vitamin B12, but cobalamin-unresponsive cases also have been reported. Results of B12 therapy are controversial. In the reported case, an 8-week-course of L-carnitine (1000 mg/day), vitamin B12 (0.5 mg/day), and a proteinrestricted diet resulted in marked improvement in the organic acid values in this dog. However, clinical improvement was not observed, which prompted euthanasia. At necropsy, enlargement of the lateral, third, and fourth ventricles of the brain and white and gray matter atrophy were grossly visible. Syringohydromyelia extended from the cervical to the lumbar intumescence. Malonic aciduria without elevated serum levels of methylmalonic acid has been reported in a family of Maltese dogs with signs of episodic seizures and stupor, along with hypoglycemia, acidosis, and ketonuria (O’Brien et al. 1999). Interestingly, treatment with frequent feedings of a low-fat diet high in medium-chain triglycerides resulted in normalization of clinical signs and a resolution of the malonic aciduria in one dog.

References and Suggested Reading Abramson CJ et al: L-2-hydroglutaric aciduria in Staffordshire bull terriers, J Vet Intern Med 17(4):551, 2003. Baiker K et al: Leigh-like subacute necrotising encephalopathy in Yorkshire Terriers: neuropathological characterisation, respiratory chain activities and mitochondrial DNA, Acta Neuropathol 118(5):697, 2009. Brenner O et al: A canine encephalomyelopathy with morphological abnormalities in mitochondria, Acta Neuropathol 94(4):390, 1997a. Brenner O et al: Hereditary polioencephalomyelopathy of the Australian cattle dog, Acta Neuropathol 94(1):54, 1997b. Brenner O et al: Alaskan Husky encephalopathy—a canine neurodegenerative disorder resembling subacute necrotizing encephalomyelopathy (Leigh syndrome), Acta Neuropathol 100(1):50, 2000.

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Bresolin N et al: Ubidecarenone in the treatment of mitochondrial myopathies: a multi-center, double blind trial, J Neurol Sci 100:70, 1990. Garosi LS et al: L-2-hydroxyglutaric aciduria in a West Highland white terrier, Vet Rec 156(5):145, 2005. Gruber AD et al: Mitochondriopathy with regional encephalic mineralization in a Jack Russell Terrier, Vet Pathol 39(6):732, 2002. Harkin KR et al: Magnetic resonance imaging of the brain of a dog with hereditary polioencephalomyelopathy, J Am Vet Med Assoc 214(9):1342, 1999. Kent M et al: Clinicopathologic and magnetic resonance imaging characteristics associated with polioencephalomyelopathy in a Shih Tzu, J Am Vet Med Assoc 235(5):551, 2009. Li FY et al: Canine spongiform leukoencephalomyelopathy is associated with a missense mutation in cytochrome b, Neurobiol Dis 21(1):35, 2006. Magistretti PJ et al: Brain energy metabolism: an integrated cellular perspective. In Bloom FE, Kupfer DJ, editors: Psychopharmacology: the fourth generation of progress, New York, 1995, Raven, p 657. Mariani CL et al: Magnetic resonance imaging of spongy degeneration of the central nervous system in a Labrador retriever, Vet Radiol Ultrasound 42(4):285, 2001. O’Brien DP et al: Malonic aciduria in Maltese dogs: normal methylmalonic acid concentration and malonyl-CoA decarboxylase activity in fibroblasts, J Inherit Metab Dis 22(8):883, 1999. Penderis J et al: L-2-hydroxyglutaric aciduria: characterisation of the molecular defect in a spontaneous canine model, J Med Genet 44(5):334, 2007. Platt S et al: Refractory seizures associated with an organic aciduria in a dog, J Am Anim Hosp Assoc 43(3):163, 2007. Podell M et al: Methylmalonic and malonic aciduria in a dog with progressive encephalomyelopathy, Metab Brain Dis 11:239, 1996. Rosenberg RN et al: Mitochondrial disorders. In Rosenberg et al, editors: The molecular and genetic basis of neurological disease, ed 2, Boston, 1998, Butterworth-Heinemann, p 35. Sanchez-Masian DF et al: L-2-hydroxyglutaric aciduria in two female Yorkshire terriers, J Am Anim Hosp Assoc 48:5, 2012. Taylor RW et al: Treatment of mitochondrial disease, J Bioenerg Biomembr 29(2):195, 1997. Wakshlag JJ et al: Subacute necrotising encephalopathy in an Alaskan husky, J Small Anim Pract 40(12):585, 1999. Wood SL, Patterson JS: Shetland Sheepdog leukodystrophy, J Vet Intern Med 15(5):486, 2001. Zauner A, Muizelaar JP: Brain metabolism and cerebral blood flow. In Reilly P, Bullock R, editors: Head injury, London, 1997, Chapman & Hall, p 89.

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229 

New Maintenance Anticonvulsant Therapies for Dogs and Cats CURTIS W. DEWEY, Ithaca, New York

O

ver the last 15 years the paradigm for treating dogs and cats with seizure disorders has changed, coincident with the introduction of several new anticonvulsant drugs. Although phenobarbital (dogs and cats) and bromide (dogs) remain valuable first-choice anticonvulsant drug options for pets with seizure disorders, a number of alternative drugs can be used as either adjunctive treatment (i.e., for refractory seizures) or sole therapy. The major impediments to widespread use of these newer anticonvulsant drugs have been principally higher cost compared with phenobarbital and bromide and clinical unfamiliarity with their usage. Since several of these drugs (gabapentin, zonisamide, levetiracetam) are now available in generic forms, cost is now less of a concern. Information is available concerning several newer anticonvulsant drugs for canine use. Unfortunately, much of the information regarding new anticonvulsant therapy for cats remains largely anecdotal, and the majority of clinical trials are neither randomized nor placebo controlled. This chapter provides information on some of these newer anticonvulsant drugs with recommendations based on published literature and my own clinical experience. Additionally, the next generation of some of these compounds is discussed briefly.

Gabapentin Gabapentin, a structural analog of γ-aminobutyric acid (GABA), probably exerts its antiseizure effects via inhibition of voltage-gated calcium channels in the brain. Gabapentin is well absorbed in both dogs and people, with peak serum concentrations occurring within 1 to 3 hours after ingestion. In dogs 30% to 40% of the orally administered dose of gabapentin undergoes hepatic metabolism to N-methyl-gabapentin. Although gabapentin undergoes some hepatic metabolism in dogs, there is no appreciable induction of hepatic microsomal enzymes in this species. The half-life of elimination for gabapentin in dogs is between 3 and 4 hours. Because of its short half-life in dogs, gabapentin probably needs to be administered at least every 8 hours and possibly every 6 hours to maintain serum gabapentin concentrations within the therapeutic range. The potential need for dosing every 6 hours can make it difficult for some pet owners to administer gabapentin consistently. 1054

The recommended daily dosage range of gabapentin for dogs is 25 to 60 mg/kg of body weight in divided doses q6-8h. I recommend an initial dosage regimen of 10 mg/ kg of body weight q8h. The suspected therapeutic plasma concentration for dogs is 4 to 16 mg/L. Gabapentin concentrations seldom are measured in dogs. The efficacy of gabapentin therapy in dogs has been evaluated in some small studies. In one prospective study evaluating gabapentin as an add-on treatment for dogs with refractory seizure activity, no significant decrease in overall seizure activity was seen over a 4-month evaluation period. Despite this, 3 of 17 dogs became seizure free, and 4 others experienced a reduction of 50% or more in seizure frequency during the evaluation period. In a similar study evaluating 11 dogs, an overall significant reduction in seizure frequency was found, and 6 dogs experienced a reduction of 50% or more in seizure frequency. Sedation and pelvic limb ataxia were the only reported adverse effects in these two studies. In my experience gabapentin occasionally is helpful as an anticonvulsant drug in dogs. In humans gabapentin appears to be much more effective in the treatment of focal seizure disorders than in the treatment of generalized seizures. Long-term canine toxicity trials for gabapentin have not been reported. However, the drug seems to be very well tolerated in this species, usually with few to no adverse effects. Sedation does not appear to be a major problem. However, I have had many clients report that their dog experienced mild sedation or mild polyphagia and weight gain in association with gabapentin use. Only anecdotal information is available regarding gabapentin use in cats. A dosage of 5 to 10 mg/kg of body weight q8-12h PO has been suggested but is not based on any published data. The elimination half-life of gabapentin in cats (approximately 3 hours) is similar to that in dogs, which suggests that a lower dose or longer dosing interval for this species is not necessary. A new gabapentin analog, pregabalin, has been approved recently for human use. Pregabalin has a greater affinity for the α2δ-subunit of voltage-gated calcium channels than gabapentin and purportedly is more effective in people than its predecessor as both an anticonvulsant and a pain-relieving drug. The elimination half-life of pregabalin is approximately 7 hours in dogs and 11 hours in cats. In a small, prospective clinical trial involving

CHAPTER  229  New Maintenance Anticonvulsant Therapies for Dogs and Cats epileptic dogs, administration of pregabalin (as an add-on therapy) was associated with an overall reduction in seizures of 57%. The response rate in this study was 78%, and the responding dogs had a mean 64% reduction in seizures. The main adverse effect of pregabalin appears to be sedation. The target dosage for canine epilepsy is about 3 to 4 mg/kg q12h. However, the starting dosage should be 2 mg/kg q12h for at least the first week to avoid severe sedation. I suspect the dosage range for cats (based on pharmacokinetic data) to be about half that for dogs (i.e., 1 to 2 mg/kg q12h).

Felbamate Felbamate is a dicarbamate drug that has demonstrated efficacy in the treatment of both focal (partial) and generalized seizures in experimental animal studies and human clinical trials. Proposed mechanisms of action include blocking of N-methyl-d-aspartate (NMDA)–mediated neuronal excitation, potentiation of GABA-mediated neuronal inhibition, and inhibition of voltage-sensitive neuronal sodium and calcium channels. Felbamate also may offer some protection to neurons from hypoxicischemic damage. Approximately 70% of the orally administered dose of felbamate in dogs is excreted in the urine unchanged; the remainder undergoes hepatic metabolism. The half-life of felbamate in adult dogs typically is between 5 and 6 hours (range, 4 to 8 hours). Felbamate is well absorbed after  oral administration in adult dogs, but bioavailability in puppies may be only 30% that in adults. The half-life of elimination also has been shown to be much shorter in puppies than in adult dogs (approximately 2.5 hours). For adult dogs I recommend an initial felbamate dosage regimen of 15 mg/kg of body weight q8h. Felbamate has a wide margin of safety in dogs, with serious toxic effects usually not apparent below a daily dose of 300 mg/kg of body weight per day. If the initial dose of felbamate is ineffective, the dose is increased by 15-mg/kg increments every 2 weeks until efficacy is achieved, unacceptable adverse effects are evident, or the cost of the drug becomes prohibitive. The therapeutic range for serum felbamate concentration in dogs is believed to be similar to that in people (20 to 100 µg/ml). Typically serum felbamate assays are costly. In addition, the wide therapeutic range and low toxicity potential of felbamate make routine serum drug monitoring of questionable clinical value. I do not routinely check felbamate levels in dogs. The limited published material regarding clinical efficacy of felbamate is similar to my experience with the drug. In one report of refractory epilepsy in dogs, 12 of 16 patients experienced a reduction of seizure frequency following initiation of felbamate therapy. In another report of six dogs with suspected focal seizure activity, all dogs experienced a substantial reduction in seizure frequency when felbamate was used as the sole anticonvulsant drug; two of these dogs became seizure free. I have used felbamate extensively in the treatment of dogs with seizure disorders. Felbamate appears to be very effective both as an add-on therapy and as a sole anticonvulsant agent for patients with focal and generalized seizures. Because of its lack of sedative effects, felbamate is

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particularly useful as monotherapy in dogs exhibiting obtunded mental status as a result of their underlying neurologic disease (e.g., brain tumor, cerebral infarct). I have found adverse effects from felbamate to be very infrequent, especially when it is used as the sole anticonvulsant drug. Hepatic dysfunction associated with felbamate use tends to resolve following discontinuation of the drug. In dogs with evidence of preexisting hepatic disease, felbamate should be avoided. Because of the potential for hepatoxicity, it is recommended that serum biochemistry analysis be performed every 6 months in dogs receiving felbamate, especially if the drug is given concurrently with phenobarbital. It also may be advisable to evaluate complete blood counts every few months in the unlikely event that a blood dyscrasia develops. Adverse effects are observed infrequently with felbamate use in dogs. Unlike other anticonvulsants, felbamate does not cause sedation. Because felbamate does undergo some hepatic metabolism, liver dysfunction is a potential adverse effect. In one study 4 of 12 dogs receiving felbamate as an add-on therapy developed liver disease; however, each of these dogs was also receiving high doses of phenobarbital. In humans felbamate has been shown to increase serum phenobarbital concentrations in some patients receiving combination therapy. It is unclear whether felbamate, phenobarbital, or the combination of the two drugs is responsible for the reported hepatotoxicity in dogs. In humans serious hepatotoxicity rarely is associated with felbamate use and usually occurs in patients concurrently receiving other anticonvulsant drugs. Aplastic anemia (caused by bone marrow suppression) has been reported to occur in people receiving  felbamate at a rate of 10 per 100,000 patients; this uncommon and severe adverse effect also usually is encountered in patients receiving combination anticonvulsant drug therapy. Fortunately this does not appear to occur in dogs. However, in one report reversible bone marrow suppression was suspected in two dogs receiving felbamate; one dog developed mild thrombocytopenia, the other mild leukopenia. Both of these abnormalities resolved following discontinuation of the drug. One patient in this report developed bilateral keratoconjunctivitis sicca; it is unknown whether this was related to felbamate use, although I have encountered several patients given felbamate that developed keratoconjunctivitis sicca. Generalized tremor activity in small-breed dogs receiving high dosages of felbamate also has been reported as a rarely encountered adverse effect. To my knowledge there is no clinical information regarding the use of felbamate in cats. Because of the potential for felbamate-associated hepatotoxicity and blood dyscrasias in dogs, felbamate is not likely to become a viable anticonvulsant option for cats. Because of the problems of hepatoxicity and blood dyscrasias occasionally associated with felbamate use in people, a new derivative of the drug—fluorofelbamate— has been developed and is undergoing clinical trials for human use. In experimental animal epilepsy models fluorofelbamate has been shown to have equal or superior anticonvulsant potency compared with felbamate. A  reactive aldehyde intermediate that is formed from felbamate metabolism has been linked to the hepatic and

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SECTION  XI  Neurologic Diseases

hematologic adverse effects of this drug. This toxic  intermediate is not produced from metabolism of fluorofelbamate.

Levetiracetam Levetiracetam is a new piracetam anticonvulsant drug that has demonstrated efficacy in the treatment of focal and generalized seizure disorders in people as well as in several experimental animal models. Although generally recommended as an add-on anticonvulsant drug, levetiracetam has been used successfully as monotherapy in people. In humans with refractory epilepsy, levetiracetam has manifested antiseizure effects within the first day of treatment. The mechanism of action of the anticonvulsant effects of levetiracetam is not entirely clear but appears to be related to its binding with a specific synaptic vesicle protein (SV2A) in the brain. Unlike other anticonvulsant drugs, levetiracetam does not appear to have a direct effect on common neurotransmitter pathways (e.g., GABA, NMDA) or ion channels (e.g., sodium, T-type calcium). Levetiracetam has demonstrated neuroprotective properties and may ameliorate seizure-induced brain damage. Levetiracetam also has been reported to have an “antikindling” effect, which may diminish the likelihood of increasing seizure frequency over time. Orally administered levetiracetam is approximately 100% bioavailable in dogs, with a serum half-life of 3 to 4 hours. In dogs approximately 70% to 90% of the administered dose of levetiracetam is excreted unchanged in the urine; the remainder is hydrolyzed in the serum and other organs. The effective serum levetiracetam concentration in people is 5 to 45 µg/ml. Because there is no clear relationship between serum drug concentration and efficacy for levetiracetam, and because the drug has an extremely high margin of safety, routine therapeutic drug monitoring is not typically recommended for this drug in humans. In one small, uncontrolled clinical study, oral levetiracetam was found to decrease seizure frequency by over 50% in epileptic dogs when used as an add-on therapy. Subsequent to that report, however, levetiracetam was shown to be ineffective as an add-on antiseizure drug in a placebo-controlled clinical trial. There was also one report suggesting that levetiracetam shows a distinct “honeymoon” effect in dogs, working fairly well initially, then fading in efficacy over time. There is evidence that levetiracetam metabolism is accelerated over time in dogs concurrently receiving phenobarbital. This phenomenon may explain at least partially the apparent failure of levetiracetam as an add-on antiseizure drug. In the placebocontrolled levetiracetam study, it was found that 38% of dogs had levetiracetam plasma drug concentrations below the level considered to be the lower limit of the therapeutic range for the drug. In terms of cost, levetiracetam is more expensive than zonisamide but less expensive than felbamate. Based on recent evidence, it may be that the recommended levetiracetam dosage of 20 mg/kg three times daily may be too low for dogs, especially for those patients concurrently receiving phenobarbital therapy. Long-term toxicity data for levetiracetam in dogs confirm that the drug is extremely safe. In one study dogs

were administered levetiracetam at dosages of up to 1200 mg/kg/day PO for 1 year. One of eight dogs receiving 300 mg/kg/day developed a stiff, unsteady gait. Other adverse effects (salivation, vomiting) were seen only in dogs receiving 1200 mg/kg/day. There were no treatmentrelated mortalities or histopathologic abnormalities. My colleagues and I have prospectively investigated the use of oral levetiracetam as an add-on anticonvulsant therapy for cats with epilepsy refractory to phenobarbital. Levetiracetam appears to be very well tolerated in this species, usually with no apparent adverse effects. The half-life of elimination is approximately 3 hours after oral administration. A dosage of 20 mg/kg q8h PO typically achieves a serum drug level within the therapeutic range reported for people. Two of twelve cats experienced transient inappetence and lethargy that resolved without dose adjustment within 2 weeks. Although there is some degree of variability among cats, the mean reduction of seizure frequency in cats receiving levetiracetam as an add-on drug is approximately 68%; this was found to be statistically significant when compared with seizure frequency before initiation of levetiracetam therapy. In addition, 7 of 10 cats evaluated for seizure frequency reduction showed a response (i.e., reduction of seizure frequency  of 50% or more), with a mean reduction of seizures of 92%. I consider levetiracetam to be the preferred add-on anticonvulsant drug for cats receiving phenobarbital because of lack of serious adverse effects and evidence of efficacy. Intravenous administration of levetiracetam has shown promise as a treatment for experimental status epilepticus in a rat model. In this study intravenous  levetiracetam and diazepam appeared to potentiate the anticonvulsant effect of one another. Intravenous levetiracetam seems well tolerated in dogs, even at doses as high as 400 mg/kg of body weight. The pharmacokinetics of intravenous levetiracetam has been investigated in dogs. In my practice I have had success using intravenous levetiracetam for years as an emergency seizure drug. There is recent clinical evidence supporting the efficacy of intravenous levetiracetam for treating canine seizures in an emergency situation (e.g., status epilepticus and cluster seizures). Since the discovery of levetiracetam’s unique binding site in the brain, two related anticonvulsant drugs— brivaracetam and seletracetam—have been developed that have higher affinity than levetiracetam for the SV2A receptor. These drugs have been demonstrated to have better anticonvulsant activity than levetiracetam in experimental animal seizure models and currently are being evaluated in human clinical epilepsy trials.

Zonisamide Zonisamide is a sulfonamide-based anticonvulsant drug recently approved for human use; it has demonstrated efficacy in the treatment of both focal and generalized seizures in people with minimal adverse effects. Suspected anticonvulsant mechanisms of action include blockage of T-type calcium and voltage-gated sodium channels in the brain, facilitation of dopaminergic and serotonergic neurotransmission in the central nervous system, scavenging

CHAPTER  229  New Maintenance Anticonvulsant Therapies for Dogs and Cats of free radical species, enhancement of the actions of GABA in the brain, inhibition of glutamate-mediated neuronal excitation in the brain, and inhibition of  carbonic anhydrase activity. Zonisamide is metabolized  primarily by hepatic microsomal enzymes, and the elimination half-life in dogs is approximately 15 to 20 hours. The elimination half-life of zonisamide in cats is substantially longer (approximately 33 hours). In humans it has been shown that the elimination half-life of zonisamide is dramatically shorter in patients who are already receiving drugs that stimulate hepatic microsomal enzymes than in patients who are not receiving such drugs. A similar phenomenon appears to occur in dogs. When zonisamide is used as an add-on therapy for dogs already receiving drugs requiring hepatic metabolism (e.g., phenobarbital), I recommend an initial zonisamide dosage of 10 mg/kg of body weight q12h PO. This dosage regimen has been shown to maintain canine serum zonisamide concentrations within the therapeutic range reported for people (10 to 40 µg/ml) when used as an add-on therapy. For dogs not concurrently receiving drugs that induce hepatic microsomal enzymes, it is recommended that zonisamide be started at a dosage of 5 mg/kg of body weight q12h. I generally check trough serum zonisamide concentrations after approximately 1 week of zonisamide treatment. Zonisamide has a high margin of safety in dogs. In one study minimal adverse effects occurred in beagles administered zonisamide at dosages of up to 75 mg/kg of body weight per day for 1 year. However, there is some potential for hepatotoxicity with zonisamide use in dogs; routine blood monitoring (every 6 months) therefore is recommended. In one study zonisamide was found to decrease seizure frequency by at least 50% in 7 of 12 dogs with refractory idiopathic epilepsy. In this responding group the mean reduction in seizure frequency was 81.3%. In six of the seven responding dogs phenobarbital dose was able to be reduced by an average of 92.2%. Mild adverse effects (e.g., transient sedation, ataxia, vomiting) occurred in six dogs (50%); none of the adverse effects was considered severe enough to require discontinuing zonisamide therapy. In another similarly designed study, 9 of 11 dogs with refractory epilepsy treated with zonisamide showed a response, with a median seizure reduction of 92.9%; transient ataxia and sedation occurred in six dogs. Zonisamide has been shown to be very effective as a sole anticonvulsant drug in people. I have used zonisamide as the sole anticonvulsant drug in a large number of dogs. Zonisamide appears to be effective as anticonvulsant monotherapy, with few to no apparent adverse effects  in dogs. My colleagues and I have successfully treated a number of epileptic cats with zonisamide as a sole drug or as an add-on to phenobarbital therapy. In some cats, once-  daily dosing is possible, presumably due to the long

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elimination half-life in this species. The recommended starting dosage is either 5 mg/kg twice daily or 10 mg once daily in cats. The main adverse effect of zonisamide use in cats is anorexia; the occurrence of this adverse effect has necessitated discontinuation of zonisamide for resolution. Further data are needed regarding the use of zonisamide in cats.

References and Suggested Reading Bailey KS et al: Levetiracetam as an adjunct to phenobarbital treatment in cats with suspected idiopathic epilepsy, J Am Vet Med Assoc 232:867, 2008. Bialer M: New antiepileptic drugs that are second generation to existing antiepileptic drugs, Expert Opin Investig Drugs 15:637, 2006. Dewey CW: Anticonvulsant therapy in dogs and cats, Vet Clin Small Anim 36:1107, 2006. Dewey CW et al: Zonisamide therapy for refractory idiopathic epilepsy in dogs, J Am Anim Hosp Assoc 40:285, 2004. Dewey CW et al: Pharmacokinetics of single-dose intravenous levetiracetam administration in normal dogs, J Vet Emerg Crit Care 18:153, 2008. Dewey CW et al: Pregabalin as an adjunct to phenobarbital, potassium bromide, or a combination of phenobarbital and potassium bromide for treatment of dogs with suspected idiopathic epilepsy, J Am Vet Med Assoc 235:1442, 2009. Govendir M, Perkins M, Malik R: Improving seizure control in dogs with refractory epilepsy using gabapentin as an adjunctive agent, Aust Vet J 83:602, 2005. Hardy BT et al: Double-masked, placebo-controlled study of intravenous levetiracetam for the treatment of status epilepticus and acute repetitive seizures in dogs, J Vet Intern Med 26:334, 2012. Hasegawa D et al: Pharmacokinetics and toxicity of zonisamide in cats, J Feline Med Surg 10:418, 2008. Mazarati AM, Sofia RD, Wasterlain CG: Anticonvulsant and antiepileptogenic effects of fluorofelbamate in experimental status epilepticus, Seizure 11:423, 2002. Moore SA et al: The pharmacokinetics of levetiracetam in healthy dogs concurrently receiving phenobarbital, J Vet Pharmacol Ther 34:31, 2010. Munana K et al: Evaluation of levetiracetam as adjunctive treatment for refractory canine epilepsy: a randomized, placebocontrolled, crossover trial, J Vet Intern Med 26:341, 2012. Ramael S et al: Levetiracetam intravenous infusion: a randomized, placebo-controlled safety and pharmacokinetic study, Epilepsia 47:1128, 2006. Salazar V et al: Pharmacokinetics of single-dose oral pregabalin administration in normal dogs, Vet Anaesth Analg 36:574, 2009. Sia KT et al: Pharmacokinetics of gabapentin in cats, Am J Vet Res 71:817, 2010. Vartanian MG et al: Activity profile of pregabalin in rodent models of epilepsy and ataxia, Epilepsy Res 68:189, 2006. Volk HA et al: The efficacy and tolerability of levetiracetam in pharmacoresistant epileptic dogs, Vet J 176:310, 2008. Von Klopman T et al: Prospective study of zonisamide therapy for refractory idiopathic epilepsy in dogs, J Small Anim Pract 48:134, 2007.

CHAPTER 

230 

Treatment of Cluster Seizures and Status Epilepticus DANIEL J. FLETCHER, Ithaca, New York

A

cute-onset seizures are common presenting complaints in veterinary emergency practice. They are caused by focal groups of abnormal neurons that initiate and then propagate bursts of aberrant activity. These episodes generally are short-lived, but prolonged seizure activity or repeated seizures can be life threatening and must be treated aggressively. Treatment of cluster seizures or status epilepticus should focus on rapid treatment of the seizures, identification and treatment of systemic sequelae such as hypoperfusion, hyperthermia, and deficits in ventilation and oxygenation, and in-patient therapy targeted at achieving a 24-hour seizure-free interval. Additional workup to identify the underlying cause of the seizures should be initiated once the patient’s condition has been stabilized. Finally, an anticonvulsant treatment plan tailored to the needs of the patient and client must be devised. This chapter considers these aspects of diagnosis and therapy.

Pathophysiology A seizure is initiated by a high-frequency burst of action potentials within a local, hypersynchronized population of neurons. When a large enough population of neurons is involved, a characteristic spike can be seen in the electroencephalogram (EEG). Within this population, individual neurons experience a sequence of events that includes the following: (1) an intracellular influx of calcium and sodium, leading to a high-frequency burst of action potentials at approximately 700 to 1000/sec; (2) a phase during which the cell remains depolarized; and finally (3) rapid influx of chloride or efflux of potassium mediated by γ-aminobutyric acid (GABA) receptors, which leads to rapid repolarization and hyperpolarization. Although the cause commonly is forebrain disease, other areas of the brain, including the thalamus, subcortical nuclei, and brainstem, can participate in the genesis and propagation of seizures. Individual, infrequent, and short-duration seizures may not require therapy, but severe, acute seizures are life-threatening emergencies, and aggressive therapy is warranted. Cluster seizures and status epilepticus are the two most life-threatening types of seizures. A cluster of seizures is defined clinically as more than one seizure within a 24-hour period, between which the patient returns to normal mentation and activity. Status epilepticus is seizure activity that continues unabated for longer than 5 minutes or multiple seizures between which the 1058

patient does not return to normal mentation. With these types of severe seizures, direct neuronal damage is common and predisposes the patient to more frequent and severe seizures in the future. In addition, systemic sequelae such as traumatic injury to other parts of the body, hyperthermia leading to disseminated intravascular coagulation (DIC), aspiration pneumonia, and noncardiogenic pulmonary edema are common, so that close monitoring and intensive supportive care are required even after the seizures have been controlled. Aggressive management of cluster seizures and status epilepticus is essential, and both intracranial and extracranial priorities must be addressed.

Differential Diagnoses and Diagnostic Workup Both extracranial and intracranial diseases may cause seizures. Determining the definitive cause of an individual patient’s seizures can require an extensive diagnostic workup, but development of the best treatment plan and accurate estimation of prognosis depends upon an accurate diagnosis.

Extracranial Causes of Seizure Metabolic disturbances and systemic disease can lead to alterations in the electrophysiology of the brain, causing paroxysmal neuronal discharges and seizures. In general, these types of diseases are likely to cause widespread disturbances affecting both hemispheres. Therefore generalized seizures are more common than focal seizures. Endogenous toxins accumulating because of hepatic or renal disease can lead to seizures. Metabolic disturbances such as hypoglycemia, hyperlipidemia, hypocalcemia, and hypermagnesemia as well as endocrine diseases such as hypothyroidism and hyperosmolar nonketotic diabetes mellitus also can lead to seizures. Many toxicoses, including bromethalin, theobromine, caffeine, lead, or organophosphate poisoning, can result in seizures. Initial diagnostic testing should include a complete blood count to rule out systemic inflammation or infection and platelet disorders, as well as a chemistry panel and urinalysis to rule out electrolyte and glucose derangements and to assess renal and hepatic function. Taking a thorough history to rule out potential toxin exposure also is essential. For patients in which there is a high index  of suspicion of extracranial disease, further diagnostic

CHAPTER  230  Treatment of Cluster Seizures and Status Epilepticus

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studies including abdominal ultrasonography or specific organ function testing may be warranted.

catteries and multicat households, feline infectious peritonitis becomes more likely.

Intracranial Causes of Seizure

Treatment

Once extracranial causes of seizure are ruled out, the many primary intracranial causes of seizure must be considered. In patients with localizing neurologic deficits (e.g., cranial nerve dysfunction or lateralized proprioceptive deficits), intracranial disease is more likely than extracranial disease. A classification scheme such as DAMNIT-V can be helpful for organizing this large list of disorders. See Table 230-1 for a compilation of differential diagnoses using the DAMNIT-V scheme. Definitive diagnosis of intracranial causes of seizure commonly requires advanced imaging such as magnetic resonance imaging or computed tomography and cerebrospinal fluid analysis, which usually cannot be done until the patient is in stable condition and seizures are controlled. Basic historical and signalment data can be useful in ranking the relative likelihood of each of the differential diagnoses. In dogs younger than 6 months of age, infectious or anomalous diseases are most common. In dogs between 6 months and 6 years of age, idiopathic epilepsy is most common, and in dogs older than 6 years of age, neoplasia is most likely. In younger cats, infectious and anomalous diseases are most common. In outdoor cats, parasitic  diseases like cuterebriasis should be considered, and in

Treatment includes emergent anticonvulsant therapy and extracranial stabilization. A number of anticonvulsant drugs are effective in the acute setting, but careful patient monitoring is important. The management of extracranial complications and support of other organ systems is also of vital importance.

TABLE 230-1  Differential Diagnosis of Acute-Onset Seizures (DAMNIT-V Scheme) D

Degenerative

Storage diseases

A

Anomalous

Hydrocephalus, lissencephaly

M

Metabolic

Extracranial diseases: hepatic, renal

N

Neoplasia

Primary: meningioma, glioma, astrocytoma Metastatic: lymphoma, hemangiosarcoma, carcinomas, etc.

I

Infectious

Viral: rabies, distemper, feline infectious peritonitis Bacterial: inoculation via wounds or hematogenous spread Fungal: cryptococcosis Protozoal: toxoplasmosis (dog and cat), neosporosis (dog) Rickettsial: Rocky Mountain spotted fever (Rickettsia rickettsii infection) Parasitic: cuterebriasis, visceral larva migrans Granulomatous meningoencephalomyelitis, steroid-responsive meningitis/arteritis, necrotizing encephalitis (Yorkshire terrier, pug) Epilepsy

Inflammatory

Idiopathic T

Trauma Toxin

Traumatic brain injury Bromethalin, theobromine, caffeine, lead, organophosphate poisoning

V

Vascular

Thromboembolic disease, intracranial hemorrhage

Emergent Anticonvulsant Therapy It is vital that seizure activity be stopped as soon as possible to prevent continued injury to the brain and to reduce the potential for systemic sequelae. The goal of emergent anticonvulsant therapy is to stop all seizure activity immediately and to prevent all additional seizures for a 24-hour period. It should be recommended strongly to the owner of any patient with cluster seizures or status epilepticus that the animal be admitted to the hospital for a minimum of 24 hours for intravenous anticonvulsant therapy. If the patient has additional seizures within the first 24 hours of therapy, the 24 hour time period should be restarted. Benzodiazepines Intravenous diazepam (0.5 to 1.0 mg/kg) or midazolam (0.066 to 0.22 mg/kg) should be considered first-line therapy for patients with severe, acute seizures. These drugs are GABA agonists and cause hyperpolarization of neurons via influx of chloride ions, which results in cessation of seizure activity. They generally are effective and safe when given intravenously in dogs and cats, and have a low likelihood of significant adverse effects, although a small number of cats have been reported to develop fatal acute hepatic necrosis when administered diazepam orally. For patients in whom intravenous access is not readily available, diazepam at a dose of 1 to 2 mg/kg can be administered rectally and is absorbed rapidly. To ensure adequate retention of the drug when administered rectally, it should be injected through a red rubber catheter passed into the colon and flushed with saline or air. Intramuscular midazolam has also recently been shown to be as effective and safe as intravenous benzodiazepines for status epilepticus in people and may be considered an alternative to rectal diazepam in patients without IV access. If the patient responds to benzodiazepine therapy but shows rapid recrudescence, an intravenous constantrate infusion should be considered. Diazepam at 0.5 to 2.0 mg/kg/hr often is effective, but the drug should be protected from light and drawn up from a glass vial freshly every 6 hours because of its capacity to bind to plastic. Barbiturates For those patients with seizures refractory to benzodiazepine therapy, barbiturates (pentobarbital, phenobarbital) sometimes can be effective. Phenobarbital is the barbiturate of choice for treating seizures. It is a highly effective anticonvulsant (2 to 6 mg/kg IV) but can take 15 to 20

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SECTION  XI  Neurologic Diseases

minutes to show an effect. If an effect is not noted  within 15 to 30 minutes, the dose may be repeated to raise blood levels to the therapeutic range more rapidly (to a maximum loading dose of 16 mg/kg within the first 24 hours); however, care must be taken to avoid overdose, which can cause hypoventilation or apnea. Close monitoring of ventilation via arterial or venous blood gas measurement or end-tidal capnography is recommended. Pentobarbital (2 to 15 mg/kg IV) can terminate the physical manifestations of seizure activity effectively within several minutes, but it generally is not considered to be an effective anticonvulsant, and its ability to stop seizure activity in the brain is questionable. Propofol Propofol is a rapidly acting injectable anesthetic that is a centrally acting GABA agonist. It may be administered to effect via slow intravenous injection at a dose of 1 to 6 mg/kg and has been shown to be effective at stopping seizure activity (cluster seizures and status epilepticus) in human and veterinary medicine. If the initial bolus dose is effective but seizures recur, a constant-rate infusion at 0.1 to 0.6 mg/kg/min may be instituted. Apnea, vasodilation, and cardiovascular depression are important adverse effects to consider, and it is the author’s opinion that any animal receiving a propofol infusion should be intubated to protect the airway. Ventilation should be closely monitored to detect hypoventilation. Patients that persistently hypoventilate while receiving propofol may need to undergo mechanical ventilation. Levetiracetam Levetiracetam (Keppra) is a piracetam anticonvulsant that has shown efficacy for treatment of seizures in people and experimental animals. This drug exerts its anticonvulsant effect via several mechanisms, including stabilization of presynaptic vesicles by V2 receptor activation, which reduces the release of excitatory neurotransmitters. It does not appear to act via the more common neurotransmitter receptors or ion channels. It has a high bioavailability in dogs and is excreted unchanged in the urine without any significant hepatic metabolism. It has no sedative adverse effects. Intravenous administration is well tolerated in dogs, even at very high doses of 400 mg/ kg (published oral dose is 20 mg/kg q8h PO). It is available in an intravenous formulation (also administered at 20 mg/kg IV as a bolus). Because of its high therapeutic index, intravenous administration may be repeated frequently in patients with cluster seizures or status epilepticus. There are limited but encouraging data suggesting that this drug also is effective in cats, both as monotherapy and as part of a multidrug anticonvulsant therapeutic regimen.

Extracranial Stabilization Rapid identification and treatment of life-threatening extracranial sequelae of seizures is essential for successful case management and good patient outcome. Rapid primary assessment to identify cardiovascular or respiratory dysfunction and adequacy of systemic perfusion is crucial.

Hyperthermia Sustained seizure activity produces a large amount of heat, overwhelming the body’s cooling mechanisms and resulting in severely elevated body temperature. Body temperature should be measured as soon after presentation as possible. Any patient with a core body temperature higher than 40.6° C (105° F) should be cooled actively. Administering room temperature intravenous fluids, wetting the fur, cooling with fans, and placing the animal directly on a metal surface are recommended. Core body temperature should be rechecked frequently, preferably with the use of an indwelling rectal temperature probe. Active cooling should be discontinued when the temperature drops to 39.4° C (103° F) to reduce the risk of hypothermia. The use of ice packs or ice baths is not recommended because these can lead to peripheral vasoconstriction, which decreases radiant, convective, and conductive heat loss through the skin. The application of alcohol to the foot pads also is discouraged because the effectiveness of evaporative cooling over such a small surface area is questionable and the flammability of the alcohol puts the patient at risk, especially if electrical defibrillation is required should the patient experience cardiopulmonary arrest. Hyperthermia can lead to many systemic sequelae, including DIC, hypoglycemia, acid-base disturbances, hypotension, pulmonary edema, and multiorgan failure. Meticulous serial monitoring of the patient after cooling is recommended and should include blood pressure measurement, assessment of oxygenation and ventilation status, and daily platelet counts to identify early signs  of DIC. Perfusion Hypotension and poor perfusion are common in patients with cluster seizures and status epilepticus because of vasodilation secondary to hyperthermia or neurogenic shock and hypovolemia from fluid loss. Aggressive fluid therapy using isotonic crystalloids, hypertonic crystalloids, or synthetic colloids (see Chapter 2) should be initiated early in the course of treatment to normalize blood pressure. In patients with persistent, inappropriate vasodilation that remain hypotensive in the face of adequate volume resuscitation, pressor therapy (e.g., norepinephrine, or vasopressin) should be considered (Chapters 3 and 4), but only if hypovolemia has been addressed adequately first. Clinical signs of persistent vasodilation include hyperemic oral mucous membranes, fast capillary refill times (2 sec) are unlikely to benefit from vasoconstrictors, and these drugs should be avoided. Recommended fluid resuscitation and vasopressor dosages are listed in Table 230-2. Ventilation The partial pressure of CO2 in the arterial blood (PaCO2) is a potent regulator of cerebrovascular tone. Normocapnia (PaCO2 > 35 mm Hg and < 45 mm Hg) is essential for the maintenance of cerebral perfusion and prevention of cerebral hyperemia, which can cause increased

CHAPTER  230  Treatment of Cluster Seizures and Status Epilepticus

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TABLE 230-2  Recommendations for Fluid Resuscitation in the Seizure Patient Indication

Drug

Dosage

Comments

Fluid Resuscitation for Hypovolemia Dehydrated patients

Isotonic crystalloids (0.9% saline, lactated Ringer’s, Normosol-R, Plasma-Lyte A)

20-30 ml/kg over 15 min; may be repeated

Generally safe, effective, and inexpensive. Repeat doses may be administered until resuscitation end points are achieved.

Euhydrated patients

Synthetic colloids (hetastarch, dextran 70, pentastarch)

5-10 ml/kg over 15 min; may be repeated

Hypertonic saline (7%) + synthetic colloid

3-5 ml/kg over 15 min; may be repeated

Hypertonic saline (7%-7.8%)

3-5 ml/kg over 15 min; may be repeated

Volume expansion effects much greater than volume administered. Particularly useful in hypoproteinemic patients. May exacerbate coagulopathies or platelet disorders. Contraindicated in hyponatremic patients. Monitor serum sodium concentrations with repeat dosing. If using 23.4% solution, dilute 1 part hypertonic saline with 2 parts colloid. Contraindicated in hyponatremic patients. Monitor serum sodium concentrations with repeat dosing. If using 23.4% solution, dilute 1 part hypertonic saline with 2 parts 0.9% saline or sterile water.

Norepinephrine

1-10 µg/kg/min

Vasopressin

1-4 mU/kg/min

Vasopressor Therapy Vasodilation and hypotension in the face of adequate volume resuscitation

intracranial pressure (ICP). Many anticonvulsants (e.g., benzodiazepines, barbiturates, propofol) can lead to sedation and hypoventilation, which requires intubation or tracheostomy and mechanical ventilation. Patients receiving constant-rate infusions of propofol should be intubated using a sterile endotracheal tube with an inflated cuff to reduce the risk of aspiration pneumonia because these patients often fail to protect the airway. The tube should be suctioned using sterile technique as needed. Acid-base disturbances and hyperthermia can lead to hyperventilation, which causes cerebral vasoconstriction and decreased delivery of oxygen and nutrients to the brain. These conditions should be treated aggressively to minimize effects on cerebral blood flow. Serial monitoring of ventilation is recommended for all patients during hospitalization. Arterial blood gas analysis is the preferred method, but the partial pressure of CO2 (PCO2) in venous blood never should be lower than that in arterial blood and can be used to monitor for hypoventilation. Endtidal CO2 monitoring is useful in intubated patients for continuous monitoring of ventilation status. Oxygenation The brain has a high basal metabolic rate and is intolerant of deficits in oxygen and nutrient delivery. Supplemental oxygen should be provided to all patients with status epilepticus or cluster seizures via mask, oxygen cage, nasal catheter, or intubation. In cases of severe edema or pneumonia, mechanical ventilation may be required to address

Potent vasoconstrictor with primarily α1 effects. Start at 1 µg/kg/min and titrate up by 1 µg/kg/min q15 min until desired blood pressure is reached. Very potent vasoconstrictor via V1 receptors. Start at 1 mU/kg/min and titrate up by 0.5 mU/kg/min until desired blood pressure reached.

hypoxemia. Serial monitoring of oxygenation using pulse oximetry measurements or arterial blood gas analysis is recommended for all patients with status epilepticus or cluster seizures because of the risk of noncardiogenic  pulmonary edema and aspiration pneumonia. Thoracic radiographs should be obtained after stabilization for any patient with persistent hypoxemia (pulse oximetry O2 saturation < 95% on room air or PaO2 < 80 mm Hg on room air). Oxygen-carrying capacity of the blood is determined primarily by the amount of hemoglobin present. Packed red blood cell or whole blood transfusion should be considered in anemic patients, especially if the anemia is acute.

Intracranial Stabilization A number of treatments and physical modifications can be used to provide intracranial stabilization. Mannitol Because of accumulations of intracellular sodium and calcium and increased cerebral vascular permeability, cerebral edema is common during and after severe acute seizures. Mannitol is a highly effective therapy for patients with increased ICP and has been shown to reduce cerebral edema, increase cerebral perfusion pressure and cerebral blood flow, and improve neurologic outcome in patients with cerebral edema. It has a rapid onset of action, with clinical improvement occurring within minutes of

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SECTION  XI  Neurologic Diseases

TABLE 230-3  Drugs and Dosages for Treatment of Increased Intracranial Pressure (ICP) in the Seizure Patient Indication

Drug

Dosage

Notes

Increased ICP in normotensive or hypertensive patients

Mannitol 25%

0.5-1.0 g/kg IV over 15 min; may be repeated

Hypertonic saline (7%)

3-5 ml/kg over 15 min; may be repeated

Can lead to severe dehydration. Treat with crystalloids to prevent dehydration and hypovolemia. Closely monitor fluid input and output. Dilute 1 part 23.4% hypertonic saline with 2 parts sterile water or normal saline. Do not use in hyponatremic or hypernatremic patients because may cause rapid changes in serum sodium concentrations. Monitor serum sodium levels.

Hypertonic saline (7%) + dextran or hetastarch

Dogs: 4 ml/kg over 15 min Cats: 2 ml/kg over 15 min May be repeated

Hypertonic saline (7%)

2-4 ml/kg over 15 min; may be repeated

Increased ICP in hypovolemic/ hypotensive patients

administration, and these effects can last as long as 1.5 to 6 hours. Mannitol boluses of 0.5 to 1.0 g/kg IV over 15 to 20 minutes have been recommended for treatment of increased ICP in dogs and cats (see Table 230-3 for dosing and indications). The diuretic effect of mannitol can be profound and can cause severe volume depletion and rebound hypotension. Therefore treatment must be followed by administration of isotonic crystalloid solutions or colloids to maintain intravascular volume. Hypertonic Saline Hypertonic saline (HTS) is a hyperosmotic solution that may be used as an alternative to mannitol in patients with cerebral edema at a dose of 4 ml/kg over 15 to 20 minutes in dogs and 2 ml/kg in cats (see Table 230-3 for dosing and indications). Because sodium does not freely cross an intact blood-brain barrier, HTS has osmotic effects similar to those of mannitol. Other beneficial effects of HTS include improved hemodynamic status via volume expansion and positive inotropic effects, as well as beneficial vasoregulatory and immunomodulatory effects. Rebound hypotension is uncommon with HTS administration because, unlike mannitol, sodium is  reabsorbed actively in the kidneys, especially in hypovolemic patients. This makes it preferable to mannitol for treating patients with increased ICP and systemic hypotension due to hypovolemia. In euvolemic patients with evidence of elevated ICP, either mannitol or HTS may be a useful treatment option. If one drug is not having the desired clinical effect, treatment with the other may be successful. Body Positioning Facilitating venous drainage from the brain also can reduce ICP and maintain cerebral perfusion to the injured

Dilute 1 part 23.4% hypertonic saline with 2 parts hetastarch or dextran 70. Do not use in hyponatremic patients because may cause rapid changes in serum sodium concentrations. Monitor serum sodium levels. Dilute 1 part 23.4% hypertonic saline with 2 parts sterile water or normal saline. Do not administer undiluted 23.4% hypertonic saline. Do not use in hyponatremic patients because may cause rapid changes in serum sodium concentrations. Monitor serum sodium levels.

brain. Placing the patient on a slant board at a 15- to 30-degree angle has been shown to optimize venous drainage while maintaining cerebral blood flow. Placing pillows or towels under the head should be avoided because bending the neck may result in occlusion of the jugular vein, which negates the beneficial effect of head elevation. Minimization of Cerebral Metabolic Rate The injured brain is at risk of ischemic damage due to decreased delivery of oxygen caused by elevated ICP as well as increased metabolic demand. Drugs that increase cerebral metabolism, including nitrous oxide and ketamine, should be avoided in these patients. Corticosteroids Although treatment with corticosteroids has been shown to be beneficial in patients with brain tumors because  it reduces peritumor vasogenic edema, there is no evidence to support the use of these drugs in patients with seizure disorders due to any other cause. Recent data from a large human clinical trial showed that in patients with brain injury caused by trauma, the use of high-dose corticosteroids in the acute setting resulted in worse outcomes than with placebo. Given the similarity between the neuronal damage resulting from trauma and that caused by seizures, the use of corticosteroids in most patients with status epilepticus or cluster seizures is not recommended.

Prognosis The prognosis for dogs and cats experiencing status epilepticus and cluster seizures has not been well studied but likely depends strongly on the underlying cause of the

CHAPTER  231  Treatment of Noninfectious Inflammatory Diseases of the Central Nervous System seizures. Animals with idiopathic epilepsy generally have a fair chance of enjoying a reasonable quality of life but are likely to require lifelong anticonvulsant therapy and are at risk of escalation of disease with every cluster of seizures or episode of status epilepticus. Patients with evidence of DIC due to hyperthermia at presentation have a guarded prognosis, are at risk of multiorgan failure, and often require intensive therapy, including administration of blood products and prolonged hospitalization. With rapid, targeted therapy, many patients with these disorders can be managed effectively long term, depending on the underlying cause of the seizures.

CHAPTER 

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References and Suggested Reading Dewey CW: Anticonvulsant therapy in dogs and cats, Vet Clin North Am Small Anim Pract 36(5):1107, 2006. Dewey CW: A practical guide to canine and feline neurology, Ames, IA, 2009, Iowa State Press. Lorenz MD, Coates J, Kent M: Handbook of veterinary neurology, ed 5, Philadelphia, 2010, Saunders. Platt SR, McDonnell JJ: Status epilepticus: clinical features and pathophysiology, Compend Contin Educ Pract Vet 22(7):660, 2000.

231 

Treatment of Noninfectious Inflammatory Diseases of the Central Nervous System LAUREN R. TALARICO, Fairfax, Virginia

N

oninfectious inflammatory diseases commonly affect the central nervous system (CNS) of small animal patients. These diseases primarily cause inflammation of the brain parenchyma (encephalitis) or meninges (meningoencephalitis).

Overview Among the subtypes of inflammatory CNS disease are granulomatous meningoencephalitis, necrotizing meningoencephalitis, necrotizing leukoencephalitis, and eosinophilic meningoencephalitis, referred to as GME, NME, NLE, and EME, respectively. GME has been reported to affect the spinal cord and cause a subsequent meningomyelitis. Steroid-responsive meningitis-arteritis (SRMA) is another suspected autoimmune disorder that affects primarily the spinal cord; this disorder is not considered here. As a group, these diseases often are referred to as meningoencephalitis of unknown cause because antemortem diagnosis is difficult to achieve in most cases. Given the increasing availability of less invasive stereotactic brain biopsy instruments guided by magnetic resonance imaging (MRI) or computed tomography (CT), we anticipate that definitive diagnoses will become more attainable in the near future.

The disorders NME and NLE sometimes are referred to as pug dog encephalitis and Yorkshire terrier encephalitis, respectively. It is important to realize that dogs of many other breeds can develop NME and NLE and that these disorders are not exclusive to pug and Yorkshire terrier breeds. The author also has diagnosed GME in pug dogs and Yorkshire terriers and therefore advises against  using this breed-specific terminology. Furthermore, the majority of the literature contains reports of noninfectious meningoencephalitis (NIME) in small-breed dogs; however, the author has definitively diagnosed GME in several large-breed retriever dogs. To date, a definitive cause of granulomatous, necrotizing, and eosinophilic meningoencephalitides has not been established. Genetic, infectious, and autoimmune causes have been proposed. A recent study by Barber et al (2010) evaluating the results of polymerase chain reaction testing of brain tissue and cerebrospinal fluid (CSF) demonstrated that Ehrlichia, Anaplasma, Rickettsia, and Borrelia are unlikely to be associated with NIME; however, the role of Bartonella still is uncertain. It is the author’s belief that GME, NME, NLE, and EME are autoimmune in origin, and this constitutes the basis for our therapeutic approach. An underlying genetic predisposition for these diseases also may play a role.

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SECTION  XI  Neurologic Diseases

Clinical Signs The majority of NIME cases are small-breed dogs between 2 and 6 years of age brought in because of peracute- or acute-onset multifocal neurologic signs. Patients with noninfectious CNS inflammatory diseases rarely have extraneural signs, and results of routine blood work usually are unremarkable. The specific deficits found on the neurologic examination reflect the location of the lesion within the brain, meninges, and spinal cord. Typically multiple areas of the brain are affected. Animals with forebrain involvement can have seizures and show behavioral or mentation changes, circling, pacing, head pressing, and central blindness with normal pupillary light reflexes. Signs referable to brainstem involvement can include severe mental depression varying from obtundation to coma; mydriasis; hemiparesis or hemiplegia; tetraparesis or tetraplegia; decreased palpebral, corneal, and gag reflexes; facial and trigeminal paralysis; and central vestibular signs. Cerebellar signs, including intention tremors, titubation, hypermetria or dysmetria, and absent menace response with normal vision often are encountered. Head pain with or without neck pain is likely secondary to inflammation of the meninges. Animals with head pain back away when the examiner attempts to pet the head, and their eyes often appear squinted. Clinical signs typically are progressive, but the rate of progression varies. It is important to realize that the severity of a patient’s clinical signs at presentation is not correlated with survival time or achievement of disease remission.

Diagnosis NIME is a histopathologic diagnosis, and a definitive antemortem diagnosis is not often achieved. With the advent of minimally invasive stereotactic MRI- or CT-guided brain biopsy tools at veterinary referral centers and veterinary colleges, definitive antemortem diagnoses are becoming more frequent. Nevertheless, the majority of cases are diagnosed presumptively based on a combination of signalment, clinical signs, MRI, and spinal fluid analysis (CSF tap). Infectious encephalitis, congenital malformations, storage diseases, toxin exposure, and neoplasia are differential diagnoses for multifocal neurologic signs with peracute onset in a young adult animal. A minimum data set consisting of results of a complete blood count, chemistry panel, urinalysis, and thoracic radiographs often is within normal limits. MRI and CSF analysis provide the most helpful information for making a presumptive diagnosis. MRI typically reveals multifocal infiltrative lesions within the brain parenchyma that are hyperintense on T2-weighted and FLAIR (fluid-attenuation inversion recovery) images and hypointense to isointense compared with the surrounding parenchyma on T1-weighted sequences. Contrast enhancement is variable. The meninges also can be hyperintense on T2-weighted and T1-weighted postcontrast sequences. The lesion and associated edema often are space occupying, causing compression of the surrounding brain parenchyma and a midline shift. In extreme cases,

subfalcine and/or transtentorial herniation of the caudal cerebellum through the foramen magnum will occur. GME tends to have a predilection for the white matter and typically affects both the brainstem and forebrain. There is a focal form of GME that produces a solitary space-occupying mass lesion which can closely resemble a neoplastic process. The majority of NME cases are supratentorial in distribution, predominately affecting both the gray and white matter of the forebrain. NLE is characterized by defacement of the white matter of both the brainstem and cerebral cortex. Additionally, the necrotizing encephalitides (NME and NLE) can be associated with visible areas of necrosis within the brain parenchyma in addition to inflammatory lesions as described earlier. Occasionally the MRI findings are normal and the diagnosis is based solely on the results of CSF analysis. CNS inflammation is best documented by CSF analysis, consisting of cytologic examination and protein evaluation. GME, NME, and NLE are characterized by mononuclear cell pleocytosis (elevated lymphocytes and monocytes) and elevated protein level. These CSF findings are nonspecific because they cannot discriminate between autoimmune, neoplastic, viral, and protozoal CNS infections. EME is characterized by eosinophilic pleocytosis and elevated protein level. Differential diagnoses for eosinophilic pleocytosis are parasitic, protozoal, autoimmune, and neoplastic diseases. Cell counts and protein level can be quite variable, ranging from zero to several thousand cells per microliter and zero to several hundred grams per deciliter, respectively. The magnitude of the pleocytosis or protein level in the CSF is not prognostic. Occasionally the CSF tap findings can be normal, especially if the patient recently received corticosteroids. It is possible that animals with normal imaging findings but CSF results consistent with NIME are being seen early in the disease process before the formation of brain lesions.

Treatment A standardized treatment regimen for NIME has yet to be determined, and the mainstay of treatment is aggressive immunosuppression. At the Cornell University Hospital for Animals, we treat GME, NME, NLE, and EME with a similar protocol which is based on the presumption that these diseases are autoimmune in origin. The combination of immunosuppressive agents used and the timing of their administration is individualized for each patient. It is important that a presumptive diagnosis be made (see earlier) before therapy is initiated. In addition to the diagnostic studies listed previously, we recommend routine infectious disease testing for toxoplasmosis, neosporosis, cryptococcosis, rickettsial diseases, and canine distemper to ensure that the underlying disease truly is noninfectious. In severe cases in which the animal’s clinical status is declining rapidly, aggressive immunosuppression must be implemented before the results of infectious disease testing are available.

Corticosteroids Initial therapy consists of immunosuppressive dosages of prednisone (1 to 2 mg/kg twice daily PO) for a minimum

CHAPTER  231  Treatment of Noninfectious Inflammatory Diseases of the Central Nervous System of 3 to 4 months. If the patient’s mental status precludes the use of oral medications, an equivalent dose of dexamethasone can be given intravenously. In addition to having immunomodulatory properties, corticosteroids decrease perilesional edema and ideally improve neurologic signs. Treatment of NIME with corticosteroid monotherapy generally results in a guarded to poor prognosis, and relapses are common. In a study by Munana and Luttgen (1998), the mean survival time for 30 dogs with histopathologically confirmed GME treated with prednisone monotherapy was 14 days (range, 1 to >1215 days). These results may be biased toward the most severe cases because postmortem histopathologic confirmation of GME was an inclusion criterion. The dose of prednisone used in this study also was variable (0.25 mg/kg to 2 mg/ kg twice daily), which possibly accounted for the variable survival times. A recent study reporting survival data for dogs treated with corticosteroid monotherapy noted a survival time of 357 days when the drug was administered at 1 to 2 mg/kg twice daily and tapered over a 3-month period. Several unwanted side effects including polyuria, polydipsia, polyphagia, weight gain, liver and gastrointestinal damage, pancreatitis, and iatrogenic endocrinopathies can result from long-term steroid therapy. In an effort to maintain the patient’s quality of life and owner compliance, the author typically uses a multimodal drug protocol (see later). The goal is to induce a clinical remission as soon as possible and to taper the dose of corticosteroids slowly to the lowest effective dose to minimize unwanted drug-related side effects. In the author’s experience, most NIME patients require prolonged low-dose corticosteroid therapy to maintain remission.

Other Immunosuppressive Therapies The reported overall median survival time ranges from 240 to 590 days for dogs treated with corticosteroids plus any other immunosuppressive drug combination (cyclosporine, lomustine, procarbazine, mycophenolate, cytarabine arabinoside, or leflunomide) compared with 28 to 357 days for those treated with corticosteroids alone. At the Cornell University Hospital for Animals, NIME cases are treated using an aggressive multimodal immunosuppressive drug regimen. Our initial therapeutic protocol consists of immunosuppressive doses of prednisone (1 mg/kg twice daily PO), cyclosporine (4 mg/kg twice daily PO), and cytarabine (200 to 600 mg/m2 as a constantrate infusion over 24 hours). While infectious disease titers are awaited, doxycycline (10 mg/kg once daily PO) and clindamycin (10 mg/kg twice daily PO) also are administered. Patients that do not experience clinical remission within the first 48 to 72 hours of treatment according to this protocol are given additional immunosuppressive medications, including procarbazine, azathioprine, leflunomide, or some combination of these. Cytarabine (cytosine arabinoside) is a chemotherapeutic agent. At the recommended dosages, it has immunosuppressive properties and can cross the blood-brain barrier, which makes it useful in the treatment of suspected autoimmune meningoencephalitis. Cytarabine exerts its effects on actively dividing cells by causing

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premature strand breaks and inhibition of repair. Commonly reported adverse effects include leukopenia and mild gastrointestinal upset. At the author’s institution we administer this medication as a constant-rate infusion over 24 or 48 hours based on the clinical severity of the patient’s neurologic signs. Previous reports have described giving this medication as four subcutaneous injections 12 hours apart over a 48-hour period. Our decision to administer this drug as a constant-rate infusion is based on the requirement for prolonged exposure to cytarabine to maintain minimum cytotoxic concentrations in the CNS. A complete blood count is performed 10 to 14 days after the first administration of the drug. If results are normal, continued monitoring of the leukocyte count is done every 4 to 6 months. We administer cytarabine initially at 3-week intervals. Cytarabine regimens are individualized for each patient, and the interval between treatments is extended gradually over several months based on serial neurologic examinations. The cytarabine treatment intervals are increased until 8-week intervals are achieved. If the patient has not shown any indication of disease relapse after three rounds of cytarabine treatment at 8-week intervals, our group performs a repeat spinal tap to determine if the CNS inflammation has subsided. If the CSF results are normal, cytarabine treatments are discontinued. Signs that a patient may be coming out of remission can be subtle and include inappetence, lethargy, depression, increased seizure frequency, or recurrence of initial neurologic signs. When an animal comes out of remission, we recommend increasing the prednisone dosage to 1 to 2 mg/kg twice daily PO, administering cytarabine as a constant-rate infusion (400 to 600 mg/m2) over 24 hours, and instituting treatment with another immunosuppressive agent such as procarbazine, azathioprine, lomustine, or leflunomide.

Other Treatments In addition to receiving immunosuppressive therapy, patients with seizures should be treated concurrently with anticonvulsant medications. Most NIME patients have mental obtundation, stupor, or coma as part of their underlying disease process. We recommend the use of anticonvulsants with minimal sedative side effects, including zonisamide (5 to 10 mg/kg twice daily PO) or levetiracetam (20 mg/kg three times daily PO or IV). If the patient’s seizures are not adequately controlled, phenobarbital (2 to 4 mg/kg twice daily PO) is administered. Patients with severe mental obtundation, stupor, or coma also should be treated with intravenous mannitol as needed (1 g/kg repeated as necessary). Fluid resuscitation and other supportive therapies such as oxygen administration also must be instituted on a case-by-case basis.

Prognosis Historically, the prognosis for NIME has been considered to be guarded to poor. Clinical remission is achieved in the majority of the cases seen at the Cornell University Hospital for Animals within the first 24 to 36 hours of

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treatment. Relapses are uncommon at our institution, but do occur, and we counsel owners thoroughly to ensure that they are able to recognize subtle signs of a potential relapse. The average survival time for patients with NIME treated at the Cornell University Hospital for Animals is 2 to 3 years. With the advent of minimally invasive stereotactic brain biopsy equipment, it is our hope that definitive antemortem diagnoses will be achieved and more accurate data on survival times obtained.

References and Suggested Reading Barber RM et al: Evaluation of brain tissue or cerebrospinal fluid with broadly reactive polymerase chain reaction for Ehrlichia, Anaplasma, spotted fever group Rickettsia, Bartonella, and Borrelia species in canine neurological diseases (109 cases), J Vet Intern Med 24:2, 2010.

CHAPTER 

Flegel T et al: Magnetic resonance imaging findings in histologically confirmed pug dog encephalitis, Vet Radiol Ultrasound 49:5, 2008. Granger N, Smith PM, Jeffery ND: Clinical findings and treatment of non-infectious meningoencephalomyelitis in dogs: a systematic review of 457 published cases from 1962 to 2008, Vet J 184:3, 2010. Munana KR, Luttgen PJ: Prognostic factors for dogs with granulomatous meningoencephalomyelitis: 42 cases (1982-1996),  J Am Vet Med Assoc 212:12, 1998. Scott-Moncrieff JC et al: Plasma and cerebrospinal fluid pharmacokinetics of cytosine arabinoside in dogs, Cancer Chemother Pharmacol 29:13, 1991. Talarico LR, Schatzberg SJ: Idiopathic granulomatous and necrotizing inflammatory disorders of the canine central nervous system: a review and future perspectives, J Small Anim Pract 51:3, 2010.

232 

Peripheral and Central Vestibular Disorders in Dogs and Cats STARR CAMERON, Ithaca, New York CURTIS W. DEWEY, Ithaca, New York

T

he vestibular system maintains the body’s posture and balance. The vestibular system coordinates and communicates the position of the head in relation to the body and the body in relation to the ground. Vestibular disease is one of the more common presentations of an animal with neurologic disease, and it also can be one of the most terrifying for the owner to witness. This chapter reviews pertinent anatomy of the vestibular system, clinical signs of dysfunction, and some of the more common disease processes affecting the peripheral and central vestibular systems.

Vestibular Anatomy A basic understanding of the neuroanatomy of the vestibular system is very helpful in neurolocalization, which aids in distinguishing the differential diagnoses and thus in selecting the diagnostic tests and treatments required.

Peripheral Vestibular System The peripheral vestibular system is located within the inner ear and consists of receptors and the vestibular

portion of cranial nerve VIII (vestibulocochlear nerve). The bony labyrinth, which is located in the petrous temporal bone, consists of the semicircular canals, vestibule, and cochlea and is filled with perilymph. The membranous labyrinth, filled with endolymph, is located within the bony labyrinth and is composed of the semicircular ducts, utricle, saccule, and cochlear duct. The semicircular ducts are located within the semicircular canals, the utricle and saccule are located within the vestibule, and the cochlear duct is located within the cochlea. The crista ampullaris is located in the semicircular ducts and responds to acceleration, deceleration, and rotation. Hair cells in the crista ampullaris respond to displacement of the endolymph. The dendrites of cranial nerve VIII synapse on these hair cells and are stimulated when they deflect. Maculae are receptors located in the utricle and  saccule that respond to linear movement. The surface is covered by hair cells that trigger an action potential in cranial nerve VIII when they are deflected. The receptors provide continual tonic input to cranial nerve VII, which functions to maintain normal posture of the head  and body.

CHAPTER  232  Peripheral and Central Vestibular Disorders in Dogs and Cats

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Central Vestibular System

Peripheral Vestibular Disease

The central vestibular system consists of the vestibular nuclei located in the medulla and the projections to the spinal cord, brainstem, and cerebellum. Spinal cord projections from the vestibular nuclei exert facilitatory and inhibitory effects on ipsilateral extensors and flexors, respectively. These projections also inhibit contralateral extensors. Brainstem projections relay information to the motor neurons of cranial nerves III, IV, and VI (oculomotor, trochlear, and abducens nerves, respectively) via the medial longitudinal fasciculus. These projections are responsible for normal eye position and physiologic nystagmus. Other brainstem projections are directed to the vomiting center within the reticular formation. Cerebellar projections travel via the caudal cerebellar peduncle to the vestibulocerebellum to maintain coordination.

Peripheral vestibular disease is characterized by any combination of vestibular ataxia, head tilt, strabismus, and nystagmus. With peripheral disease the nystagmus can be in any direction, but vertical nystagmus is extremely rare in peripheral disease and should be considered central in origin. Many believe that nystagmus associated with peripheral disease should not change in character or direction, but nothing definitive has been published regarding this finding. Nystagmus can be spontaneous or positional. It is important not to misinterpret vestibular ataxia as proprioceptive deficits. Animals with peripheral vestibular disease often have quite dramatic clinical signs, and examining them thoroughly can be challenging. It is important to support the animal’s weight during proprioception to prevent orthopedic disease or weakness from interfering with the ability of the animal to replace the paw to a normal position. Bilateral vestibular disease can be confused easily with a more central condition because the clinical signs often are symmetric. Animals with bilateral vestibular disease tend to walk low to the ground in a crouched position and often fall to both sides. Lateral head excursions are common with bilateral vestibular disease. A head tilt and vestibuloocular reflex often are absent.

Clinical Signs of Vestibular Disease Nystagmus can be physiologic or pathologic and usually has a fast and a slow phase. Physiologic, or naturally occurring, nystagmus can be elicited during the neurologic examination by testing the vestibuloocular reflex,  as by moving the head in a lateral or medial direction. Physiologic nystagmus requires coordination between the vestibular system and cranial nerves III, IV, and VI and the medial longitudinal fasciculus. Some animals, such as the Siamese cat, have resting nystagmus, which is considered normal for the breed. Pathologic nystagmus is the jerking eye movements seen with physiologic nystagmus but it occurs when the head is at rest. Pathologic nystagmus can occur when the animal is in a normal position, termed resting nystagmus, or when the animal is put in an unusual position such as on its back, termed positional nystagmus. Traditionally, the nystagmus is characterized by the direction of the fast phase, and in most cases this movement is away from the lesion. For example, nystagmus in which the fast phase is toward the left and the slow phase is toward the right is termed fast phase left and is suggestive of a left-sided lesion in most cases. This terminology can be confusing, and a way to help remember the direction is the mnemonic that the nystagmus is “running away” from the lesion. Strabismus is an abnormal eye position. Strabismus may be spontaneous (occurring at rest) or positional. In vestibular disease strabismus is either ventral or ventrolateral and occurs on the same (ipsilateral) side as the lesion. Ataxia describes an uncoordinated gait. Vestibular ataxia is characterized by turning, rolling, falling, or circling to the side of the lesion. Usually it is very asymmetric and generally the circles are very tight circles. Some animals may be unwilling to walk and some have a broad-based stance. A head tilt often is present in vestibular disease and usually is toward the side of the lesion. Head tilts can range from very mild to quite severe. For reasons unknown, a head tilt often persists long term or indefinitely after resolution of the other clinical signs of vestibular disease.

Central Vestibular Disease Central vestibular disease has several hallmark features that can distinguish it from peripheral vestibular disease (Table 232-1). Central lesions may be accompanied by a change in mentation; for example, the animal may be overly dull or obtunded. If abnormalities in other cranial nerves, besides cranial nerves VII and VIII, are found on neurologic examination, then a central lesion should be considered. Proprioceptive deficits often are present with central lesions and are characterized by decreased placing or hopping on the side ipsilateral to the lesion. Any form of nystagmus, including vertical or changing nystagmus,

TABLE 232-1  Clinical Signs of Peripheral versus Central Vestibular Disease Neurologic Sign

Peripheral

Central

Head tilt

Yes

Yes

Strabismus

Yes

Yes

Nystagmus   Horizontal   Rotary   Vertical

Yes Yes Yes No

Yes Yes Yes Yes

Cranial nerve deficits (other than in cranial nerves VII or VIII)

No

Possible

Change in mentation

No

Possible

Proprioceptive deficits

No

Possible

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may be present with central lesions. The other signs listed for peripheral vestibular disease, such as ataxia, head tilt, and strabismus, also can be seen with central lesions. Paradoxic vestibular disease is the term used to describe the situation in which head tilt is contralateral to the lesion. Paradoxic vestibular disease always is a central lesion and occurs due to early disinhibition of the vestibular nuclei. All clinical signs seen with conventional central lesions may be observed with paradoxic vestibular disease. The proprioceptive deficits are always on the side of the lesion. For instance, a dog with a right-sided head tilt and left-sided proprioceptive deficits would have a left-sided central paradoxic lesion.

Causes of Vestibular Disease The cause of the vestibular disease is a consideration in terms of both prognosis and therapy. Furthermore, different diagnostic tests may be appropriate based on the location-determined differential diagnosis for the lesion.

Peripheral Vestibular Disease Otitis media/interna is the most common infectious cause of peripheral vestibular disease and accounts for up to 50% of canine peripheral vestibular disease cases. With otitis media/interna, cranial nerve VII, the facial nerve, also may be affected. Bilateral otitis media/interna can cause signs of bilateral vestibular disease. An otoscopic examination should be performed in every animal that has peripheral vestibular signs at presentation (see Chapter 108). Animals with chronic ear disease often have a stenotic or inflamed external ear canal, which can make examining the ear difficult or impossible. In addition, the presence of an intact tympanic membrane does not exclude otitis media/interna as a differential diagnosis. Bulla radiography, computed tomography (CT), or magnetic resonance imaging (MRI) can be used to investigate the internal ear structures further if otitis media interna is suspected. A myringotomy can be performed to collect samples for cytologic analysis and culture so that appropriate treatment can be initiated. Treatment should include cleaning the ears with solutions that are not ototoxic as well as administering systemic antibiotics for 6 to 8 weeks. Ideally the antibiotics should be chosen based on culture and sensitivity testing of a sample obtained by myringotomy. However, if a myringotomy is not possible, then broad-spectrum antibiotics should be used. If the animal shows no response to medical treatment, then a surgical procedure such as a bulla osteotomy or total ear canal ablation should be considered. Ototoxicity has been reported with aminoglycoside antibiotics, erythromycin, furosemide, chemotherapy agents containing platinum, and certain ear-cleaning solutions. Vestibular signs may resolve if the medication is removed promptly. Deafness frequently accompanies vestibular signs and often is permanent. Idiopathic (geriatric, old dog) vestibular disease is one of the most common causes of peripheral vestibular signs. If an animal is exhibiting clinical signs suggesting a central lesion, then the disorder cannot be idiopathic

vestibular disease. Idiopathic vestibular disease also has been reported in cats but much less commonly than in dogs. Cats may be any age at presentation, whereas dogs tend to be older. Vestibular signs may be mild or quite severe, and the onset usually is acute. Clinical signs may take 2 to 3 weeks to resolve completely, but signs of improvement often are seen within 48 to 72 hours. Although many theories have been proposed regarding the origin of the disorder, no definitive cause has yet been found. Congenital vestibular disease is uncommon but has been reported in Doberman pinschers, English cocker spaniels, Akitas, beagles, and German shepherd dogs. Siamese, Tonkanese, and Burmese cats also are known to be affected. Animals are young at presentation and may show bilateral vestibular signs. No definitive abnormality has been identified as the underlying cause, and there is no treatment for congenital vestibular disease. Hypothyroidism can cause vestibular signs as well as affect cranial nerve VII, the facial nerve. Other clinical signs of hypothyroidism also may be present. It is important to measure thyroid function in an animal with peripheral vestibular signs when other causes of vestibular dysfunction have been ruled out. Clinical signs should resolve once the animal is receiving appropriate thyroid hormone supplementation. Neoplasia such as ceruminous gland adenocarcinoma, squamous cell carcinoma, fibrosarcoma, chondrosarcoma, osteosarcoma, and lymphoma may affect the middle or inner ear. In addition, peripheral nerve sheath tumors can affect or compress cranial nerve VIII. Some tumors may be visible on otoscopic examination; however, CT or MRI may be needed. Depending on tumor location and extent of invasion, it may be possible to biopsy or even excise some tumors. Inflammatory polyps may cause peripheral vestibular signs in addition to upper respiratory tract or pharyngeal disease. Polyps are much more common in cats than in dogs and usually cause unilateral signs. Polyps may be visualized with an oral or otoscopic examination. Removal of the polyp usually is possible. Recurrence has been noted with oral removal of the polyp as well as with bulla osteotomy and total ear canal ablation. Finally, trauma to the petrous temporal bone is very rare but is possible, and can result in peripheral vestibular signs.

Central Vestibular Disease Metronidazole toxicity has been shown to cause central vestibular signs in both dogs and cats and usually is associated with very high dosages of the drug (>60 mg/kg/day), although toxicity also can be seen with long-term use of lower dosages. Asking about metronidazole use always should be included as part of the history taking for an animal with central vestibular signs. Stopping the metronidazole treatment usually leads to resolution of clinical vestibular signs within 1 to 2 weeks, with an average of approximately 11 days. However, recently it was shown that administering diazepam at an initial IV bolus of 0.4 mg/kg, followed by 0.4 mg/kg PO q8h for 3 days, shortened the duration of clinical signs to a median of 38 hours.

CHAPTER  232  Peripheral and Central Vestibular Disorders in Dogs and Cats Thiamine deficiency has been correlated with central vestibular signs in both dogs and cats and causes areas of necrosis and hemorrhage. Deficiency most commonly occurs when animals are fed cooked diets or diets that contain thiaminase. In cats the vestibular nuclei often are affected, which produces central vestibular signs. If the deficiency is diagnosed and treated early, animals may recover with appropriate thiamine supplementation. Inflammatory disease, such as granulomatous meningoencephalomyelitis (GME), may cause vestibular signs, depending on the area of the brain affected (see Chapter 231). GME usually is seen in young to middle-aged smallbreed dogs, but dogs of any breed or age may be affected. A diagnosis of GME usually is obtained by MRI and cerebrospinal fluid (CSF) analysis, along with negative results on infectious disease titers. GME is a very aggressive disease and should be treated aggressively with immunosuppressive medications. The prognosis is quite variable, and the severity of clinical signs at presentation does not correlate with short- or long-term prognosis. Infectious organisms may enter the central nervous system and cause central vestibular signs. Viral infections include canine distemper and feline infectious peritonitis. There are no available treatments for either of these diseases, and prognosis is grave. Neosporosis, toxoplasmosis, cryptococcosis, coccidioidomycosis, blastomycosis, protothecosis, Rocky Mountain spotted fever, and ehrlichiosis are other infections that may affect the vestibular system. In addition, infection from otitis media interna can extend into the brain if severe. Neoplasia can compress or infiltrate any area of the vestibular system. Meningiomas, choroid plexus carcinomas, gliomas, adenocarcinomas, squamous cell carcinomas, and lymphomas all have been reported to cause central vestibular signs. Intracranial arachnoid cysts are nonneoplastic but space-occupying masses that may compress the cerebellum or brainstem and cause central vestibular signs. Depending on the location and tumor type, a combination of surgery, chemotherapy, and radiation therapy may be used for palliation or potential cure. Vascular events such as infarcts or transient ischemic attacks (TIAs) are diagnosed with increasing frequency. The possibility of a vascular event should be considered in an animal with central or paradoxic vestibular signs. Both infarcts and TIAs can cause abrupt vestibular signs, and the signs of TIAs often improve within 24 hours. Diagnostic testing such as serum biochemistry studies, complete blood count, thyroid panel, and blood pressure measurement should be undertaken to investigate the cause of the infarct or TIA. If an underlying disease process is not found and properly treated, the animal is at greater risk of having another infarct or TIA. Hypothyroidism has been reported to cause central vestibular signs as well as peripheral vestibular signs. Therefore a thyroid panel should be included as part of a workup for central vestibular disease. The pathophysiology is thought to be related to infarction from atherosclerosis secondary to hypothyroidism. Dogs usually recover with appropriate hormone supplementation. Paradoxic vestibular disease occurs with lesions in  the cerebellum or medulla. Signs of paradoxic vestibular disease usually are caused by a vascular or space-occupying

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lesion, such as a neoplasm or intracranial arachnoid cyst. However, vascular events also may cause paradoxic vestibular signs.

Diagnostic Tests A thorough history taking and physical and neurologic examinations are important for localizing the disease to the vestibular system as well as for differentiating peripheral from central vestibular causes (see earlier section on clinical signs). A history of ear infections, topical ear treatments, consumption of a thiamine-deficient diet, or metronidazole ingestion could provide direction for further diagnostic testing and treatments. Physical examination findings consistent with an ear infection, clinical signs of hypothyroidism, or indications of an underlying coagulopathy could be suggestive of the underlying cause of the vestibular signs. As discussed previously, mentation changes, proprioceptive deficits, cranial nerve abnormalities (apart from those in cranial nerve VII or VIII), and the presence of vertical nystagmus are signs indicative of a central lesion. A workup for peripheral vestibular disease in a dog should include an otoscopic examination, complete blood count, biochemistry studies, urinalysis, thyroid panel, and blood pressure measurement. Clinical signs indicative of a central lesion warrant further investigation in addition to the diagnostic tests listed previously, such as MRI and CSF analysis. An MRI scan may show neoplasia, evidence of an inflammatory brain disease, or an intracranial arachnoid cyst. CSF analysis may help support the diagnosis of a vascular event or inflammatory disease. In addition, in cases in which an infectious cause is suspected, titers may be performed specifically on the CSF or blood. Routinely, titers are ordered for Neospora, Toxoplasma, Rickettsia rickettsii, distemper virus (dogs only), Cryptococcus, Anaplasma, and Ehrlichia when an infectious cause is strongly suspected.

Treatment and Prognosis The treatment and prognosis for vestibular disease depends completely on the underlying cause. Idiopathic vestibular disease often has the most dramatic presentation, yet it carries a very good prognosis. Animals with central vestibular disease may have had the intracranial lesion longer and therefore have learned to compensate for their disease, and they often have the most subtle signs at presentation. Benign and sinister causes can be cited for both peripheral and central vestibular disease. Therefore no animal should be condemned to a poor prognosis without identification of the underlying lesion or, in the case of idiopathic vestibular disease, the passage of time.

References and Suggested Reading Bischoff MG, Kneller SK: Diagnostic imaging of the canine and feline ear, Vet Clin North Am Small Anim Pract 34(2):437, 2004. Caylor KB, Cassimatis MK: Metronidazole neurotoxicosis in two cats, J Am Anim Hosp Assoc 37(3):258, 2001. Cherubini GB et al: Rostral cerebellar arterial infarct in two cats, J Feline Med Surg 9(3):246, 2007.

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De Lahunta A: Veterinary neuroanatomy and clinical neurology, ed 3, St Louis, 2009, Elsevier. Dewey CW: A practical guide to canine and feline neurology, ed 2, Ames, IA, 2008, Wiley-Blackwell. Evans J et al: Diazepam as a treatment for metronidazole toxicosis in dogs: a retrospective study of 21 cases, J Vet Intern Med 17(3):304, 2003. Garosi LS et al: Thiamine deficiency in a dog: clinical, clinicopathologic, and magnetic resonance imaging findings, J Vet Intern Med 17(5):719, 2003. Garosi LS et al: Neurological manifestations of ear disease in dogs and cats, Vet Clin North Am Small Anim Pract 42(6):1143, 2012. Higgins MA, Rossmeisl JH Jr, Panciera DL: Hypothyroid-associated central vestibular disease in 10 dogs: 1999-2005, J Vet Intern Med 20(6):1363, 2006. Kent M, Platt SR, Schatzberg SJ: The neurology of balance: function and dysfunction of the vestibular system in dogs and cats, Vet J 185(3):247, 2010.

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Marks SL et al: Reversible encephalopathy secondary to thiamine deficiency in 3 cats ingesting commercial diets, J Vet Intern Med 25(4):949, 2011. Negrin A et al: Clinical signs, magnetic resonance imaging findings and outcome in 77 cats with vestibular disease: a retrospective study, J Feline Med Surg 12(4):291, 2010. Pickrell JA, Oehme FW, Cash WC: Ototoxicity in dogs and cats, Semin Vet Med Surg (Small Anim) 8(1):42, 1993. Rossmeisl JH Jr: Vestibular disease in dogs and cats, Vet Clin North Am Small Anim Pract 40(1):81, 2010. Rossmeisl JH Jr et al: Survival time following hospital discharge in dogs with palliatively treated brain tumors, J Vet Med Assoc 242(2):193, 2013. Troxel MT, Drobatz KJ, Vite CH: Signs of neurologic dysfunction in dogs with central versus peripheral vestibular disease, J Am Vet Med Assoc 227(4):570, 2005.

233 

Canine Intervertebral Disk Herniation JONATHAN M. LEVINE, College Station, Texas

I

ntervertebral disk herniation (IVDH) is the most common cause of spinal cord injury (SCI) in the dog, accounting for 2.3% of admissions to academic veterinary centers (Priester, 1976). The clinical signs associated with IVDH are numerous and reflect a combination of primary (biomechanical) injury to surrounding neuroparenchyma and secondary (biochemical) mechanisms. A basic understanding of the epidemiology and pathophysiology of this disease process is essential in making diagnostic and treatment recommendations.

bounded by the anulus fibrosus, and contains an abundance of extracellular matrix. It arises from remnant notochordal and chondrocyte-like cells. These cell populations are responsible for the synthesis and maintenance of proteoglycans that bind extracellular water. The cartilaginous end plate serves as a connection between the bony end plate and anulus fibrosus. The hyaline cartilage that composes this structure has pores, which are essential in providing nutrition and removing waste materials from the largely avascular nucleus and anulus.

Pathophysiology of Intervertebral Disk Disease

Intervertebral Disk Degeneration

The intervertebral disk has three anatomic zones: the anulus fibrosus, nucleus pulposus, and cartilaginous end plate. The anulus fibrosus arises from mesenchymal cells and consists of overlapping lamellae, which are predominantly composed of type I collagen. These lamellae attach to the cartilaginous end plate and are capable of parallel motion during biomechanical loading. In some species, the outermost portions of the anulus are supplied by minute blood vessels and innervated by small, penetrating nerve fibers. The nucleus pulposus is centrally located,

Disk degeneration has been defined as structural failure of the intervertebral disk associated with abnormal or accelerated changes seen in aging (Adams and Roughley, 2006). Both mechanical and biochemical factors are responsible for disk degeneration. Mechanical degeneration results from chronic vertebral column loading,  which leads to anular tearing with subsequent histologic changes in the nucleus and cartilaginous end plate.  Biochemical degeneration results from either failure of nutrient delivery or premature senescence of remnant notochordal cells.

CHAPTER  233  Canine Intervertebral Disk Herniation In veterinary medicine, disk degeneration traditionally is classified as chondroid or fibroid. This scheme probably is a vast oversimplification of complex, inherently interwoven processes. Chondroid metaplasia is primarily biochemical and is identified most commonly in young chondrodystrophoid dogs. Specifically, early notochordal cell senescence within the nucleus pulposus results in loss of proteoglycans, shifts in proteoglycan ratios, disk dehydration, and nuclear mineralization (Cappello et al, 2006). Fibroid metaplasia is identified frequently in older large-breed dogs and is believed to be principally the result of mechanical influences. The affected nucleus contains abundant fibrous tissue, has shifts in proteoglycan ratios, and is dehydrated; nuclear mineralization also has been recognized. A recent large-scale study suggested that disk degeneration in dogs and disk degeneration in humans bear critical similarities with reference to gross morphological changes, reductions in nuclear glycosaminoglycans, and increases in matrix metalloproteinases; histologic differences in degenerative patterns were not detected between chondrodystrophoid and nonchondrodystrophoid dogs (Bergknut et al, 2012). It is important to note that disk degeneration may not result in clinically detectable signs. Clinical neurologic disease is believed to occur only when IVDH is present. Some individuals use the expression intervertebral disk disease as an umbrella term to refer to disk degeneration, subclinical IVDH, and clinical IVDH.

Intervertebral Disk Herniation Intervertebral disk herniation is synonymous with the term intervertebral disk prolapse and refers to abnormal focal displacement of the intervertebral disk. Most frequently, displacement is dorsal or dorsolateral and impacts structures within the vertebral canal or intervertebral foramen. In dogs IVDH most often occurs in the setting of a previously degenerated disk. Traumatic IVDH has been reported and occurs when a supraphysiologic load is applied to the vertebral column. In such a case, it is possible for nondegenerate intervertebral disks to herniate. Disk herniation is classified as disk extrusion (Hansen’s type I disk herniation) or disk protrusion (Hansen’s type II disk herniation). Many investigators have ceased using Hansen’s terminology because these eponyms are specific to veterinary medicine and do not reflect pathologic mechanisms. Disk extrusion is defined as rupture of the anulus fibrosus with displacement of the nucleus pulposus into the vertebral canal or intervertebral foramen. In dogs disk extrusion typically is an acute event and is associated with chondroid metaplasia. Disk extrusion can be subclassified as nondispersed, dispersed, sequestered, and noncompressive. Nondispersed disk extrusion is contiguous with the intervertebral disk space and extruded material does not extend significantly over vertebral bodies. Dispersed disk extrusion is more extensive and implies that herniated material extends beyond the limits of the vertebral articulation. Disk sequestration occurs when extruded material is no longer contiguous with the  anulus fibrosus. Noncompressive disk extrusion results in minimal displacement of nervous system tissues, even in the setting of significant clinical signs.

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Disk protrusion is defined as rupture of the inner layers of the anulus fibrosus, partial displacement of the nucleus into the disrupted anulus, and annular hypertrophy. It is associated most frequently with fibroid metaplasia and may result in slowly progressive clinical signs. Spatial relationships with spondylosis deformans may exist. Disk bulge is reported uncommonly in veterinary medicine and is technically not a form of IVDH (Fardon and Milette, 2001). It is defined as symmetric hypertrophy of the anulus fibrosus over greater than 50% of the disk circumference without nuclear displacement.

Spinal Cord Injury and Pathologic Features Mechanisms of nervous system injury typically are described as primary and secondary. Primary injury refers to the initial mechanical insult delivered to tissues. Subcategories of primary injury may include compression, contusion, concussion, laceration, and traction. Secondary injuries occur following primary events and are biochemical in nature. Inflammation (innate and adaptive), oxidative stress, excitotoxicity, and vascular injury are just a few of the often overlapping processes involved in secondary injury. Dogs with acute SCI resulting from IVDH typically have significant spinal cord compression and contusion. The pathologic lesions seen with IVDH involve white  and gray matter (Smith and Jeffery, 2006). White matter involvement may predominate and usually is most obvious in the dorsolateral, lateral, and ventral portions of the spinal cord. Intraparenchymal hemorrhage, axonal fragmentation, and demyelination typically occur in combination. In some cases wedge-shaped, infarctlike lesions are located within the white matter. Within the gray matter, ischemic neuronal necrosis, hemorrhage, and neuronal chromatolysis have been recognized. Limited data are available concerning the pathologic alterations seen with chronic SCI resulting from IVDH, especially in the setting of disk protrusion. At the site of compression there is typically axonal loss and demyelination in all white matter funiculi. Cranial and caudal  to the compression, stereotypical loss of white matter tracts reflecting wallerian-like degeneration has been described.

Epidemiology and Clinical Signs Dogs with IVDH typically are young to middle-aged males of chondrodystrophoid breeds. Dachshunds have been reported to represent 48% to 72% of affected animals and may have a lifetime incidence of IVDH that approaches 20% (Levine et al, 2011). In one study, 83.6% of dogs with IVDH had compression located in the thoracolumbar vertebral column, whereas 16.4% had lesions in the cervical vertebral column (Gage, 1975). The clinical signs associated with IVDH are variable. In the cervical vertebral column, IVDH may result in hyperesthesia, root signature, tetraparesis, and general proprioceptive ataxia in all limbs. Severely affected dogs may be tetraplegic and require mechanical ventilation.

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Many dogs with cervical IVDH have hyperesthesia as their only clinical sign, perhaps because the ratio of vertebral canal diameter to spinal cord diameter is larger in the cervical region than in other vertebral column locations. In dogs with thoracolumbar IVDH either the T3 to L3 or L4 to S3 spinal cord can be involved. Animals may have hyperesthesia, paraparesis or paraplegia, pelvic limb general proprioceptive ataxia, urinary voiding disability, fecal incontinence, and loss of pelvic limb nociception. Animals with acute IVDH localized to T3 to L3 may have Schiff-Sherrington syndrome. In some instances of acute IVDH, spinal shock can occur. Spinal shock results from interruption of corticospinal tracts and is manifest as  a transient loss of pelvic limb spinal reflexes in the  setting of an upper motor neuron lesion (Smith and Jeffery, 2005). About 5% to 10% of dogs with IVDH that lack pelvic limb deep nociception develop ascendingdescending myelomalacia. The clinical signs of myelomalacia may include severe hyperesthesia, loss of pelvic limb reflexes in the setting of a compression located in the T3 to L3 vertebral column, anal dilation, flaccid bladder paralysis, and cranial migration of the cutaneous trunci reflex. In some instances myelomalacia may result in thoracic limb paresis and ventilatory compromise due to involvement of the cervical spinal cord.

Spinal Cord Injury Scores Recently several groups have advocated the routine use of physical examination–based SCI scores in dogs with IVDH and other myelopathies. Examples of currently validated systems are the modified Frankel score, Texas Spinal Cord Injury Score, and 14-point gait score (Table 233-1) (Levine et al, 2011). These systems allow for objective, reliable measurement of clinical facets of SCI, such as nociception and gait. Scoring systems enhance medical record keeping, facilitate clinician communication, and provide objective functional milestones during recovery.

Diagnosis Radiographic features of IVDH include disk space narrowing, disk space wedging, increased articular process overlap, and the presence of mineralized material in the vertebral canal. The diagnostic accuracy of radiography has been reported as 35% for cervical IVDH and 51%  to 61% for thoracolumbar IVDH (Lamb et al, 2002; Somerville et al, 2001). Radiography is still viewed as a reasonable screening test because it is easy to perform, highly specific for vertebral fracture and luxation, has a high sensitivity for detecting diskospondylitis, and may permit the detection of osseous neoplasia.

TABLE 233-1  Comparison of Validated Ordinal Physical Assessment–Based Spinal Cord Injury Scales Commonly   Used in Dogs MFS*

TSCIS–Gait* (Individual Limb)†

14-Point Motor Score‡

0 = No motor function or deep nociception caudal to lesion site.

0 = No limb movement.

0 = No motor function or deep nociception caudal to lesion site.

1 = No motor function and no superficial nociception caudal to lesion site; deep nociception preserved.

0 = No limb movement.

1 = No motor function caudal to lesion site, but deep nociception preserved.

2 = No motor function caudal to lesion site, but deep and superficial nociception preserved.

0 = No limb movement.

1 = No motor function caudal to lesion site, but deep nociception preserved.

3 = Nonambulatory status with paresis and general proprioceptive ataxia.

1 = Limb protraction with no ground clearance. 2 = Limb protraction with inconsistent ground clearance.

3 = Non–weight-bearing protraction in at least one joint. 5 = Non–weight-bearing protraction with more than one joint involved >50% of the time.

3 = Limb protraction with consistent ground clearance. 4 = Ambulatory with paresis and ataxia.

4 = Ambulatory, consistent ground clearance, moderate paresis-ataxia (falls occasionally). 5 = Ambulatory, consistent ground clearance, mild paresis-ataxia (does not fall).

7 = Weight-bearing protraction 10%-50% of the time. 10 = Weight-bearing protraction 100% of the time with reduced strength. Mistakes 50%-90% of the time.

5 = Normal gait. Spinal hyperesthesia and hyperreflexia may be present.

6 = Normal gait.

14 = Normal gait.

*From Levine GJ et al: Description and repeatability of a newly developed spinal cord injury scale for dogs, Prev Vet Med 89:121, 2009. †Only the gait component of the TSCIS is displayed. The TSCIS gait component scores each limb individually on a scale of 0 to 6. ‡From Olby NJ et al: Development of a functional scoring system in dogs with acute spinal cord injuries, Am J Vet Res 62:1624, 2001. MFS, Modified Frankel scale; TSCIS, Texas Spinal Cord Injury Scale (gait component).

CHAPTER  233  Canine Intervertebral Disk Herniation Myelography can be used to detect IVDH, with a reported accuracy in identifying surgical thoracolumbar lesions that ranges from 83.6% to 98% (Israel et al, 2009). The ability of myelography to detect diseases that may mimic IVDH, especially those that primarily involve spinal cord parenchyma, may be inferior to that of more modern modalities. Myelography has been associated with adverse events related to contrast delivery, such as seizures, myelopathy, cardiac arrhythmia, hemorrhage, and death. For these reasons, and because standard myelography is a two-dimensional technique, many clinics use other imaging modalities to detect IVDH. Like myelography, computed tomography (CT) is used commonly to identify IVDH. Recent studies suggest that the accuracy of CT in detecting surgical thoracolumbar lesions ranges from 81.8% to 100% (Hecht et al, 2009; Israel et al, 2009). Imaging findings associated with IVDH include visible spinal cord compression, loss of epidural fat opacity surrounding the compressed spinal cord, the presence of mineral-dense material within the epidural space, and the presence of extradural material with a density consistent with hemorrhage. Like myelography, CT is believed to be a poor means of identifying intraparenchymal spinal cord diseases that can clinically resemble IVDH. At many centers, magnetic resonance imaging (MRI) is used as the first-line technique for imaging the vertebral column. Like CT, MRI produces multiplanar images, can be performed quickly with a high-field magnet, and is noninvasive. It has a distinct advantage over CT in that it provides superior soft tissue contrast, which enhances imaging of the spinal cord, epidural space, and intervertebral disk. Unlike other modalities, MRI allows for the classification of disk degeneration and disk herniation subtypes. Additionally, in dogs with thoracolumbar IVDH the degree of hyperintensity within the spinal cord on T2 weighting has been shown to correlate with initial injury severity and functional recovery (Levine et al, 2009). MRI also is the best means to detect intraparenchymal diseases that mimic IVDH, such as myelitis, fibrocartilaginous embolism, and syringohydromyelia.

Treatment Treatment of IVDH can involve nonsurgical and surgical methods. The optimal approach depends on the clinical evaluation and situation. Often combinations of therapeutic modalities are needed.

Nonsurgical Treatment Medical treatment alone typically is selected for animals with acute mild clinical signs referable to IVDH (e.g., hyperesthesia with or without ambulatory ataxia and paresis). The hallmarks of medical therapy are analgesia, cage rest, and physical rehabilitation. Limited data are available regarding the best type of medical treatment. In one large retrospective study (Levine et al, 2007), dogs with presumptive IVDH that received medical treatment with glucocorticoids had poorer outcomes than dogs receiving other treatments, even after correction for duration and severity of injury in the analysis. Severe SCI 

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and chronic SCI both were negatively associated with outcome. In this same report, 14.4% of medically treated dogs with thoracolumbar IVDH experienced treatment failure (e.g., required euthanasia or surgery) and 30.9% had signs of clinical recurrence. Dogs with cervical IVDH had outcomes similar to those of dogs with thoracolumbar lesions. Our current medical treatment protocol consists of 2 to 4 weeks of cage rest and analgesia with nonsteroidal antiinflammatory drugs and opioids, with or without additional drugs for neuropathic pain. Physical rehabilitation is also a component of nonsurgical treatment.

Surgical Treatment Surgical treatment is recommended for dogs with moderate to severe clinical signs (e.g., nonambulatory status or marked ambulatory ataxia and paresis), dogs with chronic clinical signs, and those that show no response to nonsurgical treatment. The goal of surgical therapy is to decompress the spinal cord or nerve roots. In dogs with cervical disk herniation this is typically accomplished via a ventral slot procedure. Dorsal laminectomy has been used in the cervical vertebral column, especially in cases of multilevel disk protrusion or disk protrusion associated with cervical spondylomyelopathy. Dorsal laminectomy has the disadvantage of not permitting direct removal  of herniated disk material in most instances. Recently cervical hemilaminectomy has been described and may provide access to lateralized compressive lesions. In  the thoracolumbar vertebral column, hemilaminectomy, pediculectomy, mini-hemilaminectomy, partial lateral corpectomy, and dorsal laminectomy all have been used to gain access to the vertebral canal. For IVDH involving the cervical vertebral column, limited data are available regarding outcomes and clinical recurrence following surgery. Most studies suggest significant clinical improvement in more than 90% of dogs following decompression. In one report, 10% of dogs with cervical IVDH had recurrence of clinical signs following surgery (Cherrone et al, 2004). In dogs with thoracolumbar IVDH, pelvic limb deep nociception is the most important physical examination–based predictor of functional outcome. Among animals with intact pelvic limb deep nociception at admission, voluntary ambulation occurred in 86% to 96% following surgery (Levine et al, 2011). Dogs lacking pelvic limb deep nociception before surgery have a 43% to 62% chance of voluntary ambulation following surgery (Levine et al, 2011). In paraplegic dogs with intact deep nociception before surgery the median time to regain ambulation following surgical decompression is 9 days (Ferreira et al, 2002). Dogs lacking pelvic limb deep nociception have a mean time to ambulation of 7.5 weeks (Olby et al, 2003). Recently biomarkers and MRI findings have been studied as outcome predictors in dogs with surgically treated thoracolumbar IVDH. For example, dogs with a cerebrospinal fluid myelin basic protein concentration  of 3 ng/ml or more had 0.09 times the odds of long-  term ambulation compared with dogs with a cerebrospinal fluid myelin basic protein concentration of less  than 3 ng/ml (Levine et al, 2011). Cerebrospinal fluid

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creatine kinase concentration and matrix metalloproteinase 9 expression also are related to long-term ambulatory status. Two reports have shown that the length of a hyperintense area within the spinal cord on T2-weighted sagittal images is associated with initial severity of SCI and functional outcome. Data suggest that the biomarkers and MRI signal changes studied appear independent of the Modified Frankel Score, which may permit their use in combination with traditional physical examination– based measures of SCI severity to determine long-term ambulatory outcome. Clinical recurrence has been identified in 12.7% to 20.2% of dogs with surgically treated thoracolumbar IVDH (Brisson et al, 2011). Episodes of reported recurrence may be mild or severe, requiring surgical intervention. Early recurrence often occurs at the surgical site, whereas later recurrence occurs at vertebral articulations adjacent to surgical sites. Results of a small, nonblinded, prospective study suggested that fenestration at the site of surgically treated IVDH reduces herniation of additional disk material in the early postoperative period  (Forterre et al, 2008). A large, nonblinded, prospective study found that the rate of recurrence was lower in dogs with multisite fenestration (7.5%) than in those with single-site fenestration (17.9%); no dogs with IVDH  that did not receive fenestration were studied (Brisson et al, 2011).

Glucocorticoids Glucocorticoids, including methylprednisolone sodium succinate (MPSS), dexamethasone, and prednisone, have been used in the medical treatment of IVDH. Administration of glucocorticoids to dogs with IVDH can have two purposes: (1) neuroprotection in the setting of acute, severe SCI, and (2) modulation of inflammatory mediators in the setting of chronic IVDH-associated compression. Glucocorticoid therapy has been studied in animal models and in humans with SCI for decades. In humans with traumatic myelopathies, only MPSS has been associated with improved outcomes. The benefits realized with MPSS administration likely relate to the antioxidant properties of the drug when it is administered at high dosages. In humans with SCI, MPSS must be administered within 8 hours of SCI, and effects on motor function have been reported as modest. Currently, the use of MPSS in humans with traumatic SCI is contentious due to variable outcome data. The only completed study on treatment with highdose MPSS in dogs with thoracolumbar IVDH was retrospective and did not show an association with better outcomes. Currently a multicenter prospective clinical trial is under way to study the effects of MPSS in dogs with acute, severe IVDH-associated SCI. The use of glucocorticoids such as dexamethasone is strongly discouraged as a treatment for acute SCI resulting from IVDH because positive effects on outcome have not been detected. Dexamethasone administration increases the risk of urinary tract infection and gastrointestinal signs in dogs with thoracolumbar IVDH. Limited data are available on the use of glucocorticoids in dogs with mild or chronic myelopathy associated with IVDH. A multicenter retrospective study suggested that,

in dogs with presumptive IVDH, glucocorticoid therapy was negatively associated with improved functional outcome (Levine et al, 2007). Because this patient population was heterogeneous with respect to SCI severity, it is challenging to understand the implication of this result for mildly affected animals. A recent retrospective study in dogs with lumbosacral disk protrusion suggested a benefit for epidural administration of glucocorticoids (Janssens et al, 2009). At many clinical centers, glucocorticoids are no longer administered to dogs suspected of having IVDH-mediated SCI. The reasons for this include the current lack of evidence to support an association with better outcomes, reported adverse events, and the recognition that dogs suspected of having IVDH can have other causes of SCI (e.g., myelitis) with divergent pathologic mechanisms.

Novel Therapies The use of neuroprotective agents (those that mitigate acute secondary injury) and treatments to facilitate spinal cord regeneration or plasticity currently are under investigation in dogs with thoracolumbar IVDH. Polyethylene glycol (PEG) is a surfactant that physiologically and  anatomically fuses spinal cord axons in SCI models. In 2004 an open-label phase I-II study (Laverty et al, 2004) examined the use of PEG in dogs lacking deep nociception because of thoracolumbar IVDH and compared outcomes with those for historical controls. The drug appeared to be safe, and in 17 of 19 dogs recovery of pelvic limb nociception occurred within 2 days of PEG administration. The open-label design of this study and the use of historical controls have led some to question the effects of PEG in dogs with IVDH. A phase III clinical trial is currently under way in dogs with IVDH that will provide valuable data regarding the efficacy of PEG administration. Olfactory ensheathing cells (OECs) promote axonal growth and remyelination in SCI models. In dogs with thoracolumbar SCI lacking deep nociception, data from a phase I trial (Jeffery et al, 2005) suggest that OECs can be harvested safely and delivered via myelotomy. Spinal walking was observed in a subset of treated dogs. Recently, a blinded, randomized phase II investigation suggested that OECs improve motor function in dogs with chronic, complete SCI; in this population, there was no improvement in limb nociception, suggesting the possibility that OECs modulate the central pattern generator but do not result in repair of long tracts (Granger et al, 2012).

References and Suggested Reading Adams MA, Roughley PJ: What is intervertebral disk degeneration, and what causes it? Spine 31:2151, 2006. Brisson BA et al: Comparison of the effect of single-site and multiple-site disk fenestration on the rate of recurrence of thoracolumbar intervertebral disk herniation in dogs, J Am Vet Med Assoc 238:1593, 2011. Bergknut N et al: The dog as an animal model for intervertebral disc degeneration? Spine 37:351, 2012. Cappello R et al: Notochordal cells produce and assemble extracellular matrix in a distinct manner, which may be responsible for the maintenance of healthy nucleus pulposus, Spine 31:873, 2006.

CHAPTER  234  Canine Degenerative Myelopathy Cherrone KL et al: A retrospective comparison of cervical intervertebral disk disease in nonchondrodystrophic large dogs versus small dogs, J Am Anim Hosp Assoc 40:316, 2004. Fardon DF, Milette PC: Nomenclature and classification of lumbar disc pathology. Recommendations of the combined task forces of the North American Spine Society, American Society of Spine Radiology, and American Society of Neuroradiology, Spine 26:E93, 2001. Ferreira AJ, Correia JH, Jaggy A: Thoracolumbar disc disease in 71 paraplegic dogs: influence of rate of onset and duration of clinical signs on treatment results, J Small Anim Pract 43:158, 2002. Forterre F et al: Influence of intervertebral disc fenestration  at the herniation site in association with hemilaminectomy on recurrence in chondrodystrophic dogs with thoracolumbar disc disease: a prospective MRI study, Vet Surg 37:399, 2008. Gage ED: Incidence of clinical disc disease in the dog, J Am Anim Hosp Assoc 11:135, 1975. Granger N et al: Autologous olfactory mucosal cell transplants in clinical spinal cord injury: a randomized double-blinded trial in a canine translational model, Brain 135:3227, 2012. Hecht S et al: Myelography vs. computed tomography in the evaluation of acute intervertebral disk extrusion in chondrodystrophic dogs, Vet Radiol Ultrasound 50:353, 2009. Israel SK et al: The relative sensitivity of computed tomography and myelography for identification of thoracolumbar disk herniations in dogs, Vet Radiol Ultrasound 50:247, 2009. Janssens L, Beosier Y, Daems R: Lumbosacral degenerative stenosis in the dog. The results of epidural infiltration with methylprednisolone acetate: a retrospective study, Vet Comp Orthop Traumatol 22:486, 2009.

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Jeffery ND, Lakatos A, Franklin RJM: Autologous olfactory glial cell transplantation is reliable and safe in naturally occurring canine spinal cord injury, J Neurotrauma 22:1282, 2005. Lamb CR et al: Accuracy of survey radiographic diagnosis of intervertebral disc protrusion in dogs, Vet Radiol Ultrasound 43:222, 2002. Laverty PH et al: A preliminary study of intravenous surfactants in paraplegic dogs: polymer therapy in canine clinical SCI,  J Neurotrauma 21:1767, 2004. Levine JM et al: Evaluation of the success of medical management for presumptive thoracolumbar intervertebral disk herniation in dogs, Vet Surg 36:481, 2007. Levine JM et al: Magnetic resonance imaging in dogs with neurologic impairment due to acute thoracic and lumbar intervertebral disk herniation, J Vet Intern Med 23:1220, 2009. Levine JM et al: Naturally occurring disk herniation in dogs: an opportunity for pre-clinical spinal cord injury research, J Neurotrauma 28:675, 2011. Olby N et al: Long-term functional outcome of dogs with severe injuries of the thoracolumbar spinal cord: 87 cases (19962001), J Am Vet Med Assoc 222:762, 2003. Priester WA: Canine intervertebral disk disease—occurrence by age, breed, and sex among 8,117 cases, Theriogenology 6:293, 1976. Smith PM, Jeffery ND: Spinal shock—comparative aspects and clinical relevance, J Vet Intern Med 19:788, 2005. Smith PM, Jeffery ND: Histological and ultrastructural analysis of white matter damage after naturally-occurring spinal cord injury, Brain Pathol 16:99, 2006. Somerville ME et al: Accuracy of localization of cervical intervertebral disk extrusion or protrusion using survey radiography in dogs, J Am Anim Hosp Assoc 37:563, 2001.

234 

Canine Degenerative Myelopathy JOAN R. COATES, Columbia, Missouri SHINICHI KANAZONO, Columbia, Missouri

C

anine degenerative myelopathy (DM) was first described as an insidious, progressive general proprioceptive ataxia and upper motor neuron (UMN) spastic paresis of the pelvic limbs ultimately leading to paraplegia and necessitating euthanasia (Averill, 1973). Although most of the dogs in the initial reports were German shepherd dogs, other breeds were represented (Averill, 1973; Braund and Vandevelde, 1978; Griffiths and Duncan, 1975). DM is now recognized as a common problem in a number of breeds, with an overall prevalence of 0.19% (Coates et al, 2007; Coates and Wininger, 2010). Additionally, the clinical spectrum of DM has been

broadened to encompass both the UMN and lower motor neuron (LMN) systems. Discovery of a missense mutation in the superoxide dismutase 1 gene (SOD1) provided further understanding that this canine disease may share pathogenic mechanisms with some forms of human amyotrophic lateral sclerosis (ALS, or Lou Gehrig’s disease) (Awano et al, 2009).

Pathophysiology Since it was first described by Averill (1973), canine DM, because of its histopathologic features, was termed a

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nonspecific degeneration of spinal cord tissue of undetermined cause. Awano and colleagues (2009) identified a c.118G>A transition of glutamate to lysine in SOD1 that predicted an E40K missense mutation underlying canine DM. In this initial study there was a highly significant association between homozygosity for the SOD1:c.118A allele and the DM phenotype in Pembroke Welsh corgis and also in four other dog breeds: boxer, Chesapeake Bay retriever, German shepherd dog, and Rhodesian ridgeback. SOD1 is a ubiquitous intracellular protein functioning as a free radical scavenger. Mutations in SOD1 are known to cause some forms of familial ALS in humans. ALS, the most common adult motor neuron disease, is characterized by loss of motor neurons causing stiffness and slowing of muscle movements, difficulty speaking and swallowing, muscle atrophy, and severe weakness. The Greek word amyotrophy means “muscles without nourishment.” Lateral is the location within the spinal cord of axonal disease, and sclerosis refers to replacement of diseased axons by sclerotic or “scar” tissue. In addition, Awano and associates (2009) demonstrated that, as in ALS, cytoplasmic aggregates that bind anti-SOD1 antibodies were present in the spinal cords of dogs with DM that were homozygotic for SOD1:c.118A. The aggregates are thought to form because amino acid substitutions force SOD1 to assume an unstable conformation. It is unclear if the aggregates cause or contribute to the neurodegeneration or are a by-product of other neurodegenerative processes. No similar SOD1 antigen–containing aggregates are found in healthy dogs lacking known SOD1 mutations. Not all SOD1:c.118A homozygotes develop clinical signs; therefore DM appears to be an incompletely penetrant autosomal-recessive disease, whereas most human SOD1 mutations are autosomal dominant. Thus homozygosity for the E40K mutation is a major risk factor for canine DM. We have detected the DM-associated SOD1:c.118A allele in over 100 different dog breeds. The mutant allele appears to be very common in some breeds. It remains to be seen whether or not homozygosity for the mutation puts dogs of all of these different genetic backgrounds at risk of developing DM. Recently another mutation in SOD1 has been discovered in a DM-affected Bernese mountain dog (Wininger et al, 2011). This finding serves as a reminder that direct DNA tests can indicate the presence or absence of disease-causing alleles but cannot be used to rule out a diagnosis because other sequence variants in the same gene or in a different gene might produce a similar disease phenotype.

Clinical Spectrum Subsequent to the discovery of the SOD1 mutation underlying canine DM, the clinical spectrum became more clearly defined with identification of the stages of disease progression (Table 234-1). Dogs with DM follow a predictive pattern of clinical signs that begins with UMN pelvic limb paresis and general proprioceptive ataxia, progresses to LMN paraparesis, and then spreads to involve the thoracic limbs and brainstem. The earliest clinical signs appear when dogs are at least 8 years or older, and the mean age of onset is 9 years. There is no sex predilection.

TABLE 234-1  Neurologic Signs in Dogs with Degenerative Myelopathy Based on Disease Progression Time from Onset of Signs (Months) Neurologic Signs 6 to 12

Upper motor neuron paraparesis and general proprioceptive ataxia Progressive general proprioceptive ataxia Asymmetric spastic paraparesis Intact spinal reflexes (patellar reflex may be decreased)

9 to 18

Nonambulatory paraparesis to paraplegia Mild to moderate loss of muscle mass in pelvic limbs Reduced to absent spinal reflexes in pelvic limbs ± Urinary and fecal incontinence Lower motor neuron paraplegia to thoracic limb paresis Signs of thoracic limb paresis Flaccid paraplegia Severe loss of muscle mass in pelvic limbs Urinary and fecal incontinence Lower motor neuron tetraplegia and brainstem signs Flaccid tetraplegia Difficulty with swallowing and tongue movements Reduced to absent cutaneous trunci reflex Generalized and severe loss of muscle mass Urinary and fecal incontinence

14 to 24

>24-36

NOTE: Shading represents the disease stages at which lower motor neuron signs are present.

The clinical course of DM can vary after the presumptive diagnosis is made; the mean disease duration is 6 to 12 months in larger dog breeds, at which point dogs become nonambulatory paraparetics. Pet owners usually elect euthanasia when their dogs can no longer support weight with their pelvic limbs. Dogs of smaller breeds can be cared for by the pet owner over a longer time; for example, the median disease duration in the Pembroke Welsh corgi was 19 months (Coates et al, 2007). DM-affected Pembroke Welsh corgis often have signs of thoracic limb paresis at the time of euthanasia.

Early Disease (Upper Motor Neuron Signs) The earliest clinical signs of DM are general proprioceptive ataxia and mild spastic paresis in the pelvic limbs. Worn nails and the appearance of asymmetric pelvic limb lameness can be seen on physical examination. Asymmetry of signs at disease onset is reported frequently. At disease onset, spinal reflex abnormalities are consistent with UMN paresis localized in the T3 to L3 spinal cord segments. Patellar reflexes may be normal or exaggerated to clonic; however, hyporeflexia of the patellar reflex also has

CHAPTER  234  Canine Degenerative Myelopathy been described in dogs at a similar disease stage (Griffiths and Duncan, 1975). Involvement of the dorsal roots of the femoral nerve may inhibit sensory impulses from stretch receptors located in the quadriceps muscle. Flexor (withdrawal) reflexes also may be normal or show crossed extension (suggestive of chronic UMN dysfunction). Often within 6 to 12 months from the time of disease onset, dogs progress to nonambulatory paraparesis.

Late Disease (Lower Motor Neuron Signs) If the DM-affected dog is not euthanized early, clinical signs will progress to LMN paraplegia and ascend to affect the thoracic limbs within 18 to 24 months. LMN signs emerge as hyporeflexia of the patellar and withdrawal reflexes, flaccid paralysis, and widespread muscle atrophy beginning in the pelvic limbs as the dogs become nonambulatory (Awano et al, 2009; Matthews and de Lahunta, 1985). The paresis becomes more symmetric and progresses to flaccid tetraplegia in dogs with advanced disease. Widespread and severe loss of muscle mass occurs in the axial and appendicular musculature. Most previous reports attributed loss of muscle mass to disuse, but flaccidity in dogs with protracted disease suggests denervation. Cranial nerve signs include difficulty swallowing and inability to bark. Urinary and fecal continence usually are spared until the latter disease stage of LMN paraplegia.

Differential Diagnoses The diagnosis of DM in the early disease stage can be challenging because the clinical presentation can mimic that of other acquired spinal cord diseases. These disorders differ in anatomic distribution, clinical signs, and  age of onset. Older dogs often have concurrent orthopedic and neurologic disease that can confound the interpretation of the neurologic findings. Paw replacement (proprioceptive positioning) is a very useful test that distinguishes between orthopedic and neurologic diseases because it does not require weight bearing. Animals with orthopedic disease do not have paw replacement deficits. Disorders that often mimic and coexist with DM include degenerative lumbosacral syndrome, intervertebral disk disease, spinal cord neoplasia, and degenerative joint diseases such as hip dysplasia or cruciate ligament disease. The Pembroke Welsh corgi is a chondrodystrophic breed and prone to Hansen type I intervertebral disk herniation. Hansen type II intervertebral disk herniation can be an incidental or clinically significant finding and is more common in older dogs of the large nonchondrodystrophic breeds. Pelvic limb dysfunction can present before thoracic limb paresis in cervical spinal cord disease (e.g., caudal cervical spondylomyelopathy) and in generalized neuromuscular diseases such as neuropathy, neuromuscular junction disorders, and myopathy.

Diagnostic Approach Accurate antemortem diagnosis is based on recognition of the pattern of progression of clinical signs supported by inclusionary and exclusionary diagnostic testing.

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Neurodiagnostic Testing A careful neurologic examination is fundamental to developing a diagnostic approach. Lack of paraspinal hyperesthesia is a key clinical feature of DM that distinguishes it from other compressive myelopathies. As in a patient with a “definite” diagnosis of ALS, in a DM-affected dog neurologic signs progress from UMN to LMN signs, spread to two or more spinal regions, and eventually involve the brainstem (bulbar signs). An antemortem diagnosis of canine DM is based on ruling out other spinal cord–compressive diseases. Neurodiagnostic techniques for evaluation of spinal cord disease include cerebrospinal fluid (CSF) analysis, spinal cord imaging, and electrodiagnostic testing. A presumptive diagnosis of DM often is made based on lack of clinically relevant compressive myelopathy as determined by magnetic resonance imaging (MRI). If MRI is unavailable, computed tomography/myelography can also be used. MRI is especially useful for identifying early intramedullary spinal cord neoplasia and providing evidence of extradural compressive myelopathy. Imaging often reveals disk protrusions, which can confound the diagnosis of DM. The clinician must be guided by clinical experience to evaluate for rapidity of disease progression, presence of paraspinal hyperesthesia, and amount of spinal cord compression to account for the severity of the myelopathy. CSF analysis can help to rule out meningitis and myelitis. Electrodiagnostic testing is useful for detecting evidence of neuromuscular disease. Early in the progression of DM when UMN signs predominate, no spontaneous activity is detected by electromyography (EMG) and nerve conduction velocities are within normal limits. Later in the disease course with the emergence of LMN signs, EMG reveals multifocal spontaneous activity in the distal appendicular musculature. Fibrillation potentials and positive sharp waves are the more common waveforms recorded. Recordings of compound muscle action potentials (M waves) from stimulation of the tibial and ulnar nerves have been found to show temporal dispersion and decreases in amplitudes (Awano et al, 2009). The proximal and distal motor nerve conduction velocities have been found to be decreased when compared with the normal reference range. These findings provide evidence of motor axonopathy and demyelination in the late disease stage of DM. A DNA test based on the SOD1 mutation is commercially available. Dogs homozygous for the mutation are at risk of developing DM and will contribute one chromosome with the mutant allele to all of their offspring. Heterozygous dogs are DM carriers and are less likely to develop clinical DM, but they can pass on a chromosome with the mutant allele to half of their offspring. Dogs homozygous for the nonmutated (normal) allele are unlikely to develop DM and will provide all of their offspring with a protective normal allele. A test result showing that the dog is at risk can support a presumptive diagnosis of DM in the setting of typical clinical signs and normal findings on neuroimaging and CSF analysis. The SOD1 DNA test is of potential use to dog breeders wishing to reduce the incidence of DM in the breed or line.

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Neuropathologic Features Because a variety of common acquired compressive spinal cord diseases can mimic DM by compromising the UMN pathways, a definitive diagnosis of DM can be accomplished only at postmortem examination. The pathologic features of DM include axonal degeneration with secondary demyelination and astroglial proliferation (sclerosis) in all spinal cord funiculi but consistently most severe in the dorsal portion of the lateral funiculus and in the dorsal columns of the middle to lower thoracic region (March et al, 2009). Absence of neuronal cell body degeneration or loss in the ventral horn of the spinal cord is not a prominent histopathologic finding. Histopathologic studies of tissue from dogs in late disease stage with LMN signs have documented denervation atrophy in muscle, nerve fiber loss with axonal degeneration, and secondary myelin loss in myelinated fibers of peripheral nerves (Awano et al, 2009; Shelton et al, 2012). Similarly, in ALS patients and DM-affected dogs, muscle biopsy specimens show evidence of reinnervation in the early disease stages (Shelton et al, 2012). Based on clinical signs and pathologic findings, DM is now considered a multisystem disease involving central and peripheral axons that has similarities to UMN-onset ALS.

Management Overview The long-term prognosis of DM is poor. In the face of the inevitable gradual progression of DM regardless of the use of various therapeutic modalities, it is important to realize the emotional support a pet owner can provide to maintain quality of life for the pet. As a DM-affected dog progresses through the disease stages, the pet owner encounters the challenges of at-home management  and provision of appropriate daily care for the pet. Ultimately, the pet owner will need to make a decision for humane euthanasia, often with the assistance of the veterinarian.

Pharmacotherapy Pharmacotherapies for canine DM, including drugs and nutritional supplements, have been empiric, with a lack of evidence-based approaches for determining efficacy. The antiprotease agent ε-aminocaproic acid has been advocated for long-term management of DM (Clemmons, 1989). However, a recent study that evaluated combined therapy with ε-aminocaproic acid, N-acetylcysteine, and vitamins B, C, and E found no beneficial effects  (Polizopoulou et al, 2008). Treatment with parenteral cobalamin or oral tocopherol did not affect neurologic progression in a study of DM-affected dogs; furthermore, serum concentrations of α-tocopherol in DM-affected German shepherd dogs were not significantly different from the concentrations in normal dogs (Fechner et al, 2003; Johnston et al, 2001; Williams et al, 1985). ALS has no known cure, and effective treatments have remained elusive. The only drug currently approved by the U.S. Food and Drug Administration for use in treating humans with ALS is riluzole (Rilutek), an anti-excitotoxic agent that inhibits release of glutamate, and this drug has

shown only marginal benefits in slowing disease progression (Bensimon et al, 1994; Miller et al, 2007). There has been no report of the use of riluzole in DM-affected dogs. Explanations for the negative results of other treatments for ALS include heterogeneity in disease susceptibility and pathogenic mechanisms, and defective design of clinical trials (Beghi et al, 2011). The pattern of clinical progression of canine DM is relatively uniform within breeds and among breeds. This may facilitate the establishment of longitudinal measures of disease progression for determining the efficacy of therapeutic approaches.

Physiotherapy Physical rehabilitation is an evolving area in veterinary medicine. Goals for rehabilitation of the neurologic patient include maintaining joint function and range of motion, improving balance and proprioception, preserving or increasing muscle strength, and improving overall functioning (Millis, 2009). Physiotherapy and implementation of the principles of physical rehabilitation may improve quality of life and retard deterioration of function in DM-affected dogs (Millis, 2009; Sherman and Olby, 2004). Rehabilitation of dogs with neurologic disease has focused primarily on recovery after a disease insult. These protocols involve a combination of active and passive exercise, functional activities, and therapeutic modalities (Drum, 2010; Olby et al, 2005; Shealy et al, 2004). In veterinary medicine no formal evidence-based guidelines have been published for physiotherapy for animals with neuromuscular disease. Moreover, physiotherapy regimens and the efficacy of such regimens for management of neurodegenerative disorders in animals remain to be determined. The rationale for physiotherapy in the management of canine DM will continue to evolve as we gain further understanding of DM and its resemblance to ALS. The role of exercise in people with ALS has been controversial, and it is possible that excessive exercise or strengthening exercises might induce overwork damage. The pattern of ALS onset and progression is highly variable, which has limited advancement in understanding whether exercise has beneficial effects in ALS management. Much of the current evidence for the neuroprotective potential of exercise in ALS comes from studies in rodent ALS models (McCrate and Kaspar, 2008). Transgenic ALS mice that engaged in moderate exercise showed slower disease progression, improved function, and longer survival than sedentary animals living in cages (Kaspar et al, 2005; Kierkinezos et al, 2003). However, highresistance strengthening exercises do not have any benefit over moderate-resistance programs and can accelerate neurologic deterioration (Mahoney et al, 2004). Further beneficial effects of extensive exercise in the mouse ALS model were shown when exercises were alternated with periods of rest and were performed regularly (Kierkinezos et al, 2003; Liebetanz et al, 2004). In human ALS, strength training in conjunction with aerobic training was considered more likely to be beneficial than to be deleterious in patients with ALS provided the exercise is individualized, monitored, and involves progressive resistance (Bello-Haas et al, 2007; Drory et al,

CHAPTER  234  Canine Degenerative Myelopathy 2001). A recent review assigned a level II evidence rating (likely to be effective) for muscle strengthening in ALS (Chen et al, 2008). For humans with ALS recommendations are for exercises that do not cause fatigue and that focus on maintaining mobility. Additionally, focused exercise programs can have positive psychologic effects on a patient’s coping strategies. The efficacy of therapeutic interventions is related to the timing of interventions as well as the motivation and persistence of the patient and support from family members (Hallum, 2007). To date, no prospective studies have established whether exercise has a beneficial effect in DM-affected dogs. Kathmann and colleagues (2006) reported survival data for 22 DM-affected dogs that received varying degrees of physiotherapy. Dogs that received intensive physiotherapy had significantly longer survival times (mean, 255 days) than dogs that received moderate physiotherapy (mean, 130 days) or no physiotherapy (mean, 55 days). The physiotherapy regimen consisted of active and passive exercises that did not take into account disease stage or UMN-LMN signs. Although study limitations included lack of randomization and definitive diagnosis, small group size, and bias from owner perceptions, the results warrant further investigation into the efficacy of physiotherapy in DM-affected dogs. Physiotherapy Considerations Two major factors must be considered when planning and implementing an activity or exercise program for patients with ALS and should be taken into account in cases of degenerative myelopathy: slowing of disuse muscle atrophy and minimizing of overuse injury (Figure 234-1). Disuse Muscle Atrophy.  Disuse muscle atrophy occurs with UMN weakness. Type I muscle fibers involving the postural muscles and those crossing one joint are most vulnerable to disuse atrophy. Disuse muscle weakness lowers muscle force production and reduces muscle endurance. Furthermore, disuse atrophy in combination with pathologic weakness and spasticity of specific muscle groups contributes to loss of coordination and lower efficiency of movements (Ropper and Samuels, 2009). Exercise recommendations for ALS patients suggest that progressive resistive exercises begin in the early stage of

ge ma

Da

tea u

Normal muscle

Pla

anc e nten

Training

Mai

Disuse A

trophy

Safe exercise range

Impaired muscle Safe exercise range

Figure 234-1  Exercise window for normal and damaged or

denervated muscles. (Adapted from Maloney FP, Burks JS, Ringel SP, editors: Interdisciplinary rehabilitation of multiple sclerosis and neuromuscular disorders, New York, 1985, JB Lippincott. In Umphred DA, editor: Neurological rehabilitation, ed 5, St Louis, 2007, Elsevier.)

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the neuromuscular disorder because strength training in patients with less than 10% of normal function generally was not effective (Milner-Brown and Miller, 1998). It is important to try to differentiate between muscle weakness from disuse and muscle weakness from overwork. Diagnosis of overwork weakness is based on a decrease in strength and endurance that can reasonably be related to specific overuse and by failure to regain strength with specific exercise (Bennett and Knowlton, 1958). Muscles weak from disuse will respond favorably to specific graduated exercise by showing increased strength. Exercise-Induced Damage.  In ALS patients fatigue occurs more easily in damaged or denervated muscle during anaerobic and aerobic exercise because of motor inefficiency caused by weakness (Sanjak et al, 2001). Loss of LMN innervations results in secondary compensatory axonal sprouting and a larger muscle mass innervated by a smaller pool of motor neurons. These macro motor units may be susceptible to failure due to dropout and defective neuromuscular transmission along the reinnervated nerve sprouts. In experimentally neurectomized muscles of rats, vigorous exercise caused further muscle damage if fewer than one third of motor units were functional (Reitsma, 1969). If more than one third of the motor units remained intact, exercise promoted hypertrophy of the functioning myofibers. Thus the extent of strengthening is proportional to the number of intact motor units. Importantly, exercise at a level to elicit a training effect in normal muscle may actually cause overwork damage in weakened, denervated muscle (Bennett and Knowlton, 1958; Tam et al, 2001). In concert with physiotherapy in ALS patients, high-resistance strengthening should be limited and strengthening exercises should emphasize concentric (muscle-shortening) rather than eccentric (muscle-lengthening) muscle contractions (Hallum, 2007). Thus when a physiotherapy program is being designed for animals with neuromuscular disease it is important that one “first do no harm.” Exercise Interventions Suggested for Canine Degenerative Myelopathy When UMN signs predominate in DM-affected dogs, physiotherapy is directed at retarding further deconditioning and disuse muscle atrophy, and relieving spasticity. Spasticity, a hallmark clinical sign of UMN paresis, is a velocity-dependent increase in the resistance of muscles to a passive stretch stimulus. Spasticity is characterized by an increase in tonic stretch reflexes with an increase in resistance against quick and strong flexion force but a normal or lesser increase in resistance against slow and gradual flexion force (Ropper and Samuels, 2009). Spasticity in ALS patients contributes to worsening muscle dysfunction. A randomized controlled trial assessed the effect of moderate exercise on spasticity in ALS patients (Drory et al, 2001; reviewed in Ashworth et al, 2006). Although the study was too small to determine whether exercise was useful, the patients who performed the exercises had significantly less spasticity. Active exercises are recommended for DM-affected dogs while spinal reflexes and at least some voluntary movements remain intact. Active exercises improve muscle mass and strength, neuromuscular balance, and

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coordination (Olby et al, 2005). Exercises that involve repetitive range-of-motion activity also serve to decrease spasticity (Katz, 1988). Such therapies include sit-to-stand and standing exercises, weight shifting, and ambulation exercises. Hydrotherapy such as walking on an underwater treadmill allows support of the dog’s body weight through buoyancy effects, and the water provides resistance to movement for muscle strengthening. Dynamic balance exercises using balance balls or rolls or a balance board can improve proprioception. Other proprioceptive exercises include standing or walking on an uneven surface (e.g., air mattress, sand, and cushion) or weaving through obstacles or over obstacles. Balance exercises and coordination activities also strengthen core muscles of the trunk and reduce the exaggerated tone in antigravity muscles of the limbs. Moreover, ongoing or maintenance exercise programs serve to decrease muscle stiffness and slow immobility. If a DM-affected dog shows evidence of significant, persistent weakness after an exercise regimen is instituted or has persistent fatigue the day after exercise, the therapist will need to adjust the exercise program to prevent damage from excessive overwork and fatigue. Passive range-of-motion (PROM) exercise is performed before active exercises and in neurologic patients who lack voluntary movement or strength. Regularly performing PROM exercise maintains joint health, retards contracture, enhances mobility of soft tissues and circulation, and reduces pain and spasticity (Millis et al, 2004; Olby et al, 2005). Before PROM exercise, the limbs should be warmed and massaged using stroking and pressure techniques. The therapist should gently grasp the limb, and the motion should be slow and steady. During flexion and extension of the limb, the joints are positioned into flexion to the point of resistance, and then extended in the same manner. The limb also is manipulated in a “bicycling” manner to simulate a normal gait pattern. PROM exercise is recommended at all stages of progression of DM. Extreme stretching exercises should be performed with caution in denervated muscle to prevent further muscle damage. Once LMN paresis develops, as indicated by severe muscle atrophy, flaccidity, and absence of spinal reflexes, preservation of muscle mass becomes difficult. In DM-affected dogs development of neurogenic atrophy confounds the interpretation of disuse atrophy. Neuromuscular electrical stimulation (NMES) may attenuate muscle atrophy in the presence of LMN signs by helping to maintain potential functional capacity of the muscle fibers. As does active exercise, NMES may improve the timing or recruitment of muscles so that the muscles exert more force in a useful and coordinated manner. Continuous NMES was found to have positive effects on reinnervation and the sprouting process in denervated muscles of experimentally neurectomized dogs (Williams, 1996). Its use is considered contraindicated in cases of extreme muscle weakness, however, because of the risk of further muscle damage. In ALS patients, a rule of thumb is that NMES should no longer be performed when the patient no longer has voluntary muscle movements (Hallum, 2007). It is important to establish outcome measures specific to DM to document prospectively the effects of active and

passive exercise in DM-affected dogs. Another consideration is the effect of age on the neuromuscular system of dogs. Muscle mass declines with age, presumably because of myofiber loss and atrophy. A comparison study of aged dogs revealed little age-related variation in the diameter of type I myofibers, but the diameter of type IIA fibers was decreased uniformly in dogs 7 years and older (Braund et al, 1982).

Other Supportive Care When the DM-affected dog becomes recumbent, supportive care that addresses psychologic and physical wellbeing is especially important. Assistive devices include a broad array of equipment to help caregivers with ambulation of their pets, to protect the extremities, and to improve quality of life for pets and their owners (Millis, 2009; Millis et al, 2004). In dogs with loss of proprioceptive placement, protective boots shield the dorsum of the paws and prevent wearing of the nails. The boots should be fitted properly and have properties that promote hygiene, water resistance and durability. Slings are available commercially for use as the dog becomes paraparetic. The sling should have a soft lining and be fitted properly to prevent chaffing. In dogs that are unable to ambulate without support, two- or four-wheel carts are available commercially. These assistive devices can provide independence for the DM-affected dog. However, the pet owner must monitor for fatigue in the thoracic limbs and ensure that the cart fits appropriately as the disease progresses. It is important to prevent or minimize the secondary consequences of DM, such as contracture, decubitus ulcers, and pneumonia. Bedding should be supportive enough to distribute the dog’s weight evenly, especially over bony prominences, to prevent decubital ulcers. The skin should be assessed twice daily for redness or other evidence of ulceration. Absorbent materials (lamb’s wool, diaper pads) should overlay supportive materials (air, foam mattresses). If the dog is unable to reposition itself into a sternal position, rotation should be performed every 4 to 6 hours. Cleanliness is critical to prevent fecal and urine scalding because incontinence develops when the dog becomes nonambulatory. Hydrotherapy also can play a role in increasing circulation in the limb vasculature and preventing decubitus ulcers. In the late disease stage when the dog is tetraplegic, dysphagia will develop, which predisposes to aspiration pneumonia.

References and Suggested Reading Ashworth NL, Satkunam LE, Deforge D: Treatment for spasticity in amyotrophic lateral sclerosis/motor neuron disease, Cochrane Database Syst Rev 1:CD004156, 2006. Averill DR: Degenerative myelopathy in the aging German Shepherd dog: clinical and pathologic findings, J Am Vet Med Assoc 162(12):1045, 1973. Awano T et al: Genome-wide association analysis reveals a SOD1 mutation in canine degenerative myelopathy that resembles amyotrophic lateral sclerosis, Proc Natl Acad Sci U S A 106:2794, 2009. Beghi E et al: The epidemiology and treatment of ALS: focus on the heterogeneity of the disease and critical appraisal of therapeutic trials, Amyotroph Lateral Scler 12:1, 2011.

CHAPTER  234  Canine Degenerative Myelopathy Bello-Haas VD et al: A randomized controlled trial of resistance exercise in individuals with ALS, Neurology 68:2003, 2007. Bennett RL, Knowlton GC: Overwork weakness in partially denervated skeletal muscle, Clin Orthop 12:711, 1958. Bensimon G, Lacomblez L, Meininger V: A control trial of  riluzole, ALS/Riluzole Study Group, N Engl J Med 330:585, 1994. Boillée S, Vande Velde C, Cleveland DW: ALS: a disease of motor neurons and their nonneuronal neighbors, Neuron 52(1):39, 2006. Braund KG, McGuire JA, Lincoln CE: Observations on normal skeletal muscle of mature dogs: a cytochemical, histochemical and morphometric study, Vet Pathol 19:577, 1982. Braund KG, Vandevelde M: German Shepherd dog myelopathy— a morphologic and morphometric study, Am J Vet Res 39(8):1309, 1978. Chen A, Montes J, Mitsumoto H: The role of exercise in amyotrophic lateral sclerosis, Phys Med Rehabil Clin N Am 19:545, 2008. Clemmons RM: Degenerative myelopathy. In Kirk RW, editor: Current veterinary therapy X: small animal practice, Philadelphia, 1989, Saunders, p 830. Coates JR et al: Clinical characterization of a familial degenerative myelopathy in Pembroke Welsh Corgi dogs, J Vet Intern Med 21:1323, 2007. Coates JR, Wininger FA: Canine degenerative myelopathy, Vet Clin North Am Small Anim Pract 40:929, 2010. Drory VE et al: The value of muscle exercise in patients with amyotrophic lateral sclerosis, J Neurol Sci 191:133, 2001. Drum MG: Physical rehabilitation of the canine neurologic patient, Vet Clin North Am Small Anim Pract 40:181, 2010. Fechner H et al: Molecular genetic and expression analysis of alpha-tocopherol transfer protein mRNA in German Shepherd dogs with degenerative myelopathy, Berl Munch Tierarztl Wochenschr 11:631, 2003. Griffiths IR, Duncan ID: Chronic degenerative radiculomyelopathy in the dog, J Small Anim Pract 16(8):461, 1975. Hallum A: Neuromuscular disease. In Umphred DA, editor: Neurological rehabilitation, ed 5, St Louis, 2007, Mosby, p 475. Johnston PEJ et al: Central nervous system pathology in 25 dogs with chronic degenerative radiculomyelopathy, Vet Rec 146(22):629, 2000. Johnston PEJ et al: Serum alpha tocopherol concentrations in German shepherd dogs with chronic degenerative radiculomyelopathy, Vet Rec 148:403, 2001. Kaspar BK et al: Synergy of insulin-like growth factor-1 and exercise in amyotrophic lateral sclerosis, Ann Neurol 57:649, 2005. Kathmann I et al: Daily controlled physiotherapy increases survival time in dogs with suspected degenerative myelopathy,  J Vet Intern Med 20:927, 2006. Katz RT: Management of spasticity, Am J Phys Med Rehabil 67:108, 1988. Kierkinezos IG et al: Regular exercise is beneficial to a mouse model of amyotrophic lateral sclerosis, Ann Neurol 53:804, 2003. Liebetanz D et al: Extensive exercise is not harmful in amyotrophic lateral sclerosis, Eur J Neurosci 20:3115, 2004.

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Mahoney DJ et al: Effects of high-intensity endurance exercise training in the G93A mouse model of amyotrophic lateral sclerosis, Muscle Nerve 29:656, 2004. March PA et al: Degenerative myelopathy in 18 Pembroke Welsh Corgi dogs, Vet Pathol 46:241, 2009. Matthews NS, de Lahunta A: Degenerative myelopathy in an adult miniature poodle, J Am Vet Med Assoc 186(11):1213, 1985. McCrate ME, Kaspar BK: Physical activity and neuroprotection in amyotrophic lateral sclerosis, Neuromolecular Med 10:108, 2008. Miller RG et al: Riluzole for amyotrophic lateral sclerosis (ALS/ motor neuron disease [MND]), Cochrane Database Syst Rev CDOO1447, 2007. Millis DL: Physical therapy and rehabilitation of neurologic patients. In Bonagura JD, Twedt DC, editors: Kirk’s current veterinary therapy XIV, St Louis, 2009, Saunders, p 1131. Millis DL, Levine D, Taylor RA: Canine rehabilitation and physical therapy, Philadelphia, 2004, Saunders. Milner-Brown HS, Miller RG: Muscle strengthening through high-resistance weight training in patients with neuromuscular disorders, Arch Phys Med Rehabil 69:14, 1998. Olby N, Halling KB, Glick TR: Rehabilitation for the neurologic patient, Vet Clin North Am Small Anim Pract 35:1389, 2005. Polizopoulou ZS et al: Evaluation of a proposed therapeutic protocol in 12 dogs with tentative degenerative myelopathy, Acta Vet Hung 56(3):293, 2008. Reitsma W: Skeletal muscle hypertrophy after heavy exercise in rats with surgically reduced muscle function, Am J Phys Med 48:237, 1969. Ropper AH, Samuels MA: Adams and Victor’s principles of neurology, ed 9, New York, 2009, McGraw-Hill. Sanjak M et al: Quantitative assessment of motor fatigue in amyotrophic lateral sclerosis, J Neurol Sci 191:55, 2001. Shealy P, Thomas WB, Immel L: Neurologic conditions and physical rehabilitation of the neurologic patient. In Millis DL, Levine D, Taylor RA, editors: Canine rehabilitation and physical therapy, Philadelphia, 2004, Saunders, p 388. Shelton GD et al: Degenerative myelopathy associated with a missense mutation in the superoxide dismutase 1 (SOD1) gene progresses to peripheral neuropathy in Pembroke Welsh Corgis and Boxers, J Neurol Sci 318:55, 2012. Sherman J, Olby NJ: Nursing and rehabilitation of the neurological patient. In Platt SR, Olby NJ, editors: BSAVA manual of canine and feline neurology, ed 3, Gloucester, UK, 2004, British Small Animal Veterinary Association, p 394. Tam SL et al: Increased neuromuscular activity reduces sprouting in partially denervated muscles, J Neurosci 21:654, 2001. Williams DA, Prymak C, Baughan J: Tocopherol (vitamin E) status in canine degenerative myelopathy. In Proceedings of the 3rd ACVIM Forum, 1985, p 154. Williams HB: The value of continuous electrical muscle stimulation using a completely implantable system in the preservation of muscle function following motor nerve injury and repair: an experimental study, Microsurgery 17:589, 1996. Wininger FA et al: Degenerative myelopathy in a Bernese mountain dog with a novel SOD1 missense mutation, J Vet Intern Med 25:1166, 2011.

CHAPTER 

235 

Diagnosis and Treatment of Atlantoaxial Subluxation BEVERLY K. STURGES, Davis, California

A

tlantoaxial (AA) instability with subluxation of C2 relative to C1 is a frequent cause of cervical pain as well as myelopathy in toy and miniature breeds of dogs. Congenital vertebral malformations along with abnormality or absence of ligamentous structures lead to contusion or compression of the cervical spinal cord and caudal brainstem. AA instability also occurs infrequently in large breeds of dogs and usually is secondary to traumatic injury of the cervical vertebral column. Because AA instability is a potentially life-threatening disease, it is important to recognize when it may be present so that the patient is handled appropriately. This will prevent exacerbation of the clinical signs until a definitive diagnosis is made and appropriate treatment is instituted.

General Considerations: Anatomy and Physiology The atlas (C1) and axis (C2) form a pivotal joint that allows free movement of the head about the longitudinal axis of the spine. Most rotational head movement centers around the dens, a bony process projecting rostrally from the body of the axis. The dens is held in place on the ventral aspect of C1, within the vertebral canal, by several ligaments (Figures 235-1 and 235-2): 1. The apical and alar ligaments leave the apex of the dens and attach to the ventral aspect of the foramen magnum and the skull medial to the occipital condyles. 2. The transverse atlantal ligament is a strong ligament that runs transversely in the vertebral canal, crossing dorsally over the dens. This ligament is particularly important to AA joint stability since it holds the dens firmly against the ventral aspect of the atlas. 3. The dorsal atlantoaxial membrane is a fibrous extension of the joint capsule running between the arch of the atlas and the spinous process of the axis. It adds support limiting the amount of dorsoventral movement between C1 and C2. The atlas articulates rostrally with the occipital condyles of the skull and forms a joint of which the main movements are flexion and extension of the head, the “yes” joint. Caudally, the atlas articulates with the axis allowing lateral and rotational movement of the head, the “no” joint. Working together, these two joints allow free motion of the head in all directions. The large nuchal ligament that attaches the spinous process of C2 to those 1082

of T1 and T2 functions in suspension of the head, forming a fulcrum at the AA joint (see Figures 235-1 and 235-2).

Pathophysiology Instability of the AA region allows excessive flexion of the C1-2 joint that may result in subluxation of C2 relative to C1 and injury to the spinal cord (Figure 235-3). This usually occurs secondary to congenital or developmental abnormalities of the bones or ligaments of the AA joint, traumatic injury to the joint, or a combination of both (Figure 235-4). In many instances the abnormalities present are associated with the dens and include agenesis or hypoplasia of the dens, dorsal angulation of the dens, and fracture or avulsion of the dens from the axis. Absence or rupture of associated AA ligaments often contributes to the instability caused by congenital anomalies in the region. All of these findings are common in toy and miniature breeds of dogs. Traumatic rupture of the AA ligaments without associated anomalies of the AA joint is possible but usually occurs as a result of major traumatic injury to the cervical vertebral column. This is the most common cause of AA instability in large-breed dogs. Recently there have been reports (Owen et al, 2008; Warren-Smith et al, 2009) of larger-breed dogs with absence or incomplete ossification of the atlas (Figure 235-5). Associated AA subluxation in most of these dogs suggests another predisposing factor to AA instability. This was further investigated in another study characterizing the morphology of the atlas on computed tomography (CT) in various classes of dog breed (Parry et al, 2010). Dogs with ossification abnormalities involving the atlas were significantly more likely to have associated AA subluxation, although the underlying pathophysiology behind these findings is not known. AA subluxation rarely is seen in cats. Only a handful of cases have been reported, and all of them have been associated with congenital occipitoatlantoaxial malformations or malformations of the dens (C2). Regardless of the underlying cause, dorsal displacement of the cranial portion of the body of the axis into the vertebral canal causes compression, edema, and inflammation of the spinal cord that may extend cranially into the caudal brainstem. In addition, intraaxial hemorrhage into the central nervous system parenchyma also may contribute to the clinical signs (Kent et al, 2010). Cervical pain, myelopathy of varying degrees, and possible caudal brainstem signs may occur.

CHAPTER  235  Diagnosis and Treatment of Atlantoaxial Subluxation Dorsal atlantoaxial ligament Spinal cord Nuchal ligament

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Diagnosis Clinical Presentation

C2

Transverse ligament Apical/alar ligaments

Figure 235-1  Normal atlantoaxial (AA) joint, lateral view. Note

the relationships of the ligamentous and bony structures of the AA joint that allow normal head movement without injury to neural structures.

Apical ligament Alar ligament Transverse ligament

C1

C2

Figure 235-2  Normal atlantoaxial joint, ventrodorsal view. The

apical and alar ligaments attach the dens to the occipital bones of the skull, whereas the transverse ligament crosses over the dens, maintaining it in place on the floor of the vertebral canal.

Malformations of the AA joint occur most frequently  in toy and miniature breeds of dogs, especially Chihuahuas, Yorkshire terriers, toy and miniature poodles,  Pomeranians, Japanese chin, Maltese dogs, and others. Clinical signs of a C1 to C5 myelopathy or cervical pain occur and may be acute or chronic in onset and progressive, nonprogressive, or intermittent. Often the signs occur secondary to mild “trauma” such as jumping off the bed or roughhousing with other dogs. Although clinical signs typically are reported in the first year of life, it is not uncommon for dogs older than a year, including middle-aged or older animals, to begin showing clinical signs. Severity of signs varies from mild cervical pain to profound cervical pain to tetraparesis, respiratory paralysis, and caudal brainstem signs (e.g., hypoventilation, obtundation, vestibular signs). Traumatic AA instability, with or without an underlying congenital malformation, usually is the cause of AA subluxation in larger-breed dogs (>10 kg). Occasionally dogs with AA instability have a history of seizurelike signs or episodes that occur intermittently. Owners often describe an associated transient apnea and paresis. The episodes may be related to a mild trauma, such as jumping out of a car or going down the stairs. These clinical signs may occur more commonly with malformations of the dens, specifically agenesis or dorsal angulation of the dens. Differential diagnoses for dogs with suspected AA instability or subluxation include intervertebral disk disease, cervical trauma or spinal fracture, infectious or inflammatory disease (e.g., granulomatous meningoencephalitis), other craniospinal anomalies (e.g., syringomyelia, Chiari-like malformation), and neoplasia (of the cervical spine or brain). Since the history, signalment, and clinical signs of AA instability may be indistinguishable from those of other differential diagnoses, it is important to take appropriate precautions in any animal that may have vertebral instability at the AA joint.

Radiography Spinal cord C2

Figure 235-3  Atlantoaxial subluxation, lateral view. Sublux-

ation of the axis (C2) relative to the atlas (C1) causes traumatic injury and compression of the cranial spinal cord. Associated hemorrhage and edema may extend rostrally to affect brainstem function.

Plain cervical radiography provides the diagnosis in most instances. Because it is essential that positioning be accurate when the AA region of the cervical spine is evaluated, general anesthesia is necessary. It is easy to misdiagnose AA subluxation when positioning is imperfect or when the beam is not centered on C1-2. Care must be taken when manipulating an animal suspected of having AA instability during intubation, handling under anesthesia, and radiography since flexion of the animal’s neck may result in further spinal cord compression. Placing a soft, padded bandage on the patient before inducing anesthesia, with the head positioned in mild extension, provides support and comfort for the animal and serves as a safeguard to keep the AA joint in extension. On radiographs the body of the axis is displaced dorsally and cranially into the vertebral canal on neutral lateral projections. The distance between the dorsal arch

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SECTION  XI  Neurologic Diseases

A B

C D Figure 235-4  Comparison of C1 and C2 vertebrae. A and B, Lateral and ventrodorsal views

illustrating the normal shape and relationship of C1 relative to C2. The spinous process of C2 typically spans the caudal third of the dorsal arch of C1 on the lateral view. The arch of the atlas is thicker than in toy or miniature breeds, with a layer of trabecular bone between the inner and outer layers of cortical bone, and the transverse process (wings) of the atlas are longer and thicker. C, Lateral view showing typical vertebral deformities seen in the atlas and axis of toy and miniature breeds. The spinous process of C2 often is foreshortened and minimally associated with the dorsal arch of C1. Dorsal atlantoaxial ligaments likely are reduced or nonexistent. The intervertebral foramen is comparatively large, and the vertebral arches of C1 and C2 are comparatively small and misshapen. D, Ventrodorsal view showing typical vertebral deformities seen in toy and miniature breeds. The wings of the atlas are very thin and often much smaller comparatively than in normal dogs. The articulation between C1 and C2 is widened and often malformed; there is much less bony mass in the body of C1 and C2. Significantly, these changes are accompanied by hypoplasia, agenesis, and abnormal angulation of the dens.

of the atlas and spinous process of the axis is increased (Figure 235-6, A). If the findings are not clearly diagnostic, the head should be extended gently to demonstrate further reduction of the subluxation (Figure 235-6, B). As a last resort, the head may be flexed gently to demonstrate abnormal movement at C1-2 and exacerbation of the subluxation. Abnormalities of the dens may be seen clearly on oblique lateral views, in which the wings of the atlas are not superimposed on the dens, or on ventrodorsal views.

Advanced Imaging Myelography, CT imaging, or both modalities may be required to confirm that subluxation is present and to provide further delineation of regional problems when multiple congenital anomalies are present (Figure 235-7).

Such imaging also may be useful to rule out other differential diagnoses within the same neuroanatomic region (e.g., disk disease). Lumbar puncture should be done since cisternal puncture for cerebrospinal fluid sampling or myelography is not recommended in dogs for which AA subluxation is on the differential list. In most cases plain radiography with or without myelography or CT-myelography is sufficient to diagnose AA instability or subluxation. Magnetic resonance imaging (MRI) may be very useful in the diagnosis of AA subluxation, especially in patients with clinical signs of brain or brainstem disease as well as cervical pain and myelopathy. The extent of central nervous system parenchymal injury to the cervical cord or caudal brainstem is best visualized with MRI (Figure 235-8). Typically a region of hyperintensity is visible in the cranial cervical spinal cord or caudal brainstem on

CHAPTER  235  Diagnosis and Treatment of Atlantoaxial Subluxation

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A Figure 235-5  Transverse computed tomographic–myelographic

image showing incomplete ossification of C1 in a 10-year-old Brittany spaniel with chronic cervical pain and tetraparesis. There is discontinuity of the dorsal arch as well as the body/ ventral arch of C1. The dens is causing marked compression and dorsal displacement of the spinal cord within the vertebral canal. (Courtesy Dr. Robert Bergman.)

T2-weighted images. In addition, MRI is useful for ruling out the presence of concurrent diseases with clinical signs localizing to the same region and for identifying underlying disease that may influence long-term prognosis. For example, cavalier King Charles spaniels should be evaluated for the presence of a Chiari-like malformation and syringomyelia as well as AA instability when signs of cervical pain and myelopathy are present. Collection of cerebrospinal fluid is recommended in cases in which the diagnosis is not straightforward on imaging, especially in breeds of dogs typically prone to inflammatory disease of the brain (e.g., granulomatous meningoencephalitis).

Treatment Animals with cervical pain only or minimal neurologic deficits may respond well to splinting of the head and neck in mild extension and strict cage rest for at least 6 weeks. However, the clinical signs may not completely resolve or may worsen, and recrudescence often occurs when the splint is removed. Surgical decompression and stabilization is indicated in animals with moderate to severe neurologic deficits or intense pain, and in those showing no response to nonsurgical treatment. Surgery also is recommended in animals in which angulation of the dens results in spinal cord injury. Animals younger than 6 months of age are best treated conservatively, if possible, to allow for more complete mineralization of bone and closure of vertebral physes before surgical stabilization is attempted. Certainly conservative treatment should be attempted in situations in which financial constraints do not allow surgical repair to be done.

Nonsurgical Treatment Cage confinement, immobilization of the AA region, and possibly nonsteroidal antiinflammatory therapy often

B Figure 235-6  Plain lateral radiographs of a 0.75-kg 5-month-

old Yorkshire terrier with acute-onset nonambulatory tetraparesis. A, The head is in a neutral position, and increased space can be seen between the arch of C1 and the spinous process of C2. This dog had several congenital abnormalities, including agenesis of the dens, an associated lack of normal atlantoaxial (AA) ligaments, and block vertebrae from C2 to C4. B, The head is now positioned in extension, which relieves compression on the spinal cord and allows C1 and C2 to assume a more normal relationship. This confirms that AA instability is present without the need to risk further spinal cord injury by flexing the head.

results in clinical improvement. Splinting allows for formation of fibrous tissues and some healing of ligamentous structures to restabilize the AA joint. Ideally the splint should extend from the mandible to the sternum incorporating the head in mild extension in an attempt to immobilize the AA joint as much as possible. Casting materials, thermoplast, or malleable metals may be used to form the splint, which then should be well padded before it is applied to the patient. Many patients do not tolerate this degree of immobilization well. Toy breeds, especially immature animals, may even have a hard time eating, walking, and supporting the cranial half of the body. Instead of a splint, a shorter, softer supportive bandage may be used that incorporates the head (including the caudal aspect of the mandible) down to the caudal cervical region. This is tolerable to the patient, keeps the head in mild extension, is easily supported, and appears to be effective, especially in very small dogs (Figure  235-9). Animals with splints and bandages of any kind

SECTION  XI  Neurologic Diseases

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A

B Figure 235-7  Computed tomographic images of a 3-year-old Yorkshire terrier with acute-onset

cervical pain and ataxia. Although initially the dog was treated conservatively, clinical signs did not resolve. A, A transverse image through C1 shows the dens luxated into the vertebral canal and compressing the spinal cord (arrow). B, A three-dimensional reconstruction confirms the abnormal position of C1 relative to C2.

Figure 235-8  Midsagittal magnetic resonance image of a

15-month-old Chihuahua with acute onset of cervical pain, ataxia, and tetraparesis. Several abnormalities are noted in this dog. Ventriculomegaly is present along with a small quadrigeminal cyst (black arrow). Mild crowding of the caudal fossa, occipital bone dysplasia, and dorsal atlantoaxial ligament hypertrophy also can be seen along with a dens that is subluxated into the vertebral canal (white arrow). Hyperintensity in the spinal cord dorsal to the dens is consistent with edema, inflammation, or hemorrhage. The neurologic status of this dog returned to normal following surgical stabilization of C1-2.

Figure 235-9  Removable supportive bandage for atlantoaxial

should be checked regularly for any signs of complication, including otitis, facial and corneal excoriations, and dermatitis. Bandages typically are left on for a period of 4 to 8 weeks and then removed. The animal is allowed a gradual return to normal activity. If clinical signs of AA instability return, nonsurgical treatment may be reinstituted; however, surgical repair is strongly recommended at this point. Clients often become distraught with repeated episodes of pain or myelopathy and usually are

amenable to more definitive treatment with surgery after the first episode.

(AA) instability in toy breed dogs. A small Styrofoam cup is cut from top to bottom and the base of the cup is removed. The cup is gently wrapped around the dog’s neck, with the lip of the cup situated at the level of the temporomandibular joint and the base of the cup ending in the midcervical region. The cup is gently tightened and secured by overlapping the cut sides and taping in place. This provides comfortable support while limiting ventroflexion at the C1-C2 joint. Ear and jaw movements are not hindered and the bandage can be easily removed and replaced as needed.

Surgical Treatment Surgery is indicated for most dogs and cats with clinical signs of AA subluxation. Stabilization of the joint usually results in immediate relief of pain and improved neurologic status, even in the most severely affected animals.

CHAPTER  235  Diagnosis and Treatment of Atlantoaxial Subluxation Stabilization of the AA joint reduces the lateral and rotational mobility of the patient’s head, although usually this is well tolerated physically by the animal. The “domino” effect, which frequently is of concern with fusion of vertebrae in the caudal cervical spine, does not appear to be a problem with stabilization of C1-2. Many surgical techniques for AA stabilization have been described in the veterinary literature that use either a dorsal or a ventral approach to the C1-2 joint. The following paragraphs briefly describe the procedures currently in common use. Dorsal-Approach Surgical Techniques Dorsal repairs of the AA joint were the earliest techniques described for immobilization (McCarthy et al, 1995). However, since fusion of the joint is not achieved, they are palliative procedures only and usually are not  recommended as the first choice for treatment of AA subluxation. In most circumstances dorsal repairs have been replaced by ventral fusion techniques. Dorsal methods that are currently used include the following (Figure 235-10). The dorsal wiring-suturing technique still is the most common dorsal method in use. The approach is technically easy, but correct placement of the wire or suture may

A

C

1087

be difficult, and the procedure may be associated with several potential complications: (1) the spinal cord may be injured further during wire placement; (2) disruption of the internal vertebral venous sinus may lead to hemorrhage or hematoma formation within the vertebral canal, which exacerbates clinical signs; and (3) the wire or suture may cut through the lamina of C1, especially in soft, immature bones. Use of a splint or bandage is recommended for 6 weeks after surgery to immobilize the AA joint until scar tissue forms. The Kishigami atlantoaxial tension band repair is an older technique. Recently the band has become available commercially, and its use in toy breeds for AA joint repair has been reported (Pujol et al, 2010). Ventral-Approach Surgical Techniques Ventral fixation of the AA joint generally is preferred since the ventral approach provides direct access to the C1-2 joint. This allows the surgeon to reduce the subluxation and decompress the spinal cord, perform an odontectomy if indicated, and promote arthrodesis between C1 and C2 by removing the articular cartilage and placing a bone graft. However, ventral approaches are technically more difficult, and complications may occur because  (1) bones usually are very small, often malformed, and

B

D

Figure 235-10  Dorsal surgical atlantoaxial (AA) repair techniques currently used to maintain C1-2 in reduction. A, Dorsal wiring technique using wire or suture. B, Kishigami band. Dorsal repairs do not provide the immobilization that ventral repairs do and are not recommended as the first choice for treatment of AA instability.

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SECTION  XI  Neurologic Diseases

A

B

C

D

Figure 235-11  Ventral surgical stabilization techniques currently used to immobilize the atlan-

toaxial joint, ventrodorsal view. In addition to the implant, cancellous bone grafts are placed intraarticularly to promote arthrodesis at C1-2. A, Transarticular pins (with or without polymethyl methacrylate [PMMA]). B, Transarticular lag screws. C, Screw anchors and PMMA. D, Butterfly locking plate.

easily fractured during reduction and implant placement; (2) vertebral movement or incorrect positioning of the implant during placement can cause further injury to the spinal cord and possible paralysis, ventilatory failure, or death; and (3) trauma can occur to vital soft tissue structures in the area (e.g., vagosympathetic trunk, carotid artery, trachea, brainstem). Many ventral techniques for surgical management of AA instability in dogs have been reported (Dickomeit et al, 2011; McCarthy et al, 1995; Platt et al, 2004; Sanders et al, 2004; Schulz et al, 1997; Sharp, 2005). In each of these procedures, the patient is positioned in dorsal recumbency with the neck in extension. Stabilization techniques in current use include the following (Figures 235-11 and 235-12): • Transarticular pins, wires, or screws (with or without polymethyl methacrylate [PMMA]). A combination of pins, screws, and bone cement is used to immobilize the joint, and bony fusion at the site is promoted by the placement of a bone graft into the AA joint. • Screw anchors and PMMA. Small screws are placed in the lateral masses of C1 and bony masses of C2, and sometimes of C3. These are then incorporated into PMMA.

• Butterfly plate. In a technique recently reported for use in small dogs (Dickomeit et al, 2011), a small (1.5-mm) locking plate is applied to the ventral aspect of C1-2 using monocortical screws. Postoperative care usually is minimal, with pain medications needed for the first 24 to 36 hours and nonsteroidal antiinflammatory drugs used to treat associated inflammation as needed. Improvement in the neurologic status and pain score of the patient usually is seen  immediately following surgery. Restriction of activity or cage confinement is recommended for the first 4 to  6 weeks.

Prognosis The prognosis for animals with AA subluxation varies depending on the chronicity and severity of the spinal cord injury that occurs. Generally speaking, the longterm outcome is very good to excellent for animals treated surgically that have clinical signs of pain or mild to moderate neurologic deficits. Animals with severe tetraparesis or tetraplegia and respiratory distress, especially those with a long history of difficulties, have a guarded prognosis for good recovery of neurologic function (Beaver

CHAPTER  235  Diagnosis and Treatment of Atlantoaxial Subluxation

A

B

C

D

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Figure 235-12  Common methods used to stabilize atlantoaxial subluxation. A and B, Postop-

erative lateral and ventrodorsal radiographs showing positive-profile threaded transarticular acrylic interface pins embedded in polymethyl methacrylate (PMMA). Note the block vertebrae present at C2, C3, and C4 in this dog. C and D, Titanium screw anchors in C1 and C2 embedded in PMMA. (C and D courtesy Dr. Andy Hopkins.)

et al, 2000; Knipe et al, 2002). Recently reported success rates for ventral surgical techniques vary from 79% to 92% for a good to excellent outcome (Beaver et al, 2000; Knipe et al, 2002; Platt et al, 2004; Sanders et al, 2004; Schulz et al, 1997); no one method proved superior to the others with respect to long-term survival. The experience and comfort level of the surgeon in performing surgery in the AA region is likely one of most important influences on the overall outcome for patients with AA disease. In practice, the patient almost always is referred to a surgical specialist for this procedure. A recent study examining long-term outcomes in dogs treated nonsurgically found that dogs that had an acute onset of clinical signs and no history of signs of AA instability had a good outcome about 60% of the time, regardless of the severity of the neurologic signs at presentation (Havig et al, 2005). Dogs treated nonsurgically that had shown clinical signs for longer than 30 days were significantly more likely to have a poor final outcome. It should be noted that the presence of pain perception is of little prognostic value in animals with AA subluxation since compression severe enough to cause loss of deep pain at this level of the spinal cord usually results in respiratory paralysis and death.

References and Suggested Reading Beaver DP et al: Risk factors affecting the outcome of surgery for atlantoaxial subluxation in dogs: 46 cases (1978-1998), J Am Vet Med Assoc 216:7, 2000. Dickomeit M et al: Use of a 1.5mm butterfly locking plate for stabilization of atlantoaxial pathology in three toy breed dogs, Vet Comp Orthop Traumatol 24:246, 2011. Havig ME et al: Evaluation of nonsurgical treatment of atlantoaxial subluxation in dogs: 19 cases (1992-2001), J Am Vet Med Assoc 222:2, 2005. Kent M et al: Intraaxial spinal cord hemorrhage secondary to atlantoaxial subluxation in a dog, J Am Anim Hosp Assoc 46:132, 2010. Knipe MF et al: Atlantoaxial instability in 17 dogs. 20th Annual ACVIM Forum Proceedings, Dallas, TX, J Vet Intern Med, 2002. McCarthy RJ, Lewis DD, Hosgood G: Atlantoaxial subluxation in dogs, Compend Contin Educ 17:2, 1995. Owen MC, Davis SH, Worth AJ: Imaging diagnosis—traumatic myelopathy in a dog with incomplete ossification of the neural arch of the atlas, Vet Radiol Ultrasound 49:570, 2008. Parry AT et al: Computed tomography variations in morphology of the canine atlas in dogs with and without atlantoaxial subluxation, Vet Radiol Ultrasound 51(6):596, 2010. Platt SR, Chambers JN, Cross A: A modified ventral fixation for surgical management of atlantoaxial subluxation in 19 dogs, Vet Surg 33:349, 2004.

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Pujol E et al: Use of the Kishigami atlantoaxial tension band in eight toy breed dogs with atlantoaxial subluxation, Vet Surg 39:35, 2010. Sanders SG et al: Outcomes and complications associated with ventral screws, pins, and polymethyl methacrylate for atlantoaxial instability in 12 dogs, J Am Anim Hosp Assoc 40:204, 2004. Schulz KS, Waldron DR, Fahie M: Application of ventral  pins and polymethylmethacrylate for the management of

CHAPTER 

atlantoaxial instability: results in nine dogs, Vet Surg 26:317, 1997. Sharp NJH: Atlantoaxial subluxation. In Sharp NJH, Wheeler SJ, editors: Small animal spinal disorders: diagnosis and surgery, ed 2, St Louis, 2005, Mosby, p 161. Warren-Smith CMR et al: Incomplete ossification of the atlas  in dogs with cervical signs, Vet Radiol Ultrasound 50:235, 2009.

236 

Diagnosis and Treatment of Cervical Spondylomyelopathy RONALDO CASIMIRO DA COSTA, Columbus, Ohio

C

ervical spondylomyelopathy (CSM) is a very common disease of the cervical spine of largeand giant-breed dogs. CSM is characterized by dynamic and static compressions of the cervical spinal cord, nerve roots, or both leading to variable degrees of neurologic deficits and neck pain. CSM certainly is a controversial disease! Few other diseases in veterinary medicine have been called by 15 different names, with wobbler syndrome, cervical vertebral instability, cervical malformation/ malarticulation syndrome, and disk-associated wobbler syndrome some of the more commonly used. Furthermore, few other disorders have been the target of 27 different proposed surgical treatments. This diversity reflects in part the lack of understanding regarding mechanisms  of CSM. Although the disease can affect essentially all canine breeds, two account for approximately 60% to 70% of all cases: the Doberman pinscher and the Great Dane. These breeds also illustrate the two distinct forms of the disease: disk-associated CSM (primarily affecting Dobermans) and the osseous form of CSM (affecting Great Danes).

Causes and Pathophysiology The cause of CSM remains unresolved. Proposed causes include genetic, congenital, body conformation, and nutritional factors, with the latter two playing a less significant role. Based on current evidence CSM appears to be congenital. The genetic contribution to the development of the disease remains unclear, although recent evidence in Dobermans suggests that CSM is inherited as an autosomal dominant trait with variable penetrance in this breed.

The pathophysiology of CSM involves both static and dynamic factors. The key static factor is vertebral canal stenosis. It may be an absolute vertebral canal stenosis, which causes direct spinal cord compression and neurologic signs, or a relative vertebral stenosis, which by itself does not lead to myelopathic signs but predisposes the patient to development of myelopathy. Despite some degree of overlap, the spinal cord compressions can be divided into osseous compression and disk-associated compression based on pathophysiology. Disk-associated compression typically is seen in middle-aged large-breed dogs (mostly Dobermans). It is caused by intervertebral protrusion with or without hypertrophy of the dorsal longitudinal ligament or ligamentum flavum (Figure 236-1). Three factors act in combination to explain the pathophysiology of disk-associated CSM: (1) relative vertebral canal stenosis, (2) more pronounced torsion in the caudal cervical spine leading to intervertebral disk degeneration, and (3) protrusion of larger-volume disks into the caudal cervical spine. Affected dogs apparently are born with a congenital vertebral canal stenosis that predisposes them to the development of clinical signs. The vast majority of disk-associated spinal cord compressions are located in the caudal cervical spine, affecting the disks at C5-6 and C6-7. The biomechanical features of the caudal cervical spine explain the high incidence of lesions there. This region experiences three times more axial rotation or torsion than the cranial cervical spine, and torsion (more than axial compression) is the main biomechanical force leading to intervertebral disk degeneration in nonchondrodystrophic dogs. Additionally, a study found that Dobermans with CSM have larger

CHAPTER  236  Diagnosis and Treatment of Cervical Spondylomyelopathy

A

B

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C

Figure 236-1  Disk-associated cervical spondylomyelopathy. Top: Ventral spinal cord compres-

sion and nerve root compression at C5-6 caused by intervertebral disk protrusion. Dorsally, hypertrophy of the ligamentum flavum causes mild spinal cord compression. A, Transverse section at the level of the C4-5 disk region showing normal spinal cord and vertebral canal.  B, Ventral compression at the C5-6 region caused by intervertebral disk protrusion and hypertrophy of the dorsal longitudinal ligament and ligamentum flavum (leading to mild dorsal compression). C, Asymmetric intervertebral disk protrusion at C6-7 causing spinal cord and nerve root compression.

intervertebral disks than clinically normal Dobermans  (da Costa et al, 2006b). This would cause a larger volume of disk protrusion into the vertebral canal. Since dogs with CSM have a narrow vertebral canal, the combination of a stenotic vertebral canal and protrusion of disks with larger volumes ultimately leads to clinical disease. The pathophysiology of osseous or bony CSM is different. Osseous CSM is seen predominantly in young adult giant-breed dogs, especially in Great Danes. Although a hereditary basis still is unproven, a familial predisposition has been identified. Giant breeds usually have severe absolute vertebral canal stenosis secondary to proliferation of the vertebral arch (dorsally), articular facets (dorsolaterally), or articular facets and pedicles (laterally) (Figure 236-2). The cause of the compression appears  to be a combination of vertebral malformation and osteoarthritic-osteoarthrotic changes at the level of the articular facets. Even though most giant-breed dogs have osseous compression, occasionally these compressions are complicated by disk protrusion, especially in older dogs. Ligamentous compression (by the ligamentum flavum) may be involved in the pathophysiology of the disease in giant- and large-breed dogs, but pure ligamentous compression as the single source of compression appears uncommon. Critical to understanding the development of clinical signs in CSM-affected large-breed dogs is the concept of the dynamic lesion. Dynamic spinal cord compressions are present in both disk-associated and osseous forms of CSM. A dynamic lesion is one that worsens or improves with changes in the position of the cervical

spine. Continuous flexion and extension of the cervical spine can lead to spinal cord elongation causing axial strain and stress within the spinal cord, and this has been proposed as a key mechanism of spinal cord injury in cervical spondylotic myelopathy in humans. This is very different from instability, which has been defined as loss of the ability of the cervical spine to maintain its normal pattern of displacement under physiologic loads and thereby prevent damage to the spinal cord or nerve roots. Instability has not yet been proven in dogs with CSM, and it appears that with the severe disk and osseous degenerative changes, a restricted rather than an excessive motion occurs at the affected sites. The most common location of compressive lesions in both large- and giant-breed dogs is at C5-6 and C6-7. The lesion is located at one of these sites in 90% of affected large-breed dogs. In giant-breed dogs, the C4-5 site also is commonly affected. Approximately 50% of large-breed dogs have a single site of spinal cord compression, and 50% have two or more sites of similar severity. In giantbreed dogs approximately 20% of dogs have a single site of compression, whereas 80% have multiple compressive lesions. A computed tomographic (CT)–myelographic study identified lesions affecting the T1-T2 and T2 regions in 14% of giant-breed dogs and the C7-T1 region in  22% of all dogs (da Costa et al, 2012). These lesions  were not the primary site of compression but were part of the multiple compressions seen in giant-breed dogs. For this reason, it is important to include the cranial thoracic region in imaging studies of dogs suspected of having CSM.

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A

B

C

Figure 236-2  Osseous cervical spondylomyelopathy. A, Severe dorsolateral spinal cord com-

pression at C2-3 caused by osseous malformation and osteoarthritic changes. B, Normal C3-4 disk region. C, Bilateral compression at C4-5 caused by osteoarthritic changes and medial proliferation of the facets resulting in absolute vertebral canal stenosis and foraminal stenosis, which lead to spinal cord and nerve root compression, respectively. Bottom: Dorsal spinal cord compression at C3-4 caused by lamina malformation and hypertrophy of the ligamentum flavum. Osteoarthritic changes also are shown at C2-3.

Diagnosis As indicated earlier, CSM is primarily a disease of largeand giant-breed dogs. It is seen occasionally in smallbreed dogs, but it is unclear whether small dogs also have vertebral canal stenosis. The majority of large-breed dogs (weimaraners, dalmatians) and Dobermans with CSM are older than 3 years of age at presentation (mean age, ~7 years). Great Danes and giant breeds (Mastiffs, rottweilers, Bernese and Swiss mountain dogs) with CSM usually are seen at a younger age. The mean age of giant-breed dogs with CSM is 3.8 years, and the disease may be seen in dogs just a few months old.

History and Clinical Signs A history of chronic progressive signs persisting for several weeks to months is typical. Acute presentations usually are associated with neck pain. Neck pain or cervical hyperesthesia is a common historical finding but is not the typical reason for presentation. Neck pain is part of the clinical findings in approximately 65% to 70% of Dobermans and in 40% to 50% of dogs of other breeds, but it is the chief complaint in only 5% to 10% of dogs with CSM. Forceful manipulations of the cervical spine are unnecessary to document the presence of neck pain and can lead to severe neurologic decompensation. Careful assessment of posture and evaluation of voluntary range of motion (side to side, ventrally and dorsally) using a food treat is recommended to assess for cervical pain. Deep palpation of the transverse processes also can assist in the identification of neck pain. Gait evaluation is the most important component of the examination in dogs suspected of having CSM because

it reliably identifies proprioceptive ataxia, even in the absence of conscious proprioceptive deficits. Proprioceptive ataxia is seen in most dogs with CSM. Dogs with lesions in the cranial or midcervical spine tend to have ataxia affecting all four limbs more uniformly. However, affected dogs typically have obvious pelvic limb ataxia with milder abnormalities in the thoracic limbs. In some cases, the thoracic limb ataxia or weakness may be very mild in comparison with the pelvic limb signs, so that the thoracic limb abnormalities go unnoticed. The thoracic limb gait can appear short-strided or spastic with a pseudohypermetric (“floating”) appearance. Occasionally thoracic limb lameness can be seen, which suggests nerve root entrapment. The pelvic limb gait often is wide based (abducted) and markedly incoordinated. The stride length of the pelvic limbs is increased, which causes the swaying movements of the hind end that are typical of the disease. Scuffing of the pelvic or thoracic limb toes and nails also can be seen. Postural reaction deficits (proprioceptive positioning deficits) are seen in most dogs with CSM but may not be evident in those with a history of longstanding signs despite the presence of proprioceptive ataxia. The reason for this discrepancy is that different tracts carry the pathways for conscious and unconscious proprioception. Approximately 10% of dogs with CSM have nonambulatory tetraparesis at initial presentation. Evaluation of the spinal reflexes in dogs with CSM indicates a lesion located at either the C1 to C5 spinal cord segments (normal to increased spinal reflexes in all four limbs, with neurologic signs as described earlier) or C6 to C8 spinal cord segments. A C6 to C8 myelopathy is typical because the osseous and disk lesions are concentrated in the C5-6 and C6-7 intervertebral regions. In these cases, the gait is affected in all four limbs but more

CHAPTER  236  Diagnosis and Treatment of Cervical Spondylomyelopathy severely in the pelvic limbs. Evaluation of the spinal reflexes in the thoracic limbs shows a decreased flexor (withdrawal) reflex indicating involvement of the musculocutaneous nerve from the C6 to C8 spinal cord segments, with normal to increased extensor tone suggesting an upper motor neuron lesion and release of the radial nerve from spinal cord segments C7, C8, and T1, mostly C8 and T1. The pelvic limb reflexes are normal to increased.

Radiography Survey radiographs can be used only as a screening test to rule out other differential diagnoses for cervical myelopathies, such as osseous neoplasia, trauma, vertebral osteomyelitis, and diskospondylitis. Radiographic findings in disk-associated CSM are primarily changes in the shape of the vertebral body (which assumes a triangular shape in severe cases), narrowing of the intervertebral disk space, and vertebral canal stenosis. Osteoarthritic, sclerotic changes of the articular facets are the radiographic hallmarks in giant-breed dogs with osseous compressions and can be seen on lateral and ventrodorsal projections. Some of the radiographic findings seen in dogs with CSM (e.g., vertebral tipping) also are seen in normal dogs. Studies in Doberman pinschers indicate that approximately 20% to 25% of clinically normal dogs have radiographic changes comparable to those seen in dogs with CSM.

Myelography Myelography is no longer the method of choice to diagnose CSM. It can be used if CT and magnetic resonance imaging (MRI) are unavailable. Lateral and ventrodorsal views should be obtained. Oblique views also should be considered to increase diagnostic accuracy. Stress myelographic views also can be obtained, primarily in largebreed dogs. Because of the risk of severe neurologic decompensation after myelography with the animal in extension and flexion positions, only traction views are recommended. Myelograms obtained in these positions can, in theory, assist in differentiating a static from a dynamic lesion, but this distinction is highly subjective and no clear guidelines for testing and interpretation have been established. For some clinicians, a dynamic lesion is one that improves with traction, whereas others consider a lesion dynamic when it reduces completely. When traction is to be performed, the recommendation is to use a cervical harness and approximately 20% of the dog’s weight for traction. Postmyelographic seizures occur in 25% of dogs with CSM. The risk of seizure can be minimized by restricting the total volume of contrast medium and using lumbar injections. Because of all of these issues, other imaging modalities are preferred.

Computed Tomography CT is a rapid technique that allows visualization of transverse sections of the cervical spine. It must be combined with myelography to identify the exact location of the compressive lesion. It provides superior visualization of

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the direction and severity of the spinal cord compression compared with myelography as well as identification of spinal cord atrophy. Atrophy is identified on CT myelography as a widening of the subarachnoid space surrounding the spinal cord, with the cord assuming a triangular shape. Spinal cord atrophy may be a negative prognostic indicator in dogs with CSM. Plain CT can be performed with sedation only, which may be useful in cases in which general anesthesia is contraindicated or for long-term follow-up of osseous compressive lesions.

Magnetic Resonance Imaging MRI is the gold standard test for evaluation of dogs suspected of having CSM. The main advantage of MRI is that it also detects signal changes in the spinal cord and thus allows assessment of the spinal cord parenchyma. These parenchymal signal changes are seen in approximately 50% of dogs with CSM and allow precise identification of the site most severely affected. A study compared myelography and MRI in the diagnosis of CSM and concluded that MRI was more accurate in predicting the site, severity, and nature of spinal cord compression (da Costa et al, 2006b). The presence of spinal cord signal changes—namely, hyperintensity on T2-weighted images—is associated with the degree of severity of clinical signs, degree of severity of spinal cord compression, and chronicity of signs. Hyperintensity on T2-weighted images does not appear to correlate with prognosis in dogs, but preliminary evidence suggests that the combination of hyperintensity on T2-weighted images and hypointensity on T1-weighted images may be associated with a worse  prognosis. Current evidence in humans suggests that multilevel hyperintensity on T2-weighted images and hypointensity on T1-weighted images are associated with a poorer prognosis. In some cases, the degree of spinal compression is minimal relative to the severity of clinical signs. Dynamic spinal cord compressions are assumed in such cases. Testing for dynamic compression using traction MRI can be performed, and guidelines for testing have been published.

Additional Diagnostic Tests Many large-breed dogs have concurrent medical conditions that potentially can increase anesthetic or surgical risk, or affect long-term prognosis. For this reason other studies beyond routine clinical laboratory tests should be performed in assembling a minimum data set. Tests of thyroid function usually are indicated because hypothyroidism is very common in Doberman pinschers and has been identified in a high percentage of dogs in association with CSM. Hypothyroidism can interfere with neurologic function and recovery from anesthesia. An understanding of the risks of hemorrhage related to von Willebrand status is necessary because a 73% prevalence of von  Willebrand disease has been found in Doberman pinschers. Finally, assessment of heart rhythm (with a 5-minute electrocardiogram or Holter electrocardiography) as well as cardiac size and function (by echocardiography) is

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recommended before surgical treatment. General anesthesia can worsen cardiac function and lead to decompensation in dogs with occult dilated cardiomyopathy.

Treatment Conservative (Medical) Treatment Traditionally, medical treatment for CSM was considered a temporary measure to alleviate clinical signs. Without surgery, it was thought, the disease would be progressive and euthanasia would have to be contemplated. The only evidence to support these views came from a study conducted over 30 years ago involving mainly Great Danes that essentially received no treatment (Denny et al, 1977). Medical management of CSM was revisited recently in two studies (da Costa et al, 2008; De Decker et al, 2009). One study compared the outcomes of dogs treated medically and surgically and found that 54% of dogs treated medically improved and 27% showed no change in longterm follow-up. By comparison, surgical treatment led to improvement in 81% of dogs. These results show that, although surgery offers the best chances of improvement, medical management is an acceptable alternative. The fact that approximately 80% of dogs can experience improvement or maintenance of neurologic status with medical management makes this approach preferable to many owners because of financial constraints or concerns about anesthetic and surgical risks, especially in Doberman pinschers, a breed with high incidence of dilated cardiomyopathy. The author also prefers to initiate medical management to evaluate the improvement obtained and to give owners the opportunity to decide on surgery. The response to medical management (corticosteroids and exercise restriction) can be used indirectly to assess the degree of reversibility of spinal cord lesions. The most important component of medical management is exercise restriction to minimize those high-impact activities that might exacerbate the dynamic component of spinal cord compression. Dogs can be walked on leash, but unsupervised exercise is strongly discouraged. A body harness should be worn instead of a neck collar. Corticosteroids appear to benefit dogs with CSM, and antiinflammatory dosages of prednisone often are used (0.5 to 1.0 mg/kg q12-24h PO), with the dosage progressively tapered over the course of 2 to 3 weeks. In some patients dexamethasone appears to elicit a better response, and it can be used for more severely affected patients or as a rescue therapy for dogs with sudden deterioration. Only low dosages of dexamethasone should be used, never more than 0.25 mg/kg q24h PO because no incremental therapeutic benefit is gained by higher dosages and the risk of adverse effects is higher. The severe complications that have been reported with dexamethasone use were seen mainly when high dosages were used (1 to 2 mg/kg/day). The author prescribes dexamethasone at an initial dosage of 0.2 to 0.25 mg/kg q24h PO (to a maximum dose of 8 mg per dog) for 1 to 3 days, depending on the severity of clinical signs, and then continues treatment at a dosage of 0.1 mg/kg q24h. Corticosteroids, particularly dexamethasone, improve neurologic function in chronic spinal cord compression predominantly

by decreasing vasogenic edema. Other proposed mechanisms include protection from glutamate toxicity and reduction of neuronal and oligodendroglial apoptosis. Despite the potential benefits associated with corticosteroid therapy, the use of corticosteroids, particularly for long periods, can be associated with important adverse effects. Because of the possibility of gastrointestinal complications, omeprazole (0.7 mg/kg q24h) or famotidine (0.5 mg/kg q12-24h) often is used in conjunction with corticosteroid therapy. Nonsteroidal antiinflammatory drugs (NSAIDs) can be used in place of corticosteroids  if neck pain appears to be a major component of  the syndrome or if the adverse effects of the corticosteroids cannot be tolerated. Although many NSAIDs can be used effectively, the author often prescribes meloxicam (0.2 mg/kg initially, followed by 0.1 mg/kg q24h). Regardless of the NSAID used, corticosteroids and NSAIDs never should be used in combination! One reason for the success of medical management is the slow progression of spinal changes associated with the disease. This has been documented in Dobermans and currently is under investigation in Great Danes. Surviving demyelinated axons also may remyelinate with treatment. Remyelination has been shown in the spinal cords of horses and humans with cervical myelopathy treated medically. As previously mentioned, some dogs with CSM have concurrent hypothyroidism (8 out of 12 dogs in a study— da Costa et al, 2006a). Hypothyroid dogs with CSM may show remarkable improvement in strength and energy when thyroid supplementation is started. In these cases improvement usually is noticeable within a week. Hypothyroidism obviously should be treated before surgery for CSM is performed. Dogs with occult dilated cardiomyopathy can develop heart rhythm disturbances or congestive heart failure if excessive dosages of thyroid hormone  are prescribed; accordingly, thyroxine levels should be measured after initiation of treatment. The general approach to diagnosis and treatment of CSM is outlined in Figure 236-3.

Surgical Treatment Surgery is generally assumed to represent the treatment of choice for most dogs with CSM. Because most affected dogs have spinal cord compression, decompressing the spinal cord in theory provides the definitive treatment. However, the decision to recommend surgical treatment should be based on several considerations, including severity of neurologic signs, degree of pain, type and severity of compressive lesions, response to medical management, short- and long-term expectations of the owner, and presence of concurrent neurologic conditions, orthopedic problems, or other diseases such as dilated cardiomyopathy that could affect the long-term outcome. Selection of a specific surgical technique can be complicated, and the following discussion provides an overview as well as the author’s perspective on current surgical methods. Direct decompressive techniques include dorsal laminectomy, dorsal laminoplasty, ventral slot technique, inverted cone slot technique, and hemilaminectomy. Indirect decompressive techniques typically are grouped

CHAPTER  236  Diagnosis and Treatment of Cervical Spondylomyelopathy

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Large or giant breed dog with signs of cervical myelopathy

Cervical spinal radiographs

Normal radiographs and/or changes suggestive of disk or osseous CSM

CBC/biochemistry profile (/ thyroid profile, von Willebrand’s test, or cardiac workup depending on age and breed)

MRI, CT-myelography, or myelography with findings suggestive of CSM

Moderate to severe compressive lesion(s), / spinal cord signal changes on MRI and moderate to severe neurologic deficits

Mild, moderate, or severe compressive lesion(s)

Pain primarily

Neurologic deficits primarily

Exercise restriction, walks using chest harness (no neck leashes), NSAIDs (e.g., meloxicam), / gabapentin, / tramadol

Exercise restriction, walks using chest harness (no neck leashes), oral corticosteroids (e.g., prednisone)

Reevaluate in 2-4 weeks Responded?

No

SURGERY

Try medical management again for 2-4 weeks (can change medication, use higher doses and/or stricter exercise restriction)

Disk-associated lesion(s)

Direct decompression (e.g., ventral slot)

Yes

Disk arthroplasty (mini ventral slot and artificial disk replacement)

Indirect decompression (distraction and stabilization) (e.g., PMMA plug, pins/ screws and PMMA)

No response

Positive response

Osseous compressive lesion(s)

Direct Indirect decompression decompression (dorsal laminectomy (distraction and stabilization) or hemilaminectomy) (PMMA plug or bone graft with screws and PMMA or plate)

Continue with medical management, wean off medications in 4-8 weeks

Progressive increase in activity, but with permanent (lifetime) restriction on high-impact activities

Figure 236-3  Algorithm illustrating the diagnostic and therapeutic approach for dogs suspected of having cervical spondylomyelopathy.

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SECTION  XI  Neurologic Diseases

into the distraction-stabilization category, and procedures have been reported that use bone grafts of several types, pins (smooth, threaded) or screws and polymethyl methacrylate, interbody screws, washers, metallic spacers, metallic plates, plastic plates, Kirschner-wire spacer, Harrington rods, interbody polymethyl methacrylate plug, and fusion cage. All of these techniques have been combined with diskectomy or with partial or complete ventral slot procedures. Intervertebral disk fenestration also has been performed, and more recently motion-preserving techniques using disk arthroplasty or artificial disk replacement have been proposed. In general, because the source and direction of compression can be divided broadly into disk associated and osseous, general treatment recommendations can be focused on management of these types of compression. It also is important to consider that a significant  proportion of dogs show a worsening of CSM approximately 2 to 3 years after surgery; therefore, whenever possible, the surgical technique should allow long-term postoperative imaging using MRI. All metallic implants except those made of titanium cause significant artifacts that preclude the use of MRI. Polymethyl methacrylate and titanium implants (screws, plate, or artificial disk) produce minimal or no artifacts, which allows postoperative MRI. Disk-Associated Compressions Disk-associated CSM is the most common form of CSM and the one for which the largest number of corrective surgical techniques have been proposed. These surgical techniques have been based on the identification of static or dynamic lesions by stress or traction myelography, but as previously discussed, such determinations are highly subjective. Nevertheless, the outcomes for most of these techniques are similar and generally positive. Ventral static compressions usually are treated with the traditional ventral slot or inverted cone slot procedure. Dynamic compressions can be treated with distractionstabilization techniques, and a polymethyl methacrylate plug or pins or screws combined with polymethyl methacrylate commonly are used. Multiple compressive sites can be treated with distraction-stabilization techniques, with the most common methods involving distraction with a polymethyl methacrylate plug. Dorsal laminectomy is an alternative for treatment of multiple ventral compressions. A newer approach is disk arthroplasty, which has the theoretical advantage of maintaining intervertebral mobility while allowing direct spinal cord decompression. Osseous Compressions Typically, osseous compressions are thought to be primarily static, and for this reason direct decompression of the affected sites is recommended. Commonly this is achieved by dorsal laminectomy, but cervical hemilaminectomy also can be used. Another way to treat osseous lesions is by distraction-stabilization of the affected segments ventrally. Stabilization and fusion of the affected segments does not decompress the affected sites directly but eliminates the dynamic component of the spinal cord compression. It also may allow regression of the osseous and

ligamentous lesions over time. The technique used in these cases is the polymethyl methacrylate plug. Pure Ligamentous Compressions Ligamentous hypertrophy usually occurs in combination with either disk-associated or osseous compressions. Pure ligamentous compression (hypertrophy of the ligamentum flavum) currently is an uncommon presentation. Surgical treatment can be achieved either by decompressing the affected sites (dorsal laminectomy) or by using the polymethyl methacrylate plug technique. Surgical Complications Surgical treatment can lead to several complications, including death. Hypotension and hemorrhage may be responsible for a large proportion of the cases of intraoperative and perioperative complications. Aggressive monitoring and maintenance of appropriate arterial blood pressure transoperatively is essential to minimize complications. When instrumentation is used, penetration of the vertebral canal or transverse foramina with implants as well as implant failure also can be observed, with  an incidence ranging from 7.5% to 30% (Platt and da Costa, 2011). “Domino” lesion, or adjacent-segment disease, is a late postoperative complication that occurs in approximately 20% of dogs following surgical treatment of  CSM, predominantly when distraction-stabilization techniques are used. It typically occurs in the second or third year after surgery. The use of ventral slot techniques reportedly decreases the risk of domino lesion. The domino effect may occur secondary to bony fusion. Typically domino lesion affects only one disk region, either cranial or caudal to the operated area. Motion-preserving techniques such as disk arthroplasty appear to decrease the incidence of adjacent-segment disease in people. It remains to be seen if the same effect will be observed  in dogs.

Natural History and Prognosis Ideally the natural history of a disease should be understood so that treatment recommendations and prognosis can be based on this knowledge. Unfortunately, the natural history of CSM has not been defined. It appears that the disease progresses slowly in many dogs with diskassociated CSM. The same may be true for giant-breed dogs with osseous compressions. Current evidence suggests that the progressive course of the disease is limited mostly to the lesions seen at the time of initial diagnosis. Follow-up imaging studies of dogs with both diskassociated and osseous CSM have demonstrated that the compressive lesions progress slowly. It is uncommon to see the appearance of additional lesions in dogs treated conservatively (da Costa and Parent, 2007; De Decker et al, 2012). When prognosis is discussed with clients, it is useful to understand that the outcome of surgical treatment of disk-associated CSM is very successful, with approximately 80% (range, 70% to 90%) of dogs improving  after surgery. No one surgical technique stands as clearly

CHAPTER  236  Diagnosis and Treatment of Cervical Spondylomyelopathy superior, even for dogs with disk-associated CSM. Intervertebral disk fenestration is not recommended because the reported success rate has been only 33%. In contrast to older studies, recent reports on medical management indicate an improvement rate of approximately 50% (range, 45% to 54%) (da Costa et al, 2008; De Decker et al, 2009). Given that surgery more consistently leads to clinical improvement, it always should be considered in the treatment of dogs with CSM. Surgery does not alter the long-term survival of dogs with CSM, however. The survival time of 76 dogs with CSM (33 dogs treated surgically and 43 dogs treated medically) was reported recently (da Costa et al, 2008). The median survival time was identical (36 months) regardless of whether the dogs were treated medically or surgically. This finding indicates that CSM continues to progress independently of the method of treatment and that the clinical deterioration seen months to years after treatment may not be due solely to failure of the surgery or development of adjacent-segment disease. Presumably, other mechanisms such as ischemia, apoptosis, or other molecular changes within the spinal cord are operative, and these represent future targets for therapy.

References and Suggested Reading Adamo PF: Cervical arthroplasty in two dogs with disk-associated caudal cervical spondylomyelopathy, J Am Vet Med Assoc 239(6):808, 2011. Burbidge HM: Caudal cervical malformation in the Doberman pinscher, doctoral thesis, New Zealand, 1999, Massey University, p 121. da Costa RC: Pathogenesis of cervical spondylomyelopathy: lessons from recent years. In Proceedings of the 25th Annual ACVIM Forum, 2007, p 318. da Costa RC: Cervical spondylomyelopathy (wobbler syndrome), Vet Clin North Am Small Anim Pract 40(5):881, 2010.

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da Costa RC et al: Comparison of magnetic resonance imaging and myelography in the diagnosis of cervical spondylomyelopathy in Doberman pinscher dogs—18 cases, Vet Radiol Ultrasound 47(6):523, 2006a. da Costa RC et al: Morphologic and morphometric magnetic resonance imaging features of Doberman pinscher dogs with and without clinical signs of cervical spondylomyelopathy, Am J Vet Res 67(9):1601, 2006b. da Costa RC et al: Outcome of medical and surgical treatment in dogs with cervical spondylomyelopathy—104 cases, J Am Vet Med Assoc 233(8):1284, 2008. da Costa RC, Echandi R, Beauchamp D: Computed tomography myelographic findings in dogs with cervical spondylomyelopathy, Vet Radiol Ultrasound 53(1):64, 2012. da Costa RC, Parent J: One-year clinical and magnetic resonance imaging follow-up of Doberman pinscher dogs with cervical spondylomyelopathy treated medically or surgically, J Am Vet Med Assoc 231(2):243, 2007. Denny HR, Gibbs C, Gaskell CJ: Cervical spondylopathy in the dog: a review of thirty-five cases, J Small Anim Pract 18(2):117, 1977. De Decker S et al: Clinical evaluation of 51 dogs treated conservatively for disc-associated wobbler syndrome, J Small Anim Pract 50(3):136, 2009. De Decker S et al: Evolution of clinical signs and predictors of outcome after conservative medical treatment for diskassociated cervical spondylomyelopathy in dogs, J Am Vet Med Assoc 240(7):848, 2012. Jeffery ND, McKee WM: Surgery for disc-associated wobbler syndrome in the dog—an examination of the controversy, J Small Anim Pract 42(12):574, 2001. Johnson JA et al: Kinematic motion patterns of the cranial and caudal canine cervical spine, Vet Surg 40(6):720, 2011. Platt SR, da Costa RC: Cervical spine. In Tobias KM, Johnston SA, editors: Veterinary surgery: small animal, ed 1, Philadelphia, 2011, Saunders, p 410. Sharp NJH, Wheeler SJ: Cervical spondylomyelopathy. In Sharp NJH, Wheeler SJ, editors: Small animal spinal disorders: diagnosis and surgery, ed 2, St Louis, 2005, Mosby, p 211.

CHAPTER 

237 

Craniocervical Junction Abnormalities in Dogs CURTIS W. DEWEY, Ithaca, New York DOMINIC J. MARINO, Plainview, New York CATHERINE A. LOUGHIN, Plainview, New York

C

raniocervical junction abnormality (CJA) is a term that encompasses a number of developmental anatomic aberrations at the region of the caudal occiput and first two cervical vertebrae. Chiari-like malformation (CM) appears to be the most common CJA encountered in dogs, and there has been a tremendous amount of clinical investigation into this disorder in recent years. Other abnormalities in this region include atlantooccipital overlap (AOO), dorsal constriction at C1 and C2, and atlantoaxial instability. Atlantoaxial instability is discussed in detail in Chapter 235 and is not covered here. CJAs in small-breed dogs increasingly are being recognized as common and challenging disorders. In particular, CM, the canine analog of human Chiari type I malformation, has emerged in recent years as the possible cause of major health problems in several small-breed dogs, most notably the cavalier King Charles spaniel. The term craniocervical junction abnormality, as used in human medicine, serves as an umbrella term for a variety of malformations that occur in the craniocervical region. The craniocervical junction refers to the occipital bone (primarily the supraoccipital component) that forms the boundaries of the foramen magnum, the atlas (C1), and the axis (C2). In veterinary medicine, the term Chiari-like malformation has been used widely to describe constrictive disorders at the cervicomedullary junction that are apparent on magnetic resonance imaging (MRI). Numerous abnormalities of the craniocervical junction in dogs are presumed to be heritable malformations; all have been associated with the secondary development of syringomyelia (SM). SM refers to the accumulation of fluid within the spinal cord parenchyma. The fluid cavity  itself is called a syrinx. The term hydromyelia specifically describes fluid accumulation only within the central canal, and hydromyelia is considered a possible precursor to SM. Although the signalment features for some of the more newly reported disorders have not been defined clearly, all of the disorders tend to affect young smallbreed dogs. The nomenclature used for these disorders often is confusing and generally assumes that these are all distinctly separate disorders. Included among these diseases is CM, also termed caudal occipital malformation syndrome or COMS, and occipital hypoplasia. Recently it has been found that many dogs have abnormalities in the craniocervical junction region that do not conform to 1098

traditional veterinary nomenclature. These include AOO and dorsal constriction at the C1-C2 vertebral junction. Both of these abnormalities may represent the canine analog of human basilar invagination. Finally, it has become apparent that some dogs with suspected “classic” atlantoaxial instability have other concurrent abnormalities at the craniocervical junction. Because the occipital region of the skull and the first two cervical vertebrae develop together embryologically, it makes inherent sense that multiple developmental disorders, as well as combinations of these disorders, should occur in this anatomic region in veterinary patients, as they do in humans. For these reasons, we place all of these disorders under the general heading of CJAs. It has been reported that, especially for purposes of surgical planning, developing an optimal description of a craniocervical junction disorder for an individual patient often depends on a combination of MRI and computed tomographic (CT) images.

Pathophysiology and Clinical Features Chiari-like malformation, as noted earlier, is thought to be the canine analog of Chiari type I malformation in people. As in the human disorder, the cranial cavity is too small to accommodate the contents of the caudal fossa (cerebellum and brainstem), which results in overcrowding of the cerebellomedullary region of the brain (Figure 237-1). On MRI, the abnormality of the supraoccipital bone that causes an indentation of the caudal cerebellum often is visible. In addition, an impingement of the dorsal subarachnoid space typically occurs at the level of the cervicomedullary junction. Herniation of the caudal aspect of the cerebellum through the foramen magnum also is commonly appreciated (Figure 237-2). Most of these dogs also have cervical SM, evident on MRI (Figure 237-3). CM generally has been considered a congenital malformation of the caudal occipital region of the skull, leading to overcrowding of the caudal fossa and compression of the cervicomedullary junction at the level of the foramen magnum. However, the anatomic abnormalities associated with CM are far more complicated than simply a malformed skull in the caudal-most aspect of the occipital bone region causing a physical constriction near the foramen magnum. It is now apparent that the malformations of CM are not limited only to the caudal part of the

CHAPTER  237  Craniocervical Junction Abnormalities in Dogs

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Cerebellum Malformed caudal occipital bone

Dura mater

Herniated cerebellar tissue

Central canal of spinal cord

A

Syrinx

B Normal canine occipital/brainstem region

Chiari-like malformation

Figure 237-1  A, Schematic illustration of the normal shape of the caudal occipital region. B, Typical shape of this region in a dog with Chiari-like malformation. (From Dewey CW: Surgery of the brain. In Fossum TW, editor: Small animal surgery, ed 4, St Louis, 2013, Mosby, p 1438.)

Figure 237-3  T2-weighted sagittal cervical magnetic resonance Figure 237-2  Midsagittal T2-weighted magnetic resonance

image of a dog with Chiari-like malformation showing syringomyelia.

skull. In addition, there is convincing evidence in Cavalier King Charles spaniels that there is a mismatch between the volume available in the caudal fossa region (also referred to as the caudal cranial fossa) and the parenchyma (cerebellum and brainstem) that resides within this volume; in other words, there is too much brain parenchyma in too small a space in the caudal fossa of Cavalier

King Charles spaniels (compared with other small-breed dogs and Labrador retrievers). This mismatch between parenchyma and available volume also has been demonstrated in the cranial fossa (rostral and middle fossae) of Cavalier King Charles spaniels. Increased ventricular size, increased relative parenchymal volume in the caudal fossa (as a percentage of total brain parenchymal volume), and increased relative cerebellar volume all have been associated with increased likelihood of the presence of SM

image of a dog with Chiari-like malformation showing cerebellar herniation through the foramen magnum.

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SECTION  XI  Neurologic Diseases

in the cavalier King Charles spaniel breed. Increased syrinx width also has been associated with increased ventricular size and relative caudal fossa parenchymal volume in this breed. There is some evidence in the cavalier King Charles spaniel breed that the caudal fossa volume itself often is too small compared with other dog breeds. Other anatomic abnormalities of the skull reported in dogs with SM include minute or absent frontal sinuses and abnormally small jugular foramen volumes. With regard to  this latter abnormality, it is hypothesized that the constricted venous drainage from the brain caused by small jugular foramina leads to intracranial venous hypertension and increased intracranial pressure; this would lead to an increased pressure differential between cranial and spinal compartments and an increased likelihood of SM development. In atlantooccipital overlap, the atlas (C1) is cranially displaced into the foramen magnum, and there is overlap of the occipital bone and the atlas (Figure 237-4). This

A

displacement tends to compress the caudal aspect of the cerebellum and elevate and compress the caudal medulla (medullary kinking). AOO likely is a form of basilar invagination. Basilar invagination is a human craniocervical junction disorder in which the atlas or axis (C2), or both, telescope toward the foramen magnum. It is possible that some cases of atlantoaxial instability in dogs are also analogs of basilar invagination. Based on combined MRI and CT imaging of dogs with CJAs, there is evidence that a substantial proportion (nearly 30%) of dogs diagnosed with CM based on MRI scans actually may have AOO as the main anatomic abnormality causing compression at the cervicomedullary junction. Bone is poorly visualized by MRI, but CT images clearly delineate what bony structures are causing compression at the cervicomedullary junction. In short, it is likely that many dogs with  constrictive disorders at the cervicomedullary junction that are diagnosed via MRI as having CM actually may have AOO. Similar to the AOO seen in small- and toy-breed dogs, we have seen a large number of dogs with dorsal compression at the level of C1 and C2. This compression varies in severity, with some dogs having a mild divot in the dorsal subarachnoid space and others having severe cervical spinal cord compression (Figure 237-5). At surgery, the majority of this compressive mass appears to be soft tissue, although several cases have had an obvious bony component. We believe that this disorder also may involve instability at the C1-C2 junction and possibly represents a form of basilar invagination like the AOO problem. It can occur as a sole entity or in combination with CM or atlantoaxial instability. Syringomyelia most often is discussed in the context of CM as a causative disorder. However, SM can occur secondary to any CJA or to any disorder that disturbs normal laminar CSF flow in the subarachnoid space of the vertebral canal. Multiple mechanisms have been proposed for the formation of SM, all of which are based on the pressure differential between cranial and spinal compartments created by constriction at the cervicomedullary junction. We have found that of dogs that undergo MRI of their entire spine (not just the cervical region), most have syrinxes in the thoracic and lumbar spinal cord

B Figure 237-4  Midsagittal T2-weighted magnetic resonance image (A) and three-dimensional reconstructed computed tomographic image (B) of a dog with atlantooccipital overlap malformation.

Figure 237-5  Sagittal T2-weighted magnetic resonance image

of a dog with a severely compressive dorsal lesion at C1 and C2.

CHAPTER  237  Craniocervical Junction Abnormalities in Dogs regions in addition to the cervical region. In a recent review of our unpublished MRI data for over 350 dogs, we found that syrinx formation begins in the cervical region and sequentially progresses to the thoracic region and finally to the lumbar region without skipping over a region. In one study of 49 Cavalier King Charles spaniels, 76% of the dogs had syrinxes in thoracic or lumbar regions or both, in addition to cervical SM (Loderstedt et al, 2011). CM typically is encountered in small-breed dogs, with the cavalier King Charles spaniel being the most commonly affected. Other breeds affected by this disorder are the Brussels griffon, miniature poodle, Yorkshire terrier, Maltese, Chihuahua, bichon frise, Staffordshire terrier, pug, Shih Tzu, miniature dachshund, miniature pinscher, French bulldog, Pekingese, and Boston terrier. The typical age range at presentation appears to have changed over time, with many dogs developing clinical signs within the first year of life. In general, although the age range at clinical presentation is broad, CM is identified in most dogs by the time they are 4 years old. Dogs that are brought to the veterinarian at younger than 2 years of age often have more severe clinical signs than older dogs. In recent years, we have seen an increasing number of younger patients (180 mm Hg). In such cases hypertension often

verse T2-weighted magnetic resonance images of the brain showing a cerebellar territorial infarct (arrow) in the vascular territory of the rostral cerebellar artery. The sharp demarcation, lack of mass effect, and gray matter involvement are typical of an infarct. C, Diffusion-weighted image of a large ischemic cerebellar infarct (arrow) in a different dog than shown in A and B. D, Corresponding apparent diffusion coefficient map of the infarct (arrow). The nature of the lesion is confirmed because of the hyperintensity and hypointensity of the lesion, respectively. (A and B courtesy Dr. Cristian Falzone.)

can be controlled with an angiotensin-converting enzyme inhibitor such as enalapril (0.25 to 0.5 mg/kg twice daily PO) or benazepril (0.25 to 0.5 mg/kg twice daily PO) with or without a calcium channel blocker such as amlodipine (0.1 to 0.25 mg/kg once daily PO). Amlodipine is more effective in severe hypertension. There is no evidence that glucocorticoid treatment provides any beneficial neuroprotection in stroke. Not only is there lack of proven benefit in veterinary stroke patients, the use of glucocorticoids may increase the risk of gastrointestinal complications and infection. Treatment strategies considered for ischemic stroke in humans that use other neuroprotective agents (N-methyl-daspartate antagonists, calcium channel blockers, sodium channel modulators) or antiplatelet and thrombolytic therapy remain to be evaluated clinically in dogs. Although these neuroprotective agents have resulted in a dramatic decrease in the size of stroke lesion in experimental animal models, they either have failed to prove their efficacy in clinical trials or are awaiting further investigation.

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At the time of this writing, there are no definitive data in humans or animals to confirm a significant improvement in clinical outcome in patients with acute ischemic stroke treated with unfractionated heparin as anticoagulant therapy. Despite conflicting results regarding the efficacy of intravenous recombinant tissue plasminogen activator, it sometimes is used in human ischemic stroke patients if it can be given within the first 3 hours. This critical time window makes the use of thrombolytic treatment largely unrealistic in veterinary practice. Furthermore, this type of treatment carries a significant risk of intracranial hemorrhage following treatment. Antiplatelet therapy with low-dose aspirin (0.5  mg/kg once daily PO) or clopidogrel (2 to 4  mg/kg once daily PO) can be used prophylactically to prevent clot formation when a cardiac embolic source has been proven. Treatment of Hemorrhagic Stroke The medical management of dogs with intracranial hemorrhage commonly includes stabilization of the patient’s condition (airway protection, monitoring and correction of vital signs); assessment and monitoring of neurologic status; determination and treatment of potential underlying causes of the hemorrhage; and assessment of the need for specific treatment measures, including management of increased ICP. The risk of neurologic deterioration and cardiovascular instability is highest during the first 24 hours after the onset of an intracranial hemorrhage as the space-occupying lesion slowly expands and cerebral vasogenic edema develops. Therefore careful monitoring, including assessment of vital parameters (e.g., oxygen levels, fluid balance, blood pressure, body temperature) and neurologic status, is essential during this initial period. Unfortunately, clinical signs of raised ICP often are delayed, inconsistent, and nonspecific. The size of an intracranial hematoma can be difficult to estimate from the neurologic examination alone. ICP monitoring systems are used frequently in human hospitals, but these systems are largely unavailable in veterinary hospitals. As a hematoma develops initially, ICP may be maintained at a constant value as a result of a system of compensation. Within the closed space of the skull a change in the volume of one intracranial constituent (brain tissue, arterial blood, venous blood, or cerebrospinal fluid [CSF]) is balanced by a compensatory change in another incompressible constituent. This is the Monroe-Kellie doctrine, which explains why some animals with large intracranial bleeds develop substantial increases in ICP at the time of herniation. The exhaustion of the compensating mechanisms for an intracranial space–occupying lesion implies that any further increase in the volume of the hematoma will produce a massive rise in ICP, and clinically this can be associated with herniation. Owing to mechanical autoregulation, CBF remains constant, even though CPP may vary between 40 and 120 mm Hg. The normal autoregulation of CBF may be impaired following a CVA, so that blood flow to damaged regions becomes directly dependent on systemic blood pressure. In such cases the animal may be unable to compensate for reductions in mean arterial blood pressure,

which causes decreased CPP in the presence of increased ICP. This possibility emphasizes the importance of maintaining systemic blood pressure. In these circumstances systemic hypotension can result in inadequate perfusion of the brain, which leads to cerebral ischemic and secondary neuronal injury. If decreased CPP is present, correction of tissue perfusion is an important stabilizing therapy in patients with hemorrhagic stroke. The primary goal of fluid therapy is rapid restoration of blood pressure, so that CPP is maintained above 70 mm Hg. Hypovolemia should be recognized and treated with volume expansion using artificial colloids or hypertonic saline (7.5%) to achieve rapid restoration of blood volume and pressure while limiting the volume of fluid administered (see Chapters 1 and 2). Central venous pressure monitoring can be useful as an aid in assessing the effectiveness of volume resuscitation, provided cardiac function is otherwise normal. The use of glucose-containing solutions is discouraged since hyperglycemia has been shown to correlate with poor outcome in human stroke patients. For this reason, blood glucose level should be monitored from the time of presentation. Moderate levels of hypertension should not be treated because systemic hypertension may be secondary to the intense reflex sympathetic response to intracranial hypertension, which is a compensatory mechanism to maintain cerebral perfusion. In ischemic stroke, attempts to lower and normalize the blood pressure should be reserved for animals at high risk of end-stage organ damage (systolic blood pressure that remains >180 mm Hg) or animals with severe ocular manifestations of hypertension such as retinal detachment or intraocular hemorrhage. Treatment recommendations for lowering blood pressure are detailed in the preceding section on treatment of ischemic stroke. There is no evidence in humans to support the routine use of oxygen supplementation for the treatment of hemorrhagic stroke in the absence of hypoxia. In a rapidly deteriorating animal hyperventilation can be used temporarily to reduce ICP. The aim of hyperventilation is to reduce cerebral blood volume and hence ICP by causing a hypocapnic vasoconstriction. However, excessive hyperventilation can be accompanied by a reduction in global CBF, which may drop below ischemic thresholds; therefore it is not a recommended therapy unless the arterial carbon dioxide pressure can be monitored closely with capnography or arterial blood gas analysis. Mannitol has been used traditionally to treat intracranial hypertension associated with pathologic conditions such as head trauma, brain tumor, or encephalitis. There is insubstantial evidence to suggest that mannitol exacerbates intracranial hemorrhage; therefore osmotic diuretics are used routinely in the control of ICP in human patients with known intracranial hemorrhage. Mannitol therapy (0.25 to 2.0 g/kg IV over 10 to 20 minutes up to q4-8h) may be initiated to treat suspected elevated ICP secondary to hemorrhagic stroke. The main effect of mannitol is to enhance CBF by reducing blood viscosity. Surgical evacuation of the hematoma can be performed in dogs that have large hematomas (mostly subarachnoid) and a deteriorating neurologic status.

CHAPTER  241  Vascular Disease of the Central Nervous System Prognosis The prognosis for ischemic or hemorrhagic stroke depends overall on the initial severity of the neurologic deficit, the initial response to supportive care, and the severity of the underlying cause if one has been identified. Fortunately, in most cases of ischemic stroke recovery occurs within several weeks with only supportive care. In the authors’ retrospective study of 33 dogs with MRI or necropsy evidence of brain infarction (Garosi 2005), there was no association between the region of the brain involved (telencephalon, thalamus-midbrain, cerebellum), the type  of infarction (territorial or lacunar), and the outcome. However, dogs with a concurrent medical condition had a significantly shorter survival time than those with no identifiable medical condition. Dogs with a concurrent medical condition also were significantly more likely to show recurrent neurologic signs caused by subsequent infarcts.

Cut dura mater DSA

3rd lumbar vertebra

Pathophysiology of Ischemic Myelopathy Spinal cord arteries are functional end arteries, and their occlusion leads to ischemia of the area which they supply. The arterial blood supply to the lumbar spinal cord is illustrated in Figure 241-2. The most common cause of ischemic necrosis of the spinal cord is embolization of spinal arteries by fibrocartilage. The embolized fibrocartilage has a structure similar to that of the intervertebral disk nucleus pulposus; however, the mechanism of entry of this material into the vasculature is not completely understood. Direct penetration of nucleus pulposus fragments into the spinal cord vessels or into the vertebral vessels often has been proposed; however, arterial walls are naturally very tough and resistant to such damage, and venous damage would result in hemorrhage that has not been described. Other possible causes of the presence of fibrocartilage in vessels are the existence of embryonic remnant vessels within the nucleus pulposus (which is normally avascular in adults) and neovascularization of a degenerated intervertebral disk, either of which would allow entrance of the material into the vasculature. Ischemic myelopathy also may result from obstruction of the intrinsic spinal blood vessels by material other than fibrocartilage, such as thrombi or bacterial, parasitic, neoplastic, or fat emboli. Preexisting medical conditions associated with CVAs in dogs and cats, including cardiomyopathy, hypothyroidism, hyperthyroidism,

DSA

LaSbch

DRA VSA

DRA VRA

VSA

VRA LaSbch

LaDbch

Ischemic Myelopathy Ischemic myelopathy is a vascular disease of the spinal cord most commonly caused by embolization of spinal cord blood vessels, but it also can be due to vessel thrombosis and vascular spasm, which often are secondary to trauma. Sudden reduction of blood flow to an area of the spinal cord causes ischemic necrosis resulting in clinical signs that can be peracute (90%), caution should be taken in handling the patient because excessive restraint or struggling on the part of the patient may result in corneal rupture. If corneal specimens for culture are to be acquired, they ideally should be obtained before instilling any drops into the eye, including proparacaine or fluorescein, because these chemicals may inhibit microbial growth. Samples for cytologic evaluation also should be obtained before instilling fluorescein if possible. Cytologic analysis and culture and sensitivity testing should be considered mandatory diagnostic studies in all cases of complicated corneal ulceration, particularly chronic lesions and those showing stromal loss, infection, or melting. The results of cytologic evaluation guide initial choice of therapy, and culture and sensitivity results confirm or alter those choices. If there is extreme stromal loss, avoiding Schirmer’s tear test (STT) or tonometry may be prudent to prevent corneal rupture. It is important to perform these tests on the opposite eye, however, since the fellow eye may hold the key to the diagnosis. In a patient with KCS, the STT results may be within the normal range in an eye with a corneal ulcer because the patient hypersecretes tears in response to ocular irritation; however, the fellow eye may have an abnormally low STT value, revealing the diagnosis of KCS.

Treatment of Complicated Ulcers The most important principle in treating complicated ulcers is to recognize the complicating factor and  address it. Treating Complicated Ulcers with Stromal Loss, Infection, and Melting If there is more than a 50% stromal loss, the ideal treatment is surgical stabilization, such as a conjunctival graft. In these cases, the cornea is at risk of rupture with subsequent loss of vision from retinal detachment or chronic uveitis and cataract formation. These patients should be referred to a veterinary ophthalmologist for evaluation. If referral is not an option, the lesion should be managed as an infected or melting ulcer. Use of an Elizabethan collar to prevent self-trauma is important. In the case of corneal laceration with iris prolapse, referral should be strongly encouraged. Results of the cytologic evaluation should guide initial antibiotic choices in the case of a deep melting or infected ulcer. If a mixed population of bacteria is observed, a fluoroquinolone such as ofloxacin 0.3% or levofloxacin 0.5% solution is recommended for broad-spectrum and potent coverage. An aminoglycoside such as gentamicin 0.3% or tobramycin 0.3% solution may be added if gramnegative bacteria or rods are observed. A cephalosporin or triple antibiotic may be added if gram-positive bacteria are noted. A triple antibiotic alone is not recommended because it has poor ability to penetrate into the cornea and anterior chamber. Antibiotic therapy should begin with administration every 2 to 4 hours and then decrease as the infection becomes controlled. Fungal keratitis is very rare in small animal patients. Since sensitivity to antifungal agents varies widely with geographic region,

CHAPTER  246  Corneal Ulcers consultation with a local ophthalmologist who has experience with effective treatments in your region may be helpful. For example, in central Illinois, voriconazole 1% solution is the most common first-line antifungal agent. Keratomalacia (melting) must be addressed with anticollagenase and antiprotease therapy. Autologous serum (serum harvested from the patient) is a highly effective anticollagenase-antiprotease. Serum can be obtained by collecting whole blood in a red-topped tube, centrifuging the clotted blood, and drawing the serum into a sterile eye dropper vial for dispensing. Serum should be stored aseptically in the refrigerator and replaced every 5 days. Ethylenediaminetetraacetic acid (EDTA), topical tetracyclines, systemic tetracyclines, and N-acetylcysteine are other anticollagenases-antiproteases that can be used in addition to autologous serum. An EDTA solution can be compounded in the clinic by filling a purple-topped (EDTA) blood collection vial half full with sterile 0.9% saline. The resultant EDTA solution can be administered directly to the corneal surface. Topical oxytetracycline/ polymyxin B ointment (Terramycin) is a convenient way to administer tetracycline to the ocular surface. Alternatively, doxycycline 5 mg/kg q12h PO can be used. The frequency of administration of topical anticollagenases depends on the severity of the disease, with administration every 1 to 2 hours recommended for the most severely affected patients. Most patients with deep infected or melting ulcers have significant concurrent uveitis. This uveitis is best addressed by administering systemic antiinflammatories such as oral NSAIDs or an antiinflammatory dose of oral corticosteroids. Topical atropine will relieve any accompanying ciliary body muscle spasm and also produce mydriasis, which prevents posterior synechiae. The use of topical corticosteroids is contraindicated for any corneal ulcer. The use of topical NSAIDs is controversial, and the author does not recommend their use in patients with complicated corneal ulcers. Treating Complicated Ulcers with Slow Healing As noted earlier, if a corneal ulcer is not healed within 7 days, it should be considered complicated. It is important then to consider why the ulcer is not healing and to look for evidence of stromal loss, infection or melting, or other complicating factors. If these all have been ruled out, then the ulcer may be indolent. Treating Complicated Ulcers with Complicating Factors Careful ophthalmic examination will reveal the presence of any complicating factors. It is imperative that these factors be corrected for the ulcer to heal. The treatment varies with the complicating factor and may include eyelid tacking to correct spastic entropion, medical therapy for dry eye, or surgical removal of an eyelid tumor that is abrading the cornea. Treatment of the complicated ulcer can be rigorous. Medications may need to be administered very frequently, and multiple medications usually are required. Frequent recheck examinations may be needed in the case of the infected or melting ulcer. Adopting a systematic approach

1151

to identifying factors that make an ulcer simple or complicated helps the clinician to create a logical and effective treatment plan.

Indolent Corneal Ulcers Indolent ulcers represent a unique type of complicated corneal ulcer. They usually are diagnosed in older dogs and boxers. The classic clinical appearance is that of a superficial ulcer with nonadherent flaps of corneal epithelium at the margin of the ulcer. Fluorescein uptake may be observed beneath the ulcer edges. Superficial vascularization may or may not be present, and ocular pain is likewise variable. Most indolent ulcers are not associated with a significant degree of uveitis. An indolent ulcer is diagnosed based on the clinical characteristics as well as by exclusion of all other possible causes of corneal ulceration. Cytologic evaluation is recommended in all cases of suspected indolent ulcer and typically demonstrates abundant corneal epithelium with few or no inflammatory cells and no infectious organisms.

Treatment of Indolent Ulcers Indolent ulcers in dogs are caused by a defect in the cellcell adhesion molecules called hemidesmosomes that anchor epithelial cells to their underlying basement membrane and stroma. Treatment of an indolent ulcer requires disruption of that basement membrane to stimulate normal cell adhesion. These techniques, collectively called anterior stromal puncture, include such well-described methods as grid keratotomy and multiple punctate keratotomy. When anterior stromal puncture techniques fail, superficial keratectomy performed by a veterinary ophthalmologist may be curative, and referral is recommended in such cases. Several methods are summarized briefly in the following sections to explain the general approach to managing indolent ulcers, but the operator should be experienced before performing these procedures, and other textbooks detailing ophthalmologic procedures should be consulted. Grid Keratotomy Grid keratotomy is performed under gentle manual restraint and with topical anesthesia (proparacaine). The corneal surface may be prepared further by instilling dilute povidone-iodine solution. The nonadherent corneal epithelium then is gently débrided using a dry cotton-tipped applicator. All nonadherent epithelium must be removed for the grid keratotomy to be successful. A 25-gauge needle then is used to make fine lines in the anterior stroma by moving from normal cornea, across the ulcer bed, and then back into normal cornea on the other side of the ulcer. The entire surface area of the ulcer should be covered. Lines should be placed approximately 1 mm apart. Therapy after grid keratotomy should be as for a simple ulcer with a recheck examination in approximately 2 weeks to ensure healing. Oxytetracycline/polymyxin B is the antibiotic of choice based on in vitro and clinical evidence of improved rates of epithelial migration and healing with tetracycline therapy. Oral doxycycline may

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SECTION  XII  Ophthalmologic Diseases

be used if a topical tetracycline is not available. If the grid keratotomy does not produce resolution of the ulcer, then the practitioner should reconsider the possibility that the ulcer may not be indolent (some other factor is keeping it from healing) and refer for further evaluation. Multiple Punctate Keratotomy Preparation and postprocedure care for multiple punctate keratotomy are identical to those for grid keratotomy.  To perform multiple punctate keratotomy, a 22-gauge needle is used to make superficial punctures in the  anterior stroma. This procedure generally is more challenging for the inexperienced practitioner and is not recommended. Diamond Burr Débridement A new technique for treatment of the indolent ulcer has been reported recently. The diamond burr (AlgerBrush) is a handheld instrument with a round, textured ball tip that functions similarly to a Dremel tool. After a topical anesthetic is applied, the rotating burr tip is moved  in smooth, circular strokes over the ulcer until all nonadherent epithelium has been removed. The instrument  simultaneously creates microabrasions in the epithelial basement membrane that contribute to improved epithelial adhesion. Advantages of the diamond burr débridement technique over traditional anterior stromal puncture techniques include minimal postprocedure scarring; the

CHAPTER 

simplicity of performing the procedure, which obviates the need for advanced surgical training; the low ulcer recurrence rate after treatment; and low cost. Treatment after débridement is similar to that for other anterior stromal puncture techniques. Preliminary work suggests that this technique is safe and efficacious for treatment of indolent ulcers in the dog; however, peer-reviewed studies comparing diamond burr débridement with anterior stromal puncture techniques are necessary.

References and Suggested Reading Bentley E: Spontaneous chronic corneal epithelial defects in dogs: a review, J Am Anim Hosp Assoc 41:158, 2005. Chandler HL et al: In vivo effects of adjunctive tetracycline treatment on refractory corneal ulcers in dogs, J Am Vet Med Assoc 237:378, 2010. Garcia da Silva E et al: Histologic evaluation of the immediate effects of diamond burr debridement in experimental superficial corneal wounds in dogs, Vet Ophthalmol 14:285, 2011. Gosling AA et al: Management of spontaneous chronic corneal epithelial defects (SCCEDs) in dogs with diamond burr debridement and placement of a bandage contact lens, Vet Ophthalmol 16(2):83, 2013. Massa KL et al: Usefulness of aerobic microbial culture and cytologic evaluation of corneal specimens in the diagnosis of infectious ulcerative keratitis in animals, J Am Vet Med Assoc 215:1671, 1999. Ollivier FJ et al: Proteinases of the cornea and preocular tear film, Vet Ophthalmol 10:199, 2007.

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Canine Nonulcerative Corneal Disease MARGI GILMOUR, Stillwater, Oklahoma

W

hen a corneal lesion is identified the practi­ tioner first should determine if the disease  is ulcerative or nonulcerative. Nonulcerative corneal disease usually is not painful, whereas ulcerative corneal disease is painful and is associated with blepha­ rospasm. It is very important to distinguish a primary nonulcerative keratitis from a keratitis secondary to a healed or healing corneal ulcer. For example, the treat­ ment for the former condition often is a topical steroid, but steroids are contraindicated in the presence of a corneal ulcer. Additionally, the practitioner always should consider the position and function of the eyelids, as well as the

quality and quantity of the tear film, whenever corneal disease is diagnosed. The cornea depends on the eyelids, tear film, and aqueous humor for maintaining its health. The tear film and aqueous humor supply nutrients to the avascular cornea, and the eyelids are responsible not only for protection but for proper distribution and restructur­ ing of the tear film. Accordingly, the diagnostic evalua­ tion for nonulcerative keratitis always should include a Schirmer tear test as well as fluorescein staining of the cornea. Nonulcerative corneal disease can be inflammatory in origin, and this keratitis can be acute or chronic. Inflam­ matory disease is indicated by the presence of active

CHAPTER  247  Canine Nonulcerative Corneal Disease corneal vascularization. Active vessels can be distinguished from chronic vessels by their multiple branching pattern. Superficial vessels have treelike branching, whereas deep stromal vessels are compacted with bushlike branching or a paintbrush appearance. Granulation tissue and corneal edema are additional signs of active keratitis. The finding of corneal pigmentation, or melanosis, is an indication of chronic corneal disease or corneal irritation.

Congenital Disorders Dermoid A corneal dermoid is a choristoma—normal tissue (skin) in an abnormal location (cornea). Corneal dermoids usually are located on the lateral aspect of the cornea. Dermoids are nonpainful; however, they usually contain hair follicles, and the hair from the dermoid may cause irritation of the adjacent normal cornea. The thickened tissue itself interferes with normal tear film spread over the cornea. Keratectomy is the treatment of choice and is curative. Keratectomy should be performed using appro­ priate microsurgical technique and instrumentation to allow complete excision and is best performed by an ophthalmologist.

Neonatal Dystrophy Congenital or neonatal corneal dystrophy is a light, gray to white corneal opacity in a patchy or lacy pattern. It may be detected in neonatal puppies and is considered an incidental finding. The opacities usually resolve by 10 weeks of age. There is no associated keratitis and the condition is nonpainful. No treatment is needed.

Noninflammatory Disorders

1153

If the patient is receiving topical steroid medications, substitution of a topical nonsteroidal medication should be considered when possible.

Calcium-Related Degenerative Keratopathy Calcium deposits in the epithelial and subepithelial cornea are seen most frequently in geriatric dogs, although dogs of all ages can be affected. The deposits are white, refractile, spicule opacities like an etching in glass. They are nonpainful and not associated with keratitis; however, it is not uncommon for a corneal ulcer to develop adja­ cent to an area of dense calcium deposits. Superficial vascularization may be seen in or surrounding the area of calcium deposition. Topical ethylenediaminetetraacetic acid (EDTA) 1% has been recommended for treatment in an attempt to chelate the calcium deposits, but even with long-term use, efficacy is variable. Calcium deposits in association with a deep corneal ulcer or descemetocele can be treated successfully with keratectomy and con­ junctival pedicle graft.

Superficial Punctate Keratitis Superficial punctate keratitis manifests as focal or multifo­ cal, punctate, epithelial corneal opacities. The surface of the cornea may have an “orange peel” irregularity in the area of the opacities. Usually the opacities do not stain with fluorescein, but occasionally they can retain a dot of stain in the center. In some dogs the condition is asso­ ciated with mild to moderate blepharospasm. Rarely there is associated superficial vascularization. The disorder appears to be familial in the sheltie and dachshund breeds. Clinical signs usually are controlled well with topical cyclosporine 1% administered every 12 hours. Lifelong treatment usually is needed.

Epithelial Inclusion Cyst

Endothelial Dystrophy

Corneal inclusion cysts are uncommon and occur when there has been injury to the epithelium. The epithelial cells form an epithelium-lined cyst that accumulates white, yellow, or tan material. The cyst is well circum­ scribed with normal surrounding cornea. It protrudes from the surface of the cornea and extends into the corneal stroma. Keratectomy is curative.

The endothelium is a single cell layer on the inner surface of the cornea responsible for keeping the cornea dehy­ drated and transparent. When it is affected by disease the result is diffuse corneal edema. Endothelial dystrophy is a bilateral genetic or age-related loss of endothelial cells. The condition is nonpainful, and usually there is no asso­ ciated keratitis. Vision loss is rare even with significant edema. With severe corneal edema epithelial bullae can develop on the surface of the cornea. Rupture of the bullae results in painful epithelial ulcers. Hypertonic sodium chloride 5% ointment can be used every 6 to 12 hours to help reduce the severity of edema and lessen  the risk of bullae formation. Very severe cases can be referred to an ophthalmologist for thermokeratoplasty or a Gunderson flap procedure.

Lipid Keratopathy Corneal lipid deposits appear as gray to white, refractile or glitterlike opacities in the superficial stroma. They can be bilateral or unilateral and usually do not significantly enlarge but can become denser over time. Vision rarely is affected, and the lesions are not painful. Causes of these deposits include genetic dystrophy, hyperlipidemia, and lipid degeneration in association with corneal injury, scar, or active keratitis. The long-term topical use of corticoste­ roids is another association. Diagnostic testing should include measurement of fasting serum cholesterol and triglyceride concentrations, particularly when the opacity is perilimbal. There is no specific treatment for the lipid deposits other than treating any existing hyperlipidemia.

Florida Spots Florida spots are a unique condition of unknown etiology seen in dogs living in tropical and subtropical climates. The underlying cause has not been identified definitively. The lesions are round, focal or multifocal, white-gray homogeneous opacities, sometimes overlapping, located

1154

SECTION  XII  Ophthalmologic Diseases

in the superficial stroma. There is no associated keratitis. The condition is nonpainful and does not progress to affect vision. No successful treatment has been reported.

Inflammatory Disorders Chronic Superficial Keratitis Formerly called pannus or German Shepherd pannus, chronic superficial keratitis (CSK) is considered an immune-mediated disease targeting the superficial corneal tissue. Greyhounds, German shepherds, German shep­ herd mixes, and related breeds such as the Belgian  Malinois, Belgian shepherd, and Belgian Tervuren are pre­ disposed. CSK presents as bilateral, nonpainful, nonulcer­ ative keratitis starting in the lower lateral quadrant of the cornea and steadily progresses to affect the entire cornea. Factors contributing to the severity of the disease include age (young dogs tend to have a more severe form that is less responsive to treatment) and ultraviolet light expo­ sure (greater exposure is associated with more severe disease). Early clinical signs include hyperemic bulbar conjunctiva, corneal edema, and corneal neovasculariza­ tion, followed by white cellular infiltrate, granulation tissue, and pigmentation (melanosis). As the vasculariza­ tion and cellular infiltrate progress, vision decreases, and vision loss eventually occurs without treatment. CSK can be controlled medically, and even severely affected dogs can regain vision; however, it cannot be cured, and lifelong treatment is required. Overall progno­ sis is good as long as maintenance therapy is continued. Treatment includes topical steroids, cyclosporine 1% or 2% or tacrolimus 0.02% or 0.03%, and in severe cases subconjunctival steroid injection. Initial therapy should be aggressive to attain control of the disease and resolve the active inflammation, then medication is tapered slowly to the lowest frequency needed to maintain remis­ sion. Topical steroids have a stronger antiinflammatory action than cyclosporine or tacrolimus and are best for controlling the initial, active keratitis. Prednisolone 1% or dexamethasone 0.1% should be used every 4 to 6 hours initially, then gradually tapered over several months once the cellular infiltrate, granulation tissue, and blood vessels are gone. Cyclosporine or tacrolimus can be started with the topical steroid, or added later, to help reduce the frequency of topical steroid administration required to maintain remission. Cyclosporine and tacrolimus also may help break up pigment with long-term use. A main­ tenance frequency of prednisolone or dexamethasone every 24 to 48 hours and/or cyclosporine or tacrolimus every 12 to 24 hours usually can be achieved. In patients with severe disease and those with a weak response to initial topical therapy, a subconjunctival steroid injection can be given to augment the topical therapy. Triamcino­ lone (Kenalog) 40 mg/ml can be used for subconjunctival injection by administering 0.1 ml (4 mg) beneath the bulbar conjunctiva.

Pigmentary Keratitis in the Pug Pigmentary keratitis in the pug begins as a triangular area of pigmentation extending from the medial limbus

toward the center of the cornea. The severity of the disease can vary from mild with minimal progression of the pigment and no effect on vision, to severe with pigment eventually covering the entire cornea and result­ ing in vision loss. The disease likely has multiple causes, including increased corneal exposure from exophthalmic conformation and macropalpebral fissures, both of which affect tear film spread; increased number of melanocytes in the limbal and perilimbal tissue; and lower medial entropion causing chronic irritation of the conjunctiva and cornea by hair. A complicating factor can be kerato­ conjunctivitis sicca because the pug is a predisposed breed. Treatment depends on the degree and progression of pigmentation. Because pigment is difficult to clear once deposited, prevention is ideal. Surgical alteration of conformation, such as medial entropion correction or permanent medial and lateral tarsorrhaphies, may be beneficial. These procedures resolve any medial entro­ pion and also narrow the palpebral fissure to lessen expo­ sure and improve tear film spread. Cyclosporine 1% or 2% or tacrolimus 0.02% or 0.03% can break up corneal pigment with long-term use in some dogs. This pigmentinhibitory effect of these drugs, in addition to their ability to increase basal tear production, makes cyclosporine and tacrolimus beneficial in the treatment of pigmentary ker­ atitis. Topical dexamethasone or prednisolone can be used with cyclosporine or tacrolimus if corneal vascular­ ization is present.

Disorders Secondary to Tear Film Deficiency The cornea is avascular and must rely on the tear film to provide nutrition to the superficial layers. With long-term lack of nutrition, vascularization and edema occur ini­ tially, followed by fibrosis and pigmentation. The tear film is composed of three dynamic layers—the inner mucin layer, the middle aqueous layer, and the outer lipid layer. The mucin layer smooths the corneal epithelium and is hydrophilic, which allows prolonged contact between the cornea and the aqueous layer. The aqueous layer is the largest layer and the primary source of nutri­ tion for the corneal cells, providing oxygen, glucose, elec­ trolytes, and water.

Keratoconjunctivitis Sicca Keratoconjunctivitis sicca (KCS) refers to inadequate pro­ duction of the aqueous component of the tear film. It can result in an ulcerative or nonulcerative keratitis and present either unilaterally or bilaterally. Common clinical signs are blepharospasm; hyperemic conjunctiva; a thick, tenacious mucoid discharge that adheres to the eyelids and cornea; and various stages of keratitis, including neo­ vascularization, edema, fibrosis, and pigmentation. Vision can be lost due to severe corneal pigmentation and fibro­ sis. Causes include immune-mediated inflammation of the lacrimal glands, neurogenic KCS caused by damage to the parasympathetic fibers that travel with the facial nerve and innervate the lacrimal glands, drug toxicity (sulfonamides and the nonsteroidal antiinflammatory drug etodolac), excision of the nictitans lacrimal gland,

CHAPTER  247  Canine Nonulcerative Corneal Disease canine distemper virus infection, and congenital lacrimal gland hypoplasia in toy breeds, particularly the Chihua­ hua and Yorkshire terrier. KCS can be diagnosed definitively by performing a Schirmer tear test. The tear strip should be placed care­ fully in the central to lateral lower conjunctival fornix. For accurate results the tear strip should be resting between the lower eyelid and cornea and not between the lower eyelid and nictitans. The strip should be read as soon as it is removed from the eye. The normal value is 15  mm or more in 60 seconds. Treatment is recom­ mended when clinical signs are present, even if the results of the Schirmer tear test are normal or decreased by only a few millimeters, since response is always better when treatment is started earlier rather than later in the disease. Treatment depends on the cause, but regardless of cause, cyclosporine often is used topically because it has been shown to increase tear production independently of its immunomodulatory effect. It is also a very safe drug to use, has antiinflammatory properties, and can inhibit pigment migration—all of which are beneficial regardless of the cause of KCS. Immune-mediated KCS usually is treated successfully with topical cyclosporine 0.2%, 1%, or 2% every 8 to 12 hours or topical tacrolimus 0.02% or 0.03% every 8 to 12 hours. Neurogenic KCS may respond to either oral pilocarpine 1% or 2%, or topical pilocarpine 0.1% or 0.2%, every 8 to 12 hours. In severe cases of  KCS that are not responsive to medical therapy parotid duct transposition surgery can be performed to maintain vision and comfort. Once the underlying cause is con­ trolled medically or surgically, the keratitis should be specifically addressed and resolved to avoid corneal scar­ ring and pigmentation. Topical dexamethasone 0.1% and prednisolone 1% have stronger antiinflammatory action than cyclosporine or tacrolimus and can improve or resolve corneal neovascularization, edema, cellular infil­ trates, and granulation tissue much more quickly. Topical steroids should be used cautiously in extremely dry eyes because such eyes may be more prone to ulceration, sec­ ondary infection, or complicated healing. The frequency of treatment can be tapered as the active keratitis is con­ trolled. KCS of any cause except that due to trauma and transient damage to the facial nerve and parasympathetic branches requires lifelong treatment and routine moni­ toring of tear production and keratitis.

Mucin Deficiency Mucin deficiency is less common than KCS. It is diag­ nosed by measuring tear breakup time. Undiluted fluo­ rescein stain is instilled into the eye to stain the tear film. From a closed position, the eyelids are opened and held open while timing commences and the fluoresceinstained tear film is observed with a cobalt blue light. As soon as the tear film starts to break up on the surface of the cornea, indicated by the formation of dark patches in the green tear film, timing stops. A tear breakup time of less than 15 seconds is indicative of a deficient mucin layer. A deficient mucin layer leads to less contact time between the aqueous portion of the tear film and the cornea, which affects the nutrition of the cornea. Clinical

1155

signs are not as severe as in KCS and usually manifest as a mild, chronic nonulcerative keratitis characterized by mild conjunctival hyperemia, superficial corneal vas­ cularization, and corneal haze. Schirmer tear test values are usually normal. Dogs with mucin deficiency often benefit from topical application of cyclosporine or tacro­ limus every 12 hours. Mucinomimetic artificial tear  products such as Refresh Liquigel and Refresh Celluvisc or Systane Ultra and Systane Gel Drops also may be beneficial.

Disorders Secondary to Eyelid Abnormalities Cilia Abnormalities Constant irritation from cilia can cause chronic nonul­ cerative keratitis. Distichia, in which cilia arise from the meibomian glands and exit out the eyelid margin, can cause nonulcerative keratitis if the cilia are long or thick. Various forms of trichiasis, hairs arising from an anatomi­ cally correct location but touching the eye, also can result in nonulcerative keratitis manifested by mild vasculariza­ tion, edema, and pigmentation. Common types of tri­ chiasis include lower medial entropion in the pug and other brachycephalic breeds; medial canthal and caruncle trichiasis, especially in the Shih Tzu; and nasal fold hairs touching the cornea in the Pekingese. In distichia the cilia are removed by cryoepilation or electrocautery. Medial canthal trichiasis is treated surgically with medial cantho­ plasty or cryoepilation of caruncle hair follicles. Lower medial entropion is treated with surgical correction of the eyelid position. Nasal fold trichiasis is treated with nasal fold excision.

Entropion and Ectropion Abnormal eyelid position can lead to compromised corneal health. Entropion can result in nonulcerative keratitis due to chronic hair irritation. Ectropion can result in nonulcerative keratitis due to increased exposure of the cornea and poor tear film spread. The degree of edema, vascularization, and pigmentation depend on both the severity and the duration of the entropion or ectropion.

Lagophthalmos and Macropalpebral Fissure Inability to completely close the eyelids over the cornea (lagophthalmos) caused by facial nerve paralysis, exoph­ thalmia, or buphthalmia, and incomplete blinks in dogs such as brachycephalic breeds with macropalpebral fis­ sures (oversized eyelid apertures) result in poor tear film spread across the cornea. Without the normal tear film distribution and restructuring of the trilayer anatomy that occurs with a normal blink, corneal nutrition is impaired, which leads to nonulcerative keratitis, espe­ cially in the most exposed area of the cornea. Treatment approaches include surgical narrowing of the palpebral fissure, administration of cyclosporine or tacrolimus to increase basal tear production, and routine application of longer-lasting artificial tear gels and ointments.

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SECTION  XII  Ophthalmologic Diseases

References and Suggested Reading

Neoplasia Corneal neoplasia is uncommon in dogs. Epibulbar  melanocytoma and hemangioma-hemangiosarcoma fre­ quently arise at the limbus and may secondarily affect the cornea. Corneal squamous cell carcinoma is rare in the dog compared with other species. Dogs with chronic kera­ titis and dogs receiving long-term cyclosporine therapy may be predisposed, but a direct causal link has not been established. Corneal squamous cell carcinoma presents as a unilateral raised, irregular, proliferative mass that is pink or red and must be differentiated from granulation tissue. Biopsy findings should provide a definitive diagnosis. Treatment is complete excision by keratectomy. The met­ astatic potential appears to be low and the prognosis good with excision.

CHAPTER 

Andrew SE: Immune-mediated canine and feline keratitis, Vet Clin North Am Small Anim Pract 38:269, 2008. Gilger BC, Bentley E, Ollivier FJ: Diseases and surgery of  the canine cornea and sclera. In Gelatt KN, editor: Veterinary ophthalmology, ed 4, Ames, IA, 2007, Blackwell Publishing, p 690. Maggs DJ: Cornea and sclera. In Maggs DJ, Miller PE, Ofri R, editors: Slatter’s fundamentals of veterinary ophthalmology, ed 4, St Louis, 2008, Saunders, p 175. Sanchez RF et al: Canine keratoconjunctivitis sicca: disease trends in a review of 229 cases, J Small Anim Pract 48:211, 2007. Williams DL: Immunopathogenesis of keratoconjunctivitis  sicca in the dog, Vet Clin North Am Small Anim Pract 38:251, 2008.

248 

Feline Corneal Disease CHERYL L. CULLEN, New Brunswick, Canada

T

he cornea is the transparent anterior aspect of the outer fibrous layer of the globe. The cornea is composed of five layers: a precorneal tear film over the outer stratified squamous epithelium, epithelial basement membrane, middle stroma, Descemet’s membrane, and inner endothelium. The main functions of the cornea are to contain the intraocular contents and to aid in the refraction and transmission of light due to its curvature and transparency, respectively. The transparency of the cornea is maintained by a number of anatomic features: a lack of blood vessels, lymphatics, or pigmentation; a nonkeratinized surface epithelium maintained by the moisture of the preocular tear film; a unique lattice organization of small-diameter stromal collagen fibrils; and a functioning inner endothelial layer to maintain its relative state of dehydration. It is noteworthy that the feline cornea is only 0.5 mm thick at its periphery and 0.6 mm thick centrally. The cornea is rich in sensory nerve supply derived from the ophthalmic branch of the trigeminal nerve (cranial nerve V). A functional tear film; an intact and healthy corneal epithelium, stroma, endothelium, and nerve supply; and lack of corneal infiltrate are crucial for the overall health and functioning of the cornea. The unique necessity for the cornea to maintain transparency often is compromised because many corneal disorders lead to corneal opacification and impaired vision. Cats are affected by a variety of nonulcerative and ulcerative corneal diseases. Feline herpesvirus type 1 is

known to play a role in many forms of feline keratopathies, including dendritic corneal ulcers, eosinophilic keratitis, and corneal sequestra. Fortunately, many feline corneal diseases are responsive to medical or surgical therapies. The identification of appropriate treatments depends on the clinician’s first establishing an accurate diagnosis. This chapter focuses on the diagnostic approach to feline corneal disease, describes both general and distinguishing clinical characteristics of the most common disorders, and provides an overview of currently available medical and surgical therapies.

Clinical Signs There are a number of clinical signs associated with corneal disease in the cat. These signs generally are not specific for a type of disease. The most common findings are summarized in Box 248-1.

Feline Herpesvirus 1 Keratoconjunctivitis Clinical Presentation and Diagnosis Feline herpesvirus 1 (FHV-1) is a ubiquitous DNA α-herpesvirus that infects and causes necrosis of the epithelial surfaces of the respiratory tract and conjunctiva and, to a lesser extent, the corneal epithelium. Infection with FHV-1 generally causes a self-limiting primary

CHAPTER  248  Feline Corneal Disease

BOX 248-1  Clinical Signs of Feline Corneal Disease Ocular discharge (serous, mucoid, mucopurulent, serosanguineous, crusty, dark brown or black) Blepharospasm Conjunctival or episcleral injection Chemosis (conjunctival edema) Corneal opacification due to the following: Edema (hazy gray in appearance) White blood cell infiltration (white to yellowish in appearance) Lipid (crystalline white in appearance) Scarring or fibrosis (dull white in appearance) Corneal vascularization (superficial branching or straighter deep blood vessels) Secondary reflex uveitis (miotic or constricted pupil; conjunctival hyperemia; aqueous flare; inflammatory cells in anterior chamber; fibrin in anterior chamber) Raised pink to white chalky plaques from medial or lateral limbus (most consistent with proliferative eosinophilic keratitis) Amber to black region of cornea (most consistent with corneal sequestrum)

disease. Primary FHV-1 disease is characterized by malaise, pyrexia, inappetence, sneezing or coughing, and nasal as well as ocular discharge. The virus is spread from cat to cat by direct contact, fomites, or aerosolization of the virus. Studies have estimated that over 90% of cats are seropositive for the virus. Approximately 80% of FHV-1– affected cats develop a lifelong latent infection (FHV-1 carriers), and of these cats, approximately 45% develop periodic reactivation of the virus and either asymptomatically shed FHV-1 or have clinical disease. Many feline ocular diseases are caused directly by or associated with FHV-1, including most commonly conjunctivitis and ulcerative keratitis. FHV-1 produces disease via at least two mechanisms: (1) cytolytic infection during active viral replication resulting in cell rupture such as occurs during primary FHV-1 infection or following viral reactivation from latency, and (2) immune-mediated inflammation. Clinical ophthalmic manifestations of FHV-1 cytolytic infection are numerous and include conjunctivitis characterized by hyperemia, blepharospasm, chemosis, and ocular discharge. Conjunctivitis, unilateral or bilateral, is the most common FHV-1–related ocular disorder in adult cats without active respiratory disease, although some cats have concurrent sneezing or other mild signs of respiratory tract infection. Keratoconjunctivitis sicca (KCS) has been reported in cats with FHV-1– related conjunctivitis as well. FHV-1 is the sole documented viral cause of keratitis in cats; therefore every case of feline ulcerative and nonulcerative keratitis should be considered to be associated with FHV-1 unless proven otherwise. Dendritic or geographic corneal ulcers are a common manifestation of FHV-1 infection. If both the cornea and conjunctiva are ulcerated because of the cytolytic effects of FHV-1, corneal stroma and conjunctival

1157

TABLE 248-1  Corneal Diseases Associated with Feline Herpesvirus 1 Infection and Their Characteristic Clinical Signs Corneal Disease

Characteristic Clinical Signs

Corneal ulceration

Positive staining with fluorescein ± rose bengal showing linear to dendritic or geographic appearance

Stromal keratitis

Vascularization and white to yellow ± gray opacification of deeper corneal stroma

Symblepharon

Adhesions of conjunctiva to cornea or itself

Keratoconjunctivitis sicca

Dry, nonlustrous corneal surface with Schirmer tear test values typically 50% of stromal depth), a graft is placed for tectonic support. Various forms of corneal grafting have been employed for affected eyes, including the use of amniotic membrane grafts and heterologous corneal grafts (canine donor cornea to avoid

SECTION  XII  Ophthalmologic Diseases

1160

A

B Figure 248-2  A, Right eye of a Devon rex cat demonstrating a small focal tea-colored area

consistent with a corneal sequestrum within the dorsomedial cornea surrounded by superficial corneal vascularization and edema. B, Right eye of a Persian cat demonstrating a large paracentrally located black corneal sequestrum with overlying corneal ulceration and corneal vascularization.

the risk of spreading infectious organisms such as FHV-1 and feline leukemia virus), autogenous corneal grafts (feline donor cornea), and conjunctival island and pedicle grafts as well as corneoconjunctival transposition, among others. The choice of grafting method depends, in part, on availability of the material or tissue as well as on the size and location of the corneal sequestrum. Recurrences of corneal sequestra can arise, even after surgical therapy, and this is likely caused by some of the contributing factors that cannot be altered, including breed predisposition and FHV-1 infection. It is the author’s experience that conjunctival pedicle flap placement without transection of the blood supply to the flap results in a reduced rate of recurrence. Medical management of corneal sequestra is also an option; however, medical treatment alone usually results in greater morbidity for the affected globe and the cat. Sloughing or extrusion of the necrotic portion of cornea can require months to years, and over this time the cornea may ulcerate, which causes acute or chronic ocular pain as well as increased corneal opacification. In some cases the cornea may perforate following natural extrusion of the corneal sequestrum because the sequestrum may extend to the depth of Descemet’s membrane. The author recommends a number of strategies. Medical therapy is aimed initially at preventing secondary infections by using broad-spectrum topical antibiotics (solutions four times daily and ointments three times daily) during periods of corneal ulceration. Alternating between different topical antibiotics on a monthly basis may help prevent changing the conjunctival microflora. The second therapeutic goal is controlling ocular discomfort by using a topical nonsteroidal antiinflammatory agent such as diclofenac 0.1% ophthalmic solution once

or twice daily. Tear supplementation (e.g., application of a viscous tear gel from two to four times daily) is prescribed if a concurrent quantitative or qualitative tear film deficiency is detected. Lastly, in cases in which FHV-1 infection is suspected, a topical or systemic antiviral agent can be used in the short term (2 to 3 weeks at a time). Topical antiviral agents can be epitheliotoxic and should not be used for protracted periods. Owners of affected cats should be made aware that in the long term the cost of medical management for a globe with corneal sequestration can be higher than the cost of surgery because medical therapy involves not only the medications for the eye but also periodic ocular reexaminations to monitor the status of the corneal sequestrum. Many cats with corneal sequestra develop superficial corneal ulcers overlying the portion of necrotic cornea that may not retain fluorescein stain. This lack of fluorescein dye uptake is due to the nonhydrophilic nature of necrotic corneal stroma along with masking by the dark coloration of many sequestra. A concurrent corneal ulcer should be suspected if the affected globe shows signs of ocular discomfort such as blepharospasm.

Surgical Indications and Options for Corneal Disease A discussion of surgical treatments for feline corneal disease is beyond the scope of this textbook, and most of these procedures should be performed by a veterinary ophthalmologist. Table 248-2 summarizes a few of the available options so that practitioners can be familiar with some of the more advanced treatment methods available for management of feline corneal diseases.

CHAPTER  248  Feline Corneal Disease

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TABLE 248-2  Surgical Indications and Options in Corneal Disease Corneal Disease

Indications for Surgery

Surgical Option(s)

Corneal ulceration

Corneal ulcer that is >50% stromal depth; visible corneal crater or defect; ulcer down to level of Descemet’s membrane (i.e., clear in center of ulcer bed) Chronic refractory superficial corneal ulcer with lips of nonadherent epithelium (indolent corneal ulcer)

Keratectomy to remove unhealthy portions of cornea associated with ulcer and some form of grafting procedure (e.g., conjunctival pedicle flap) to fill remaining corneal defect for tectonic support. Corneal débridement to remove unhealthy corneal epithelium; grid-striate or punctuate keratotomy should not be performed in cats because it could predispose to feline herpesvirus 1–related stromal keratitis or corneal sequestrum.

Stromal keratitis

Advanced generalized corneal opacification, blindness, and chronic ocular pain; poor response to medical therapy

Enucleation of severely compromised globes.

Keratoconjunctivitis sicca (KCS)

Schirmer tear test values remain consistently low or zero and medical therapies have failed to control not only the KCS but also the cat’s symptoms

Parotid salivary duct transposition; rarely performed in cats compared with dogs.

Eosinophilic keratitis

Nonsurgical ocular disease unless a complex corneal ulcer develops (see corneal ulceration above)

Not applicable unless complex corneal ulcer develops (see corneal ulceration above)

Corneal sequestrum

Shorten healing time and decrease ocular discomfort

Keratectomy ± grafting procedure

References and Suggested Reading Cullen CL et al: Ultrastructural findings in feline corneal sequestra, Vet Ophthalmol 8:295, 2005. Dean E, Meunier V: Feline eosinophilic keratoconjunctivitis: a retrospective study of 45 cases (56 eyes), J Feline Med Surg, Jan. 15 Epub, 2013. Gould D: Feline herpesvirus-1: ocular manifestations, diagnosis and treatment options, J Feline Med Surg 13:333, 2011. Lim CC, Cullen CL: Schirmer tear test values and tear film break-up times in cats with conjunctivitis, Vet Ophthalmol 8:305, 2005. Maggs DJ: Antiviral therapy for feline herpesvirus infections, Vet Clin North Am Small Anim Pract 40:1055, 2010. Maggs DJ, Nasisse MP, Kass PH: Efficacy of oral supplementation with L-lysine in cats latently infected with feline herpesvirus, Am J Vet Res 64:37, 2003.

Newkirk KM, Hendrix DVH, Keller RL: Porphyrins are not present in feline ocular tissues or corneal sequestra, Vet Ophthalmol 14:2, 2011. Sandmeyer LS, Keller CB, Bienzle D: Effects of interferon-alpha on cytopathic changes and titers for feline herpesvirus-1 in primary cultures of feline corneal epithelial cells, Am J Vet Res 66:210, 2005. Spiess AK, Sapienza JS, Mayordomo A: Treatment of proliferative feline eosinophilic keratitis with topical 1.5% cyclosporine: 35 cases, Vet Ophthalmol 12:132, 2009. Thomasy SM et al: Evaluation of orally administered famciclovir in cats experimentally infected with feline herpesvirus type-1, Am J Vet Res 72:85, 2011. Townsend WM et al: Heterologous penetrating keratoplasty for treatment of a corneal sequestrum in a cat, Vet Ophthalmol 11:273, 2008.

CHAPTER 

249 

Canine Uveitis ALEXANDRA VAN DER WOERDT, New York, New York

U

veitis is defined as inflammation of the vascular uveal tract within the eye. Anterior uveitis is inflammation of the iris and ciliary body. Chorioretinitis is inflammation of the choroid and the adjacent retina. Isolated choroiditis without involvement of the retina is rare. Panuveitis refers to inflammation that affects the entire uveal tract. Anterior uveitis and chorioretinitis are common ocular diseases in dogs and often are present at the same time. There are numerous causes of uveitis in dogs, and they include both systemic diseases and localized ocular diseases. Proper diagnosis and investigation of possible underlying diseases is important for the management of both the eye and the dog. This chapter provides a brief description of uveal anatomy and physiology, followed by a discussion of clinical signs, differential diagnoses, and treatment of uveitis in dogs.

Anatomy and Physiology The uvea consists of the iris, ciliary body, and choroid. The uvea has many functions, including production of aqueous humor, regulation of the amount of light that enters the eye through constriction and dilation of  the pupil, and supply of nutrients and oxygen to the nonvascularized or poorly vascularized portions of the eye. The uvea also is responsible for maintenance of  the blood-aqueous barrier that protects the eye from toxins, infectious organisms, and exuberant inflammation. Inflammation starts either within the eye itself or in reaction to a disease process elsewhere in the body. Microorganisms or damaged tissue release inflammatory mediators such as histamine, serotonin, prostaglandins, and leukotrienes, which result in vasodilation and increased vascular permeability. This leads to breakdown of the blood-aqueous barrier. These inflammatory mediators also cause leukocyte activation and migration. Antigens are transported through the bloodstream to the spleen or other lymphoid tissues, which results in activation of T and B lymphocytes. These activated T and B lymphocytes are transported back to the eye through the bloodstream to the uveal tract. Uveitis resolves when inhibitory cytokines eliminate the inflammatory response and the initial offending antigen is removed. Chronic inflammation may occur when the initial offending antigen cannot be removed or the inflammatory response is not adequately suppressed.

Diagnosis Clinical signs of anterior uveitis include blepharospasm, conjunctival hyperemia, corneal edema, aqueous flare, 1162

hypopyon, swelling of the iris, rubeosis iridis (neovascularization of the iris in chronic uveitis), decreased intraocular pressure (IOP), decrease or loss of vision, and miosis. Table 249-1 lists the differential diagnoses for the various clinical signs associated with anterior uveitis. Blepharospasm is a sign of ocular pain associated with spasm of the ciliary body musculature and intraocular inflammation. Conjunctival hyperemia is a nonspecific sign associated with many ocular diseases and cannot be used to rule in or rule out uveitis. Corneal edema is caused by temporary malfunction of the endothelial cells resulting in decreased removal of fluid from the cornea. Breakdown of the blood-aqueous barrier results in the leakage of protein and inflammatory cells into the aqueous humor. The anterior chamber is best evaluated for the presence of aqueous flare by illumination using a bright pinpoint or slit-beam light source held in close proximity to the cornea in a dark room. A normal eye shows a white light beam on the cornea, no light reflection from the aqueous humor, and a white light beam on the iris-lens. An eye with uveitis has increased protein and cells in the aqueous humor, which can be seen as light reflecting between the beam on the cornea and the beam on the iris-lens. Severe breakdown of the blood-aqueous barrier may result in the presence of white blood cells in the anterior chamber, a condition called hypopyon. These often settle at the bottom of the anterior chamber. It is important to remember that the presence of hypopyon does not necessarily indicate intraocular infection but is pathognomonic for intraocular inflammation. Inflammation of the iris and ciliary body causes a decrease in IOP because of a decrease in the production of aqueous humor and an increase in the removal of aqueous humor through the inflamed iris. Miosis results from elevated levels of prostaglandins in the aqueous humor that stimulate contraction of the iris sphincter muscle. Blepharospasm, corneal edema, aqueous flare, and miosis all may contribute to a decrease in vision. Chorioretinitis often causes a decrease in, or loss of, vision. Secretion of fluid between the choroid and the retina may result in focal or complete (serous) retinal detachment. Focal areas of chorioretinitis are visible within the retina as hyporeflective lesions that often are round and may have a different color from the surrounding tapetal and nontapetal areas.

Causes Uveitis can have numerous causes in the dog. Uveitis can be divided into two main types: uveitis associated with systemic disease and uveitis secondary to other ocular

CHAPTER  249  Canine Uveitis

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TABLE 249-1  Clinical Signs of Anterior Uveitis with Common Differential Diagnoses Diagnostic Tests and Other Clinical Signs to Help Differentiate Diagnoses

Clinical Sign

Differential Diagnoses

Blepharospasm

Corneal ulceration Glaucoma Lens luxation Blepharitis Entropion

Thorough ophthalmic examination Measurement of IOP

Conjunctival hyperemia

Glaucoma Conjunctivitis   Allergic   Keratoconjunctivitis sicca Corneal ulceration

Schirmer tear test Measurement of IOP Fluorescein staining

Corneal edema

Corneal ulceration Glaucoma Anterior lens luxation Endothelial cell degeneration

Fluorescein staining Measurement of IOP Evaluation of lens position

Aqueous flare

Lipid-laden aqueous humor

Biochemistry profile with evaluation of cholesterol and total lipids

Hypopyon

Focal area of depigmentation in iris

Comfortable eye with no other signs of inflammation

Iris swelling

Normal iris crypts Major arterial circle visible at base of iris Neoplastic infiltration

No other signs of inflammation present with normal iris crypts

Rubeosis iridis

Major arterial circle may appear as a red vessel at base of iris in eyes with a light-colored iris

Circular, irregular vessel at base of iris

Miosis

Neurologic disease Use of miotic agents (i.e., latanoprost, pilocarpine)

Low intraocular pressure

Advanced age

Absence of other clinical signs of uveitis in an older dog

Decreased or loss of vision

Severe corneal disease Cataract Lens luxation Retinal degeneration Sudden acquired retinal degeneration Optic neuritis Retinal detachment

Mydriasis usually present in the following:   Retinal degeneration   Sudden acquired retinal degeneration   Optic neuritis   Retinal detachment Difficult to evaluate intraocular details in severe corneal disease

IOP, Intraocular pressure.

diseases. Box 249-1 lists the most common causes of uveitis in dogs. In one large retrospective study (Massa et al, 2002), an underlying cause was unidentified in approximately 60% of cases of canine uveitis, which led to a default diagnosis of immune-mediated uveitis/uveitis of unknown cause in the majority of cases. It is important to prepare clients for this possibility because even a thorough workup may not reveal the cause of uveitis. Nevertheless, a complete workup is critically important to rule out any underlying neoplastic or infectious disease. A thorough physical examination, including careful palpation of regional lymph nodes, is indicated for all patients with uveitis. Obtaining a travel history is important because uveitis may indicate the presence of a disease not typically seen in the dog’s home area. A complete blood count, serum biochemistry profile, and urinalysis are recommended as part of a systematic workup. Submission of blood for serologic testing for specific diseases should be guided by results of the physical examination and

knowledge of diseases specific to the geographic location or travel history. Aspiration of the anterior chamber or vitreous cavity to collect samples for cytologic analysis or culture is an additional diagnostic technique that can help establish a diagnosis, but such procedures usually are done under general anesthesia and often are best performed by a veterinary ophthalmologist. Numerous infectious diseases can cause anterior uveitis in dogs. Patients typically show clinical signs of systemic disease in addition to ocular disease; however, a lack of systemic signs does not rule out systemic illness. Ocular lesions are most often bilateral but can be unilateral. Bacterial infections include leptospirosis, brucellosis, and the various tick-borne diseases. Brucellosis usually is manifested as a reproductive disease in intact male dogs, although it also can cause endophthalmitis, chorioretinitis, and hyphema. Uveitis is relatively uncommon in leptospirosis. Conversely, inflammation of the anterior and posterior segments of the eye is common in tick-borne

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BOX 249-1  Causes of Uveitis in Dogs Ocular Diseases • Ulcerative keratitis • Lens protein leakage • Ocular neoplasia • Pigmentary uveitis (golden retrievers) • Immune-mediated disease (idiopathic) • Trauma to the globe (blunt or penetrating) • Scleritis

Systemic Diseases Infectious Bacterial • Leptospirosis • Brucellosis • Lyme disease • Ehrlichiosis • Rocky Mountain spotted fever • Bacteremia or septicemia (e.g., endocarditis, pyometra) Viral • Canine adenovirus 1 infection Mycotic • Blastomycosis • Histoplasmosis • Cryptococcosis • Aspergillosis • Coccidiomycosis Parasitic • Dirofilariasis • Aberrant nematode larval migration Protozoan • Leishmaniasis • Toxoplasmosis (rare in dogs) Algal • Prototheca infection Immune Mediated • Uveodermatologic syndrome • Reaction to vaccine against canine adenovirus 1 or 2 • Idiopathic Miscellaneous • Hyperlipidemia • Hypertension • Hyperviscosity • Metastatic neoplasia

diseases. Hemorrhage, such as hyphema and retinal hemorrhage, as well as retinal detachment may be present. Any disease associated with bacteremia, such as pyometra, can cause a secondary uveitis. Blastomycosis, histoplasmosis, coccidiomycosis, and cryptococcosis are the systemic fungal diseases most commonly associated with ocular inflammation, and uveitis, chorioretinitis, endophthalmitis, and optic neuritis can be evident. The inflammation often is severe. Cryptococcosis induces  less ocular inflammation because the thick capsule of the Cryptococcus organism shields antigens from the immune system. Less common causes of canine uveitis are aberrant migration of parasitic larvae, toxoplasmosis, and infection with Prototheca or Leishmania spp. Immune-mediated disease may be associated with uveitis. Uveodermatologic syndrome (or Vogt-KoyanagiHarada–like syndrome) is a disease mediated by an immune response against pigmented tissues in the eye and the skin. Clinical signs include anterior uveitis, chorioretinitis, retinal detachment, poliosis, and vitiligo of

the mucocutaneous junctions of the head, nasal planum, scrotum, and footpads. Ulceration of the skin may occur as well. Predisposed breeds include the Akita, chow-chow, Siberian husky, and Samoyed. “Blue eye” or immunemediated uveitis is associated with a type III hypersensitivity reaction to canine adenovirus (CAV) infection. Uveitis and endotheliitis of the cornea as a reaction to CAV-1 or CAV-2 vaccination is rare with modern vaccines but still can be observed sporadically. Clinical signs include an acute onset of severe corneal edema within a few days after vaccination. Miscellaneous systemic diseases associated with uveitis include hyperlipidemia, hypertension, hyperviscosity syndromes, and metastatic neoplasia. Patients with uveitis and hyperlipidemia may be brought for evaluation of acute onset of a very cloudy appearance to the eye. The eye is often comfortable, and the anterior chamber appears to be filled with “milk-white” aqueous humor. The condition can arise suddenly but also can resolve very quickly. Breakdown of the blood-aqueous barrier is required for lipid to enter the anterior chamber. Hyperlipidemia also can be visible in the retinal vessels as lipemia retinalis, which gives the retinal vessels a lightred appearance. The anterior uveitis associated with systemic hypertension or hyperviscosity syndromes usually is mild and far less significant than the changes seen in the fundus. Retinal changes include retinal edema; supraretinal, subretinal, or intraretinal hemorrhage; hyphema; tortuous vessels; and retinal detachment. Metastatic neoplasia can manifest itself as discrete nodules in the iris, focal infiltrative lesions in the retina and choroid, or a diffuse infiltration of the iris or choroid. Primary ocular causes of uveitis can be unilateral or bilateral. Corneal ulceration can cause significant reflex uveitis, especially if secondary bacterial infection is present. The degree of inflammation may be mild in a superficial corneal ulcer but can be quite pronounced with hypopyon in a deep, infected corneal ulcer. Blunt or penetrating trauma to the eye can induce reflex uveitis but would likely be associated with other signs, including hyphema, corneal ulceration or laceration, scleral laceration, lens luxation, vitreous hemorrhage, and retinal detachment. Lens-induced uveitis occurs when proteins from a cataract leak through an intact lens capsule into the aqueous humor (phacolytic uveitis). This is most common with hypermature cataracts and may be seen with any cataract larger than an incipient size (>10% of the lens volume). Phacoclastic uveitis is caused by acute rupture of the lens capsule and the release of lens proteins into the aqueous humor. Phacoclastic uveitis typically occurs 2 to 14 days after lens capsule rupture. The sudden exposure of the eye to large quantities of lens protein causes a severe inflammatory reaction that may be blinding. When rupture of the lens capsule is suspected, immediate referral to an ophthalmologist for lensectomy is indicated to optimize the chances of preserving vision. Intraocular neoplasia is more likely to be associated with uveitis when it is secondary to ocular metastasis  or multicentric neoplasia. Primary intraocular neoplasia rarely is associated with inflammation in the early stages of tumor development.

CHAPTER  249  Canine Uveitis Pigmentary uveitis is a potentially blinding disease in golden retrievers. Clinically, iris cysts are one of the first abnormalities noted. Other clinical signs are fine streaking of pigment on the anterior lens capsule and darkening of the iris. A proteinaceous exudate may be present in the anterior chamber as the diseases progresses. The posterior segment remains unaffected unless secondary glaucoma develops. Complications including cataract  formation and glaucoma are common. The eye often is comfortable until late in the disease, when secondary glaucoma makes the globe painful.

TABLE 249-2  Antiinflammatory Medications for Treatment   of Uveitis Oral Medications

Topical Medications

Steroidal Medications

Steroidal Medications

Prednisolone 0.5-2.2 mg/kg q12-24h Prednisone 0.5-2.2 mg/kg q12-24h

Prednisolone acetate 1% suspension, see text Dexamethasone 0.1% solution, see text Dexamethasone 0.05% ointment, see text

Nonsteroidal Antiinflammatory Drugs

Nonsteroidal Antiinflammatory Drugs

Carprofen 2.2 mg/kg q12-24h Deracoxib 1-2 mg/kg q24h Meloxicam 0.2 mg/kg first day, then 0.1 mg/kg once daily Tepoxalin 10 mg/kg q24h

Flurbiprofen 0.03% q6-12h Diclofenac 0.1% q6-12h Suprofen 1% q6-12h Ketorolac 0.4% q6-12h Nepafenac 0.1% q8h

Complications Ocular complications are common in anterior uveitis, especially if the inflammation is not adequately treated or if the disease becomes chronic or recurrent. Common complications are anterior and posterior synechiae, cataract formation, lens luxation, glaucoma, and blindness. Chronic inflammation is one of several ocular diseases in which preiridal fibrovascular membranes form on the anterior surface of the iris. These membranes are composed of fibrous and vascular components, and their presence predisposes the eye to the development of hyphema, entropion or ectropion uveae, and synechiae. These membranes also can lead to occlusion of the iridocorneal angle resulting in glaucoma.

Treatment Treatment of uveitis has several components: addressing the underlying disease if possible; suppressing the inflammation; dilating the pupil; and controlling the discomfort associated with uveitis. Treatment of the underlying disease, if possible, is the most important aspect of managing uveitis. Topical symptomatic therapy for the eyes should be started at the same time as treatment for the underlying disease. Suppression of the inflammation is accomplished using topical corticosteroids, systemic corticosteroids, or nonsteroidal antiinflammatory medications (NSAIDs) (Table 249-2). Prednisolone acetate 1% solution and dexamethasone 0.1% solution are potent topical antiinflammatory medications with good intraocular penetration. Hydrocortisone is not recommended for the treatment of uveitis because of its poor intraocular penetration. The frequency of topical steroid use is determined by the severity of the uveitis and can range from once daily to hourly; however, in most cases, administration is every 4 to 8 hours and the time between doses is increased as inflammation subsides. Topical steroids should not be used when corneal ulceration is present. Topical medications are ineffective in treating inflammation of the posterior segment because a topically administered drop does not penetrate the eye past the lens. Oral corticosteroids can be used to treat inflammation of the posterior segment and also can be administered if severe anterior uveitis is present. Caution should be used in dosing oral corticosteroids when an infectious cause of chorioretinitis is suspected. Dosing should remain in the antiinflammatory range (0.5 to 1.0 mg/kg/day) and should not extend into the immunosuppressive range. Oral azathioprine (2.2 mg/kg q24h) may be useful in the longterm management of chronic uveitis. Uveodermatologic

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syndrome, for example, often is treated with a combination of oral corticosteroids and azathioprine. Topical NSAIDs are recommended to treat uveitis when a concurrent corneal ulcer is present. Many topical NSAIDs are available, and several of the newer medications (e.g., nepafenac 0.1%) are potent antiinflammatory medications. They should be used with caution in animals at risk of the development of glaucoma because some NSAIDs may potentiate elevation of IOP. Of the oral NSAIDs available, oral tepoxalin has been suggested to be superior to other NSAIDs in suppressing experimentally induced uveitis. Mydriatics such as atropine 1% solution are used to relieve the pain associated with ciliary body spasm and to induce mydriasis to prevent posterior synechiae from occluding the pupil. The use of tropicamide 1% solution is not recommended because this mydriatic has only weak cycloplegic properties and therefore is ineffective in relieving ciliary body spasm. Careful monitoring of the IOP is indicated when the various mydriatic agents are used. Severe uveitis can be very resistant to mydriatic agents. It may take multiple applications of atropine per day to dilate a pupil in the setting of uveitis. Once the pupil is dilated, the frequency of application can be reduced to the minimal frequency needed to maintain mydriasis. When treating a patient with uveitis, it is important to reevaluate the patient regularly and decrease medications only when the clinical picture is improved. For example, reduced blepharospasm, mydriasis maintained with minimal application of atropine, decreased aqueous flare, and resolution of hypopyon are indicative of resolving disease. When antiinflammatory medications are tapered, it is recommended that treatment continue for several weeks past the clinical resolution of inflammation because microscopic inflammation may be present even when gross evidence is lacking. Monitoring IOP is a useful way to detect subclinical or ongoing inflammation. IOP is expected to normalize when uveitis has been adequately controlled.

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SECTION  XII  Ophthalmologic Diseases

Treatment of Uveitis in Combination with Other Ocular Diseases

Carbonic anhydrase inhibitors are the safest antiglaucoma medication for use in a patient with uveitis and secondary glaucoma (see Chapter 251).

Uveitis and Corneal Ulceration Topical corticosteroids delay healing of a corneal ulceration and should be avoided if an ulcer is present. Topical NSAIDs and oral corticosteroids can be used to treat uveitis accompanied by a corneal ulcer.

Uveitis and Glaucoma Normal IOP is between 10 and 20 mm Hg. IOP typically is low in cases of uveitis. Secondary glaucoma should be suspected if the IOP is normal in an eye with uveitis. Mydriatics are contraindicated in eyes with glaucoma or those at risk of glaucoma. Miotic agents such as prostaglandin analogs commonly are used in the treatment of glaucoma but should be avoided in eyes with uveitis. Concurrent uveitis and glaucoma are best treated with  a combination of antiinflammatory medications and antiglaucoma medications that do not affect pupil size.

CHAPTER 

References and Suggested Reading Gilmour MA, Lehenbauer TW: Comparison of tepoxalin, carprofen, and meloxicam for reducing intraocular inflammation in dogs, Am J Vet Res 70(7):902, 2009. Johnson DA, Maggs DJ, Kass PH: Evaluation of risk factors for development of secondary glaucoma in dogs: 156 cases (19992004), J Am Vet Med Assoc 229(8):1270, 2006. Massa K et al: Causes of uveitis in dogs: 102 cases (1989-2000), Vet Ophthalmol 5(2):93, 2002. Sapienza JS, Simo FJ, Prades-Sapienza A: Golden retriever uveitis: 75 cases (1994-1999), Vet Ophthalmol 3(4):241, 2000. Sigle KJ et al: Unilateral uveitis in a dog with uveodermatologic syndrome, J Am Vet Med Assoc 228(4):543, 2006. Townsend WM: Canine and feline uveitis, Vet Clin North Am Small Anim Pract 38(2):323, 2008. Zarfoss MK et al: Canine pre-iridal fibrovascular membranes: morphologic and immunohistochemical investigations, Vet Ophthalmol 13(1):361, 2010.

250 

Feline Uveitis CYNTHIA C. POWELL, Fort Collins, Colorado

U

veitis is a painful, vision-threatening disease common in cats. Previous reports suggest that 40% to 70% of feline uveitis cases are associated with a systemic illness. A thorough workup to eliminate infectious causes is imperative because treatment of idiopathic uveitis is directed toward immunosuppression. Owners should be prepared for a potentially expensive diagnostic workup in which a definitive diagnosis is not identified. Some causes of uveitis in cats are different from those identified in the dog (see Chapter 249). The uveal tract is comprised of the iris, ciliary body, and choroid. Anterior uveitis or iridocyclitis is inflammation of the iris and ciliary body. Posterior uveitis is more commonly referred to as chorioretinitis since the choroid and retina are affected concurrently in many cases. Anterior uveitis and chorioretinitis can occur separately or together.

Clinical Manifestations Intraocular inflammation is initiated by tissue injury from trauma, infectious agents, or other antigen

challenge. The tissue factors released from the damaged tissue and microorganisms result in vasodilation and changes in the vascular permeability of the intraocular vasculature. Inflammatory mediators cause leukocyte activation and migration. With moderate or severe anterior uveitis, increases in protein concentrations and inflammatory cells numbers lead to opacity of the normally transparent aqueous humor, also called aqueous flare. Hyphema, fibrin clots, and keratic precipitates (inflammatory cell and protein aggregates on the corneal endothelium) also may be observed. Conjunctival and scleral injection, photophobia, blepharospasm, enophthalmos, and epiphora are common with anterior uveitis but often are not present with chorioretinitis unless anterior uveitis also is present. Other ocular signs of anterior uveitis are corneal edema, miosis, edema and color changes in the iris, anterior and posterior synechia, and iris bombé. Decreased intraocular pressure (IOP) frequently is observed as a consequence of decreased aqueous humor formation. Normal feline IOP is reported as approximately 10 to 20 mm Hg. Ocular hypotony should resolve as the intraocular inflammation is controlled.

CHAPTER  250  Feline Uveitis

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BOX 250-1  Causes of Uveitis in Cats Exogenous Trauma • Secondary bacterial infection • Sterile inflammation Ocular Surgery • Secondary bacterial infection • Sterile inflammation Keratitis • Ulceration • Infection

Endogenous Infection Bacterial • Ehrlichia sp. • Bartonella spp. • Bacteremia or septicemia (e.g., pyometra, abscess) Viral • Feline leukemia virus • Feline coronavirus (feline infectious peritonitis) • Feline immunodeficiency virus Mycotic • Cryptococcus neoformans • Blastomyces dermatitidis • Histoplasma capsulatum • Coccidioides immitis • Candida albicans Protozoal/parasitic • Toxoplasma gondii • Leishmania sp. • Insect larvae (ophthalmomyiasis)

Normal IOP in an actively inflamed eye raises the suspicion of concurrent glaucoma. Trends in IOP should be monitored closely throughout treatment. Inflammatory cells sometimes accumulate in the anterior vitreous, obscuring the retina from direct visualization. This is referred to as pars planitis or intermediate uveitis. In the choroid and retina, exudates of protein and inflammatory cells accumulate within and beneath the retina and cause retinal and subretinal edema, hemorrhage, and retinal detachment. Since the retina and subretinal space are immediately anterior to the tapetum, tapetal reflectivity is decreased or obscured by areas of active chorioretinitis.

Diagnosis Causes of feline uveitis generally are subdivided into the categories of trauma, infection, immune-mediated disease, and neoplasia (Box 250-1). Some causes can be identified by history (trauma) or ocular examination (trauma, lens disorders, neoplasia). Correlating infectious disease with uveitis is more challenging. Infectious causes generally cannot be differentiated by ocular findings alone, so the history, physical examination findings, and results of a complete blood count, urinalysis, and serum biochemical panel should be used to guide further diagnostic testing such as serologic studies, aqueous or vitreous humor analysis, radiography, ocular ultrasonography, and histopathologic evaluation. Ocular fluids can be used for cytologic analysis, culture and sensitivity testing, polymerase chain reaction (PCR) assay, and determination of antibody content.

Neoplasia Primary • Diffuse iris melanoma • Ciliary body adenoma • Ciliary body adenocarcinoma Metastatic • Lymphosarcoma • Others Immune-Mediated Disorders Lens Induced • Cataract • Lens subluxation/luxation • Lens perforation or rupture Idiopathic Miscellaneous Causes of Blood-Eye Barrier Disruption • Hyperviscosity syndrome • Hypertension

Infectious Diseases Associated with Feline Uveitis Toxoplasmosis Infection with Toxoplasma gondii occurs primarily by ingestion of tissue cysts in prey animals. Chorioretinitis is the most common ocular manifestation of toxoplasmosis in systemically ill cats; however, the majority of infected cats do not become systemically ill. Cats with positive results on tests for T. gondii infection often exhibit anterior uveitis but are otherwise clinically normal. Evidence suggests that T. gondii–related anterior uveitis is immune mediated. Definitive diagnosis of ocular toxoplasmosis is difficult due to the high percentage of cats with serum titers showing positivity for T. gondii. The presence of serum immunoglobulin M, a rising serum immunoglobulin G level, and antibody production in  the aqueous humor all support a diagnosis of ocular toxoplasmosis. All sick cats that test positive for T. gondii should be treated with anti-Toxoplasma drugs. T. gondii-positive cat with uveitis, but no other clinical signs of infection by T. gondii, should be treated with anti-Toxoplasma drugs when other causes have been ruled out, especially if the uveitis responds poorly to antiinflammatory therapy alone. Clindamycin hydrochloride is recommended at 10 to 25 mg/kg q12h for 14 to 21 days.

Feline Infectious Peritonitis Ocular disease (anterior and posterior uveitis) associated with feline infectious peritonitis (FIP) is most common in

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SECTION  XII  Ophthalmologic Diseases

the dry, noneffusive form of FIP and usually is accompanied by signs of systemic disease. Rarely ocular signs may be the sole presenting complaint. FIP typically occurs in cats younger than 3 years of age. Currently available tests cannot distinguish antibodies against feline enteric coronavirus from those against FIP-inducing coronavirus; however, in a young cat with ocular disease, the findings of a coronavirus antibody titer of more than 1 : 1600, lymphopenia, and hypergammaglobulinemia are highly suggestive of FIP infection. Once clinical signs occur, the prognosis for FIP is grave. Cats with less severe disease may live for several months with therapy. Immunosuppressive and antiinflammatory drugs may be used for palliative therapy. Several protocols have been described, but there is no consensus on optimal treatment of systemic disease. Ocular inflammation should be treated with topical and systemic glucocorticoids and with cycloplegics, depending on the location and severity of the inflammation (see treatment section).

Feline Leukemia Virus Infection/ Lymphosarcoma Ocular disease occurs infrequently with feline leukemia virus (FeLV) infection except in association with lymphosarcoma or secondary infection associated with chronic immunosuppression. Fewer than 2% of cats with clinical FeLV infection have ocular disease. Ocular lymphosarcoma can be nodular or diffuse. When diffuse, ocular lymphosarcoma has an appearance to similar that of uveitis due to other causes. Isolated ocular lymphosarcoma is rare, and the diagnosis most frequently is confirmed after identification of multicentric neoplasia. FeLV status is useful for prognosis but not diagnosis, since only approximately 19% of cats with ocular lymphosarcoma test positive for FeLV. Anterior chamber/centesis with gentle iris vacuuming to obtain cells for cytologic evaluation occasionally demonstrates neoplastic cells. Treatment is by combination chemotherapy and empiric therapy for anterior uveitis when present.

Feline Immunodeficiency Virus Infection Uveitis commonly is observed in cats with clinically apparent feline immunodeficiency virus (FIV) infection. The pathophysiology of disease includes direct viral invasion, opportunistic infection (57% of cats are coinfected with T. gondii), and initiation of secondary immune responses (e.g., immune complex formation). Diagnosis is supported by serum antibody testing with enzymelinked immunosorbent assay (ELISA), immunofluorescence assay (IFA), or Western blot. These tests cannot differentiate antibodies induced by vaccination, which makes accurate diagnosis challenging. Ocular signs include anterior uveitis, pars planitis, and glaucoma. Pars planitis appears as white punctate infiltrates concentrated in the peripheral anterior vitreous. Ocular lymphosarcoma also has been associated with FIV infection. Treatment of FIV infection should be aimed at management of secondary infections when identified. Although use of topical corticosteroids to treat anterior uveitis is likely safe in cases of FIV infection, systemic corticosteroids

should be used with caution since their effect on viral replication is unknown.

Systemic Mycoses Granulomatous chorioretinitis with or without anterior uveitis can occur with cryptococcosis, histoplasmosis, blastomycosis, and coccidioidomycosis in cats. Cryptococcosis is the most common systemic mycosis in cats. Diagnosis is by demonstration of the organism on cytologic analysis of skin lesions, nasal exudate, or lymph node or bone marrow samples, or cytologic evaluation of subretinal or vitreous exudates. Serum antigen titers or ELISA test results for Cryptococcus are useful for diagnosis and monitoring of response to therapy. Systemic therapy with fluconazole is considered ideal for ocular disease since it has fewer adverse effects and penetrates ocular tissues well. Treatment should continue for at least 1 month after clinical signs resolve and the Cryptococcus titer has dropped by at least two orders of magnitude. When present, anterior uveitis should be treated with a topical corticosteroid and atropine. Antiinflammatory dosages of oral corticosteroids along with antifungal therapy may be necessary to control inflammation associated with posterior segment infection. Eyes with secondary glaucoma or severe posterior segment involvement that are not responsive to antifungal medications require enucleation.

Bartonellosis Infection with Bartonella spp. is common in cats, although clinical disease is less frequent. A recent study (Fontenelle et al, 2008) showed that healthy cats were more likely to be seropositive for Bartonella than cats with uveitis. After other causes have been ruled out, cats with uveitis unresponsive to traditional therapy should be tested for Bartonella infection, especially if there is a history of flea infestation. Diagnosis is by PCR testing, culture of whole blood, or IFA or ELISA antibody testing of serum. Oral doxycycline at a dosage of 10 mg/kg q12h for 2 to 4 weeks or oral enrofloxacin at a dosage of 5 mg/kg q24h or divided q12h can be used for treatment.

General Principles of Treatment The primary goals in the treatment of uveitis are to stop inflammation, prevent or control complications caused by inflammation, and relieve pain. Specific therapy for uveitis must address any underlying cause of inflammation, including corneal ulceration or infectious disease. Nonspecific treatments include decreasing the ocular inflammatory response with antiinflammatory drugs, inducing mydriasis to prevent synechia formation, and paralyzing the ciliary body (cycloplegia) to decrease pain (Table 250-1). Therapy for glaucoma should be instituted when elevations in IOP are identified. Ocular inflammation is treated primarily with topical or systemic glucocorticoids. Anterior uveitis is treated with topical administration of drugs unless contraindicated by concurrent corneal ulceration. The frequency of administration depends on the severity of inflammation.

CHAPTER  250  Feline Uveitis

TABLE 250-1  Drugs Commonly Used for Treatment of Uveitis Topical Drugs

Dosing Schedule

Glucocorticoids Prednisolone acetate (1% suspension)

q2-12h

Dexamethasone (0.1% solution, 0.05% ointment)

q2-12h

NSAIDs Flurbiprofen (0.3% solution)

q6-12h

Ketorolac (0.5% solution)

q6-12h

Diclofenac (0.1% solution)

q6-12h

Mydriatic/Cycloplegic Drugs (Parasympatholytics) Atropine sulfate (0.5% and 1% solution and ointment)

q8-24h

Tropicamide (0.5% and 1% solution)

q8-24h

Mydriatic Drugs (Sympathomimetics) Phenylephrine hydrochloride (2.5% solution)

q8-12h Used in conjunction with parasympatholytic

Oral Drugs

Dosing Schedule

Corticosteroids Prednisolone (5-mg tablet) Prednisone (5- and 20-mg tablets)

0.5-2.2 mg/kg q12-24h (higher dosages for initial treatment of severe inflammation) 0.5-2.2 mg/kg q12-24h (higher dosages for initial treatment of severe inflammation)

NSAIDs

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topically administered ophthalmic medications; systemic administration is needed to achieve therapeutic levels. Little is known about the effectiveness of nonsteroidal antiinflammatory drugs (NSAIDs) in the treatment of feline uveitis, and caution should be used in their administration. The use of systemic NSAIDs in cats has been associated with potentially serious adverse effects, including bone marrow suppression, gastrointestinal ulceration, hemorrhage, vomiting, and diarrhea. Aspirin, ketoprofen, and meloxicam can be used systemically with careful attention to dosage and possible adverse effects. Topical application of NSAIDs may complicate bacterial or viral corneal infections and is not recommended in cases of uveitis with concurrent corneal ulceration. As ocular inflammation subsides, antiinflammatory treatment should be tapered. The rate of reduction depends on both the duration and severity of inflammation. With acute mild inflammation drugs can be discontinued over a period of 1 to 2 weeks. Chronic or severe inflammation dictates a much slower taper, potentially over several months. Some cats with chronic inflammation require maintenance antiinflammatory therapy. The dosage should be decreased to the lowest possible to maintain control of inflammation. Parasympatholytics such as atropine relieve ocular pain by relaxing the ciliary body musculature (cycloplegia). Atropine also induces mydriasis, which decreases the chance of posterior synechia. Atropine is more effective than tropicamide in the presence of uveitis because it has greater cycloplegic effects. Atropine carries a bitter taste, and cats often salivate profusely when atropine ophthalmic solutions are administered topically since they readily drain down the nasolacrimal duct. Atropine ointment generally is better tolerated. Judicious use of parasympatholytics is recommended since long-term dilation of the pupil can obstruct aqueous humor outflow. Parasympatholytic drugs also may be associated with transient decreases in tear production. Sympathomimetics, such as phenylephrine 2.5%, can be used in conjunction with parasympatholytics if severe, poorly responsive miosis is encountered.

Meloxicam

0.2 mg/kg PO in food then 0.1 mg/kg in food q24h × 2 days, then 0.025 mg/kg 2-3 times per wk

Acetylsalicylic acid (80-mg tablet)

3-10 mg/kg q48-72h

Prognosis

Ketoprofen (12.5-mg tablet)

≤2 mg/kg initially then ≤1 mg/ kg q24h

The prognosis for the feline eye with anterior uveitis is influenced by a number of factors. Inflammation that can be brought under control quickly may leave behind no evidence of prior uveitis. Chronic inflammation has significant sequelae that can result in visual impairment  or complete blindness. Iris inflammation and swelling, inflammatory cells and debris, and iris bombé secondary to posterior synechiae each can contribute to obstruction of the iridocorneal angle resulting in acute glaucoma. Chronic uveitis can stimulate the growth of a fibrovascular membrane across the iris, pupil, and iridocorneal angle, which also can lead to secondary glaucoma. Other sequelae of chronic anterior uveitis are cataract formation and extension of inflammation to the retina. Permanent visual impairment is more likely to occur with chorioretinitis. Diffuse inflammation can cause  generalized retinal degeneration and blindness. Focal

NSAIDs, Nonsteroidal antiinflammatory drugs.

Mild inflammation requires topical antiinflammatory therapy every 8 to 12 hours and severe inflammation  may require treatment as frequently as every 1 to 2  hours. When topical administration is impossible, oral  or parenteral dosing may be necessary. If systemic infection is confirmed or suspected, immunosuppressive dosages of oral corticosteroids should be avoided, and antiinflammatory dosages should be used with caution. Topical drug administration is not adequate for chorioretinitis owing to the limited intraocular penetration of

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inflammation leads to focal areas of retinal degeneration with little effect on visual function. The likelihood of visual impairment as a consequence of uveitis depends on the severity and chronicity of the inflammation, which in turn depends on the cause, the rapidity with which the diagnosis is made, and the response to appropriate therapy.

References and Suggested Reading Brightman AH, Ogilvie GK, Tompkins M: Ocular disease in FeLVpositive cats: 11 cases (1981-1986), J Am Vet Med Assoc 198(6):1049, 1991. Davidson MG et al: Feline anterior uveitis: a study of 53 cases,  J Am Anim Hosp Assoc 27(1):77, 1991.

CHAPTER 

English RV et al: Intraocular disease associated with feline immunodeficiency virus infection in cats, J Am Vet Med Assoc 196(7):1116, 1990. Fontenelle JP et al: Prevalence of serum antibodies against Bartonella species in the serum of cats with or without uveitis, J Fel Med Surg 10:41, 2008. Giuilano EA: Nonsteroidal anti-inflammatory drugs in veterinary ophthalmology, Vet Clin North Am Small Anim Pract 34(3):707, 2004. Lappin MR, Black JC: Bartonella spp. infection as a possible cause of uveitis in a cat, J Am Vet Med Assoc 214(8):1205, 1999. Maggs D: Feline uveitis an “intraocular lymphadenopathy”, J Fel Med Surg 11:167, 2009. Powell CC, Lappin MR: Causes of feline uveitis, Compend Contin Educ Pract Vet 23(2):128, 2001.

251 

Canine Glaucoma JOHN S. SAPIENZA, Plainview, New York

G

laucoma is a common cause of blindness in dogs, with an incidence of 0.5% using the Veterinary Medical Data Base (VMDB). Glaucoma generally is characterized by the death of the retinal ganglionic cells leading to rapid loss of vision. The definition of glaucoma has evolved over the years to become more than simply elevated intraocular pressure (IOP). The retinal ganglionic cells, the cells that lead to the formation of the optic nerve, are exquisitely sensitive to changes in IOP, vascular abnormalities, and movement of the posterior scleral lamina cribrosa. The normal IOP in dogs can vary, but a general guideline for a normal range of IOP is between 15 and 25 mm Hg. Glaucoma usually is associated with an IOP much higher than these published numbers, and elevated IOP is a major risk factor for further optic nerve damage and subsequent blindness. The main goals of management for the general practitioner are to diagnose the presence of glaucoma accurately, to distinguish primary from secondary causes of glaucoma, and to assess the potential for return or maintenance of vision or relief of ocular pain. Acute glaucoma truly is an ophthalmic emergency. This chapter provides practicing veterinarians with a framework for understanding the causes, diagnosis, and treatment of glaucoma in the dog.

Causes and Pathogenesis Glaucoma can arise from both primary and secondary causes that are associated with increased IOP, which damages primarily the inner retina and the retinal ganglionic cells. Primary glaucoma has been observed in many breeds (Box 251-1) and is defined as an increase in

IOP in the absence of concurrent ocular disease. It demonstrates a strong genetic basis with bilateral ocular involvement. Both primary open-angle and primary angle-closure glaucoma are identified in dogs. Primary angle-closure glaucoma is eight times more common than primary open-angle glaucoma in dogs. There is also a more than twofold higher frequency of primary angleclosure glaucoma in female dogs than in males. Secondary glaucoma occurs two times more frequently than primary canine glaucoma and may be related to disorders of the lens (cataract, intumescence, lens rupture or trauma, lens-induced uveitis), uveitis (see Chapter 249), hyphema, intraocular neoplasia, iridociliary cysts, misdirection of the vitreous, chronic retinal detachments, intraocular pigment dispersion or melanosis, and trauma. A balance exists between aqueous humor production and aqueous outflow to maintain the normal shape and function of the eye. Aqueous humor is produced by the nonpigmented epithelium of the ciliary body through both active ionic transport and hydrostatic and colloidal diffusion of fluid. Carbonic anhydrase catalyzes the combination of carbon dioxide and water to form carbonic acid and is the key enzyme in the active production of aqueous humor. The IOP remains constant because of the equilibrium between aqueous production and aqueous outflow. This has importance for therapy because reduction in the production or increase in the outflow of aqueous humor can be accomplished medically with a number of oral and topical pharmaceuticals. Two outlets for drainage of the aqueous humor are available: the conventional outflow through the iridocorneal angle and the unconventional outflow through the uveoscleral route. After production at the ciliary body, the

CHAPTER  251  Canine Glaucoma

Clinical Signs and Diagnosis

BOX 251-1  Breeds Predisposed to Glaucoma Afghan hound Akita Alaskan malamute Bassett hound Beagle Border collie Boston terrier Bouvier des Flanders Cairn terrier Cardigan Welsh corgi Chihuahua Chinese shar-pei Chow-chow Cocker spaniel (English and American) Dachshund Dalmatian Dandie Dinmont terrier English springer spaniel Fox terrier (smooth haired) Giant schnauzer

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Great Dane Maltese Manchester terrier Miniature pinscher Norfolk terrier Norwegian elkhound Pembroke Welsh corgi Poodle Saluki Samoyed Scottish terrier Sealyham terrier Shih Tzu Shiba inu Siberian husky Skye terrier Welsh springer spaniel Welsh terrier West Highland white terrier Whippet Wire fox terrier

aqueous fluid migrates into the posterior chamber (between the iris and the anterior portion of the lens), through the pupil, and into the anterior chamber, with the vast majority of fluid leaving through the iridocorneal angle into the trabecular meshwork. The conventional outflow is pressure sensitive and comprises 85% of the aqueous outflow in dogs. The uveoscleral outflow allows aqueous to drain through the iris stroma, ciliary body, and choroid into the posterior venous circulation and is independent of the IOP. Glaucoma occurs because of an obstruction to the outflow of aqueous. Overproduction of aqueous humor by the ciliary body does not occur.

Clinical signs of glaucoma differ for acute and chronic glaucoma (Table 251-1). However, the IOP should be evaluated in all cases of a red eye with a dilated pupil. Commonly observed ocular signs of acute glaucoma in dogs include a red eye caused by episcleral injection, squinting, diffuse corneal edema, a fixed or dilated pupil, and loss of vision to complete blindness (Figure 251-1). Fundus evaluation may demonstrate a swollen or edematous optic nerve head with or without peripapillary retinal edema or separation. Clinical signs that may be observed in patients with chronic glaucoma include a red eye, corneal edema, corneal striae (caused by fractures in Descemet’s membrane), a normal to enlarged globe (the latter called buphthalmos), a midsized to dilated pupil, a subluxated to completely luxated lens, degeneration of the optic nerve head with or without cupping, and tapetal hyperreflectivity (Figures 251-2 and 251-3). The diagnosis of glaucoma usually is entertained based on the classic clinical signs (red eye, corneal edema, dilated pupil, loss of vision), breed predisposition (in cases of primary glaucoma), ophthalmoscopic findings, and measurement of IOP. Gonioscopic evaluation, highfrequency ocular ultrasonography, and occasionally advanced radiologic imaging may be useful in understanding the cause and differential diagnoses. Tonometry, the measurement of the IOP, can be performed with various tonometers such as by use of an indentation instrument (Schiøtz tonometer), by applanation (TonoPen), and by the rebound process (TonoVet) as discussed in Chapter 242. There should not be a difference of more than 2 to 4 mm Hg between the two eyes. Gonioscopy is a procedure usually performed by a veterinary ophthalmologist in which a special lens is used to view the iridocorneal angle to classify glaucoma based on the degree of angle opening (normal, narrowed, closed, and dysplastic). High-frequency ultrasonography (35 to 50 MHz) can be

TABLE 251-1  Clinical Signs Observed in Acute and Chronic Glaucoma in Dogs Structure or Feature

Acute Glaucoma

Chronic Glaucoma

Intraocular pressure

Usually elevated

Usually elevated May be low to normal (due to ciliary body atrophy)

Conjunctiva

Episcleral injection

Episcleral injection

Cornea

Edema

± Edema ± Descemet’s striae

Globe size

Normal

Normal to enlarged (buphthalmos)

Pupil size

Dilated

Midsized to dilated

Lens

Normal position

Normal, subluxated, luxated

Optic nerve

Normal or swollen optic nerve head

Atrophied and/or cupped

Retina

Normal or peripapillary retinal elevation/edema

Tapetal hyperreflectivity, retinal vessel attenuation, choroidal infarcts

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SECTION  XII  Ophthalmologic Diseases

used to evaluate the iridocorneal angle and ciliary cleft as well as the relationship between the iris and the anterior lens capsule. Fundus examination is extremely important to evaluate for optic nerve damage and retinal changes. Both direct and indirect ophthalmoscopy should be employed. The PanOptic Ophthalmoscope is highly recommended to the general practitioner because of its ease of use. This instrument allows thorough fundus evaluation, particularly for the examiner who is uncomfortable performing posterior segment evaluations. With this ophthalmoscope, the optic nerve and peripapillary region can be assessed readily for glaucomatous alterations.

Treatment The treatment goals depend on whether the glaucoma is primary or secondary, whether it is acute or chronic, and whether saving vision is an attainable goal. The optimal cases for referral to a veterinary ophthalmologist are those

Figure 251-1  Acute glaucoma in a 9-year-old basset hound

in which glaucoma has been diagnosed rapidly in the early stage of disease. If the IOP remains elevated for as few as 24 to 48 hours, irreversible blindness may ensue. As stated earlier, acute glaucoma is a true ophthalmic emergency and requires immediate attention from a veterinary ophthalmologist. The three main therapeutic goals are maintenance of vision, control of the IOP, and maintenance of the health of the retinal ganglionic cells. Additional therapeutic considerations in subacute glaucoma are the potential to preserve vision and relief of ocular pain when vision has already been lost. Once glaucoma is diagnosed, medical therapy is instituted to lower the IOP rapidly. This includes the use of hyperosmotic agents (mannitol or glycerol), oral and topical carbonic anhydrase inhibitors, topical miotic agents, β-blockers, and prostaglandin analogs as well as neuroprotective agents (Table 251-2). Often multiple medications are required.

Medical Treatment Hyperosmotic agents—namely, mannitol and glycerol— are used to decrease the IOP rapidly in an acute glaucoma crisis (Box 251-2). These agents work by dehydrating the vitreous and thus decrease the intraocular volume. Mannitol typically is dosed at 1 to 2 g/kg IV administered over 30 minutes. The patient must be fasted and water must be withheld for at least 3 hours after mannitol treatment. The IOP should be evaluated 1 hour after therapy, and if it still is elevated (and the low end of the dose range was used initially), an additional mannitol treatment can be administered at one-half the original dosage. Mannitol can remain effective for 6 to 10 hours but is not the sole therapy for acute glaucoma. Glycerol is not recommended for use in diabetic dogs because blood glucose level will increase and the insulin requirements will be altered. Osmotic diuretics also should be avoided in dehydrated

with an intraocular pressure of 45 mm Hg. Note the episcleral injection, diffuse corneal edema, and dilated pupil. (Courtesy Dr. Anne Gemensky Metzler.)

Figure 251-2  Chronic glaucoma in a 10-year-old cocker

spaniel. Note the buphthalmos, severe episcleral injection, diffuse corneal edema, dilated pupil, and posteriorly subluxated and cataractous lens in this blind eye. The mucoid discharge is secondary to corneal exposure and keratoconjunctivitis sicca. (Courtesy Dr. Anne Gemensky Metzler.)

Figure 251-3  Fundus of a canine eye demonstrating a cupped

and atrophic optic nerve secondary to chronic glaucoma. (Courtesy Dr. David Wilkie.)

CHAPTER  251  Canine Glaucoma patients as well as those with congestive heart failure, systemic hypertension, or significant renal disease. During mannitol administration adjunctive topical and oral medications should be started. In some patients with marked aqueous flare, the IOP may not be reduced effectively with hyperosmotic agents. Prostaglandin drugs such as latanoprost, travoprost, and bimatoprost have changed glaucoma therapy markedly for canine patients. These agents work by increasing the uveoscleral outflow and can significantly reduce the IOP in dogs. Prostaglandin analogs can be used in acute glaucoma therapy instead of mannitol and also for longterm maintenance in chronic glaucoma. Prostaglandin analogs cause a marked miosis in canine patients, which can eliminate the pupillary blockade in some acute cases and often results in rapid resolution of the glaucoma  with just one drop of drug. Prostaglandin agents are

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contraindicated in cases of anterior uveitis and anterior lens luxation. Clinically, prostaglandin agents can be used in conjunction with topical carbonic anhydrase inhibitors (CAIs) and also β-blockers but are not recommended for concurrent use with topical miotic drugs. A generic form of latanoprost is commercially available. Topical and oral CAIs decrease the production of aqueous humor. Topical dorzolamide and brinzolamide commonly are prescribed in small animal practice. Dorzolamide is well tolerated by most dogs. Brinzolamide has been shown to reduce IOP significantly in dogs with glaucoma. A dorzolamide-timolol combination also is commercially available, and the recommended twicedaily administration may improve client compliance. Oral and topical CAIs commonly are used for long-term management of chronic glaucoma. Methazolamide and acetazolamide are available commercially, but the latter

BOX 251-2  Medications Commonly Prescribed for Treatment of Acute and Chronic Glaucoma in Dogs Hyperosmotics (Mainly Used for Acute Glaucoma) Mannitol 20% solution 0.5-1.5 g/kg IV slowly Glycerol or glycerin 50% and 75% solutions 1-2 ml/kg q8h PO of a 40 mg/ml liquid emulsion

Miotics Pilocarpine 1-2% q6h Demecarium bromide 0.25% q12h (available from a compounding pharmacy)

Carbonic Anhydrase Inhibitors* Methazolamide (Neptazane) 2-3 mg/kg q8-12h PO Acetazolamide (Diamox) 4-8 mg/kg q8-12h PO (not generally recommended due to systemic adverse effects) Dorzolamide 2% (Trusopt) q8h topically Brinzolamide 1% (Azopt) q8h topically

β-Blockers* Timolol 0.5% (Timoptic) q12h Metipranolol 0.3% (OptiPranolol) q12h Betaxolol 0.5% (Betoptic) q12h

Prostaglandin Analogs Latanoprost 0.005% (Xalatan) q12-24h Bimatoprost 0.03% (Lumigan) q12-24h Travoprost 0.004% (Travatan) q12-24h

Neuroprotective Agents Amlodipine (Norvasc) 0.125-0.4 mg/kg/day PO

*Also suitable for prophylactic therapy in eye with normal intraocular pressure. IV, Intravenous; PO, orally.

TABLE 251-2  Medical Options for Treatment of Acute Glaucoma with and without Uveitis No Uveitis

Uveitis

Consider mannitol therapy (1-2 g/kg IV slowly) or 1 drop of a prostaglandin analog (e.g., latanoprost or travoprost).

Avoid topical prostaglandin analog and miotic agents. Attempt IV mannitol therapy. Start concurrent topical and oral CAIs.

Evaluate IOP in 30-60 min. If IOP < 35 mm Hg, continue medical therapy with topical and oral CAIs and prostaglandin ± β-blocker, sympathomimetic agent, and neuroprotective agent. Provide early referral to veterinary ophthalmologist. If IOP > 35 mm Hg, may repeat mannitol (see text). If IOP < 35 mm Hg, follow above recommendations. If IOP > 35 mm Hg, refer immediately to specialist.

Evaluate IOP in 30-60 min. If IOP < 35 mm Hg, continue medical therapy with topical corticosteroid and topical and oral CAIs ± prostaglandin, β-blocker, sympathomimetic agent, and neuroprotective agent. Provide early referral to veterinary ophthalmologist. If IOP > 35 mm Hg, may repeat mannitol (see text). If IOP < 35 mm Hg, follow above recommendations. If IOP > 35 mm Hg, refer immediately to specialist.

CAIs, Carbonic anhydrase inhibitors; IOP, intraocular pressure; IV, intravenous.

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is associated with more adverse effects and generally is not recommended for use in dogs. Dichlorphenamide is no longer available commercially but can be obtained from a compounding pharmacy. Adverse effects of CAIs caused by the systemic effects of the medications include polyuria and polydipsia, metabolic acidosis (with associated panting), vomiting, diarrhea, anorexia, rare blood dyscrasias, nephrolithiasis, and skin eruptions. Because potassium excretion is increased with the use of oral CAIs, supplementation with oral potassium is advised to avoid the potential sequelae of hypokalemia. Miotic agents such as pilocarpine and demecarium bromide cause constriction of the pupil and opening of the iridocorneal angle, which increases the outflow of aqueous humor through the trabecular meshwork. These drugs are used much less often today because of their adverse effects (stinging, exacerbation of uveitis), availability of newer, improved topical medications, and difficulty in obtaining some of these miotics. Pilocarpine and demecarium bromide are direct and indirect parasympathomimetic agents, respectively. The frequency of use is every 6 to 8 hours for pilocarpine and twice daily for demecarium bromide. These miotics should never be used in patients with secondary glaucoma associated with uveitis or an anterior lens luxation because they can exacerbate the uveitis and cause entrapment of an anteriorly luxated lens. Also, miotic agents are ineffective if the IOP is more than 50  mm Hg. In terms of prevention, demecarium bromide 0.25% has been shown to delay the onset of primary glaucoma significantly in predisposed eyes. β-Blockers such as timolol were long a mainstay in human ophthalmology but have been replaced by more effective topical medications. β-Blockers decrease the production of aqueous humor and can be added to other glaucoma medications in dogs, but their effectiveness as a sole agent is very limited. In contrast to the miotic agents, β-blockers do not cause breakdown of the bloodaqueous barrier. As noted earlier, combinations of timolol and the topical CAI dorzolamide are available. With regard to prevention of glaucoma in predisposed eyes, topical betaxolol 0.5% administered twice daily has been shown to lengthen the time to development of glaucoma. β-Blockers are absorbed systemically and therefore should be used with great caution in dogs with obstructive  pulmonary disease, heart failure, or cardiac conduction system disease such as sick sinus syndrome. Sympathomimetic agents reduce IOP by decreasing the production and increasing the outflow of aqueous humor. Many of the sympathomimetic drugs have been discontinued. An epinephrine prodrug called dipivefrin hydrochloride was available as Propine but now has been removed from the market. Compounding pharmacies still supply this medication. Dipivefrin is not a highly effective medication as a sole agent but may have an additive effect when combined with other drugs. Neuroprotective pharmaceuticals have been used to minimize optic nerve damage associated with glaucoma, but their usage is controversial. Drugs such as amlodipine (a calcium channel blocker) and memantine (an N-methyld-aspartate inhibitor) have been used empirically in treatment of canine glaucoma, but efficacy data are lacking.

The author uses amlodipine in all visual glaucoma cases at a dosage of 0.125 to 0.4 mg/kg/day PO. Blood pressure should be monitored. An important component of therapy in cases of primary glaucoma is prophylactic treatment of the contralateral eye, even if IOP in that eye is normal, because there is a strong likelihood that this eye also will develop glaucoma within a year’s time. Either a topical CAI such as dorzolamide or a β-blocker such as timolol is a suitable choice for prophylactic therapy and may be administered every 8 to 12 hours. Clients should be advised of the importance of prophylactic treatment and careful monitoring of the “good” eye to ensure the best chance for long-term retention of vision.

Intraocular Pressure Monitoring Once glaucoma has been diagnosed and a therapeutic regimen established, the IOP should be monitored every 1 to 3 months to ensure adequate control in the affected eye as well as to monitor for the onset of glaucoma in the contralateral eye (in cases of primary glaucoma). Ideally, IOP should not exceed 18 to 20 mm Hg when the patient is receiving prophylactic glaucoma medications. Clients should be well educated on the clinical signs of glaucoma (red eye plus blue eye plus dilated pupil with or without vision loss) and advised that the IOP should be measured immediately if a pressure spike is suspected. When the IOP is not controlled adequately with medical therapy, surgical options should be considered.

Surgical Options The exact surgical procedure chosen depends on the surgeon’s expertise, available equipment, and goals for the patient. The most important issue related to selection of surgical therapy is whether the salvage of vision or the relief of pain is the primary goal. Other considerations are the animal’s breed, age, underlying metabolic or cardiac disorders, and globe size as well as the client’s expectations and financial constraints. The surgical therapy for secondary glaucoma must target the underlying disease process. For example, if there is an anteriorly luxated lens in a visual eye, then an intracapsular lens extraction is advised. If intraocular neoplasia is present, enucleation and ocular biopsy is recommended after a thorough evaluation for metastatic disease. Surgery has significant limitations in terms of outcomes. One must be mindful that glaucoma arguably is the most difficult disorder for an ophthalmologist to treat. Treatment failures are more frequent than surgical successes. However, in an appropriately diagnosed and treated case of early glaucoma, retention of vision may be an attainable goal. A dedicated client and an early diagnosis are imperative for success. Visual Eyes For visual eyes (or for those with a hope of retaining vision), the ophthalmologist usually performs a ciliodestructive procedure (selective damage to the ciliary body) or a fistulizing procedure (creation of an alternative outflow pathway). Combination ciliodestructive and

CHAPTER  251  Canine Glaucoma alternative pathway procedures also are commonly advocated. Ciliodestructive procedures can entail the use of lasers, cryotherapy (freezing), diathermy (heat), and ultrasonic waves; laser and cryotherapy procedures most commonly are used. The laser treatment causes a decrease in aqueous production due to destruction of the pigmented cells of the ciliary body epithelium. Poorly pigmented animals (such as albinotic, subalbinotic, or blue iris patients) may respond in a less favorable fashion to laser cyclophotocoagulation than dogs with a brown iris. Previous reports of the use of diode transscleral cyclophotocoagulation demonstrated adequate IOP control in 92% of cases and an average decrease in IOP of 58% in treated eyes over a 12-month follow-up period (Hardman and Stanley, 2001). Vision was retained in 37% to 50% of the potentially visual eyes in previous reports. Complications noted with laser cycloablation include uveitis, hyphema, cataract formation, early posttreatment spikes of high IOP, recurrence of glaucoma, retinal detachment, corneal ulcer, and dyscoria. A combination technique using a glaucoma drainage implant (gonioimplant) and photocoagulation can provide immediate relief of IOP elevation in a recently laser-treated eye. Freezing the area of the ciliary body (cyclocryotherapy) with either liquid nitrogen or nitrous oxide also is associated with cyclodestruction. The cryotherapy procedure is said to be more painful than the laser procedure in people, but in experienced hands, cryotherapy has been reported to be successful in dogs. Cryotherapy may be more effective than laser procedures in poorly pigmented eyes. Complications associated with cyclocryotherapy include an immediate IOP elevation, cataract formation, retinal detachment, ocular pain, and recurrence of glaucoma. A relatively new procedure for cyclophotocoagulation in veterinary medicine is the diode endolaser, an  endoscopically guided laser that can cause selective destruction of the ciliary body. This endoscopic cyclophotocoagulation (ECP) procedure has been used in human medicine since 1992. Complete visualization and treatment of the intended target tissue of the ciliary processes are possible with the endolaser, which allows a more precise laser placement and lower energy usage with ECP compared with the blind transscleral laser approach. Collateral damage to the lens, iris, and retina thus can be avoided. Several veterinary ophthalmologists are combining this ECP procedure with lens removal (phacoemulsification of the normal lens or cataract) to allow better access to the ciliary sulcus and ciliary processes as well as to avoid future cataract formation if the lens is left in situ. There are no published data on the results of the ECP procedure, but preliminary findings appear promising. To minimize the postoperative IOP elevation associated with any laser treatment, prior or concurrent placement of a gonioimplant also has been advocated in cases of acute canine glaucoma with the hope of preserving vision. Results presented by Bras et al (2005) for 112 canine patients with primary glaucoma treated with ECP demonstrated control of IOP in 91% of cases and preservation of vision in 70% of cases. Lutz and Sapienza (2008) presented promising results in pseudophakic or aphakic dogs with secondary glaucoma, with control of IOP in 100% of cases at 2 months after ECP surgery and

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maintenance or recovery of vision in 67% of cases. At present ECP (with or without a gonioimplant procedure) is considered the new wave of therapy for primary glaucoma in dogs. Fistulizing procedures are surgeries that create an alternate pathway for aqueous outflow. Recently the use of gonioimplants or glaucoma shunts from the anterior chamber has gained popularity in small animal ophthalmology. Many types of glaucoma shunts are used, and these generally are placed in the anterior chamber to move aqueous humor to the subconjunctival space or frontal sinus. Suprachoroidal shunts, implants that direct the flow of aqueous humor into the supraciliary space (mimicking the uveoscleral outflow), also have been described, but their long-term success has not been demonstrated to date. Short-term complications with these gonioimplants include postoperative anterior uveitis, progression of glaucoma, and fibrin occlusion of the implanted anterior chamber tube. Long-term complications of glaucoma shunt placement include tube migration, fibrous capsule formation around the reservoir base, contact of the anterior chamber tube with the corneal endothelium, and recurrence of glaucoma. The author has described and advocated a combined procedure of cyclodestruction with a contact diode laser and placement of an Ahmed glaucoma valve into the anterior chamber. In a study in which 51 dogs with primary glaucoma were treated using the combined procedure of laser diode cyclophotocoagulation and Ahmed glaucoma implant placement, a return or maintenance of vision occurred in 82% of operated eyes in the immediate short term, and long-term IOP control was achieved in 76% of cases. At 1 year after surgery, 41% of the eyes were still visual (Sapienza and van der Woerdt, 2005). Paracentesis, or insertion of a needle into the anterior chamber to relieve pressure rapidly, is considered to be a poor technique as the sole therapy for primary glaucoma. The rapid decrease in IOP may induce a disastrous intraocular hemorrhage; in addition, there is the potential for intraocular damage to the iris or lens. Thus, as a primary way to treat glaucoma, paracentesis is never advised. Painful Blind Eyes For blind and painful eyes, salvage procedures are available to reduce the pain of a blind glaucomatous eye. The choice of procedure depends on a number of factors, including the size of the globe, the type of glaucoma (primary versus secondary), the presence of concurrent ocular diseases, cost, the dog’s age and ability to undergo general anesthesia safely, and surgical preference. Choices include evisceration with intrascleral prosthesis (ISP) implantation, enucleation, intravitreal chemical injection, laser treatment, and cryocycloablation. As a general rule, for irreversibly blind canine eyes with primary glaucoma, the author usually prefers to perform evisceration with implantation of an ISP. Tissues should be submitted for ocular histopathologic evaluation. ISP implantation is a procedure in which the intraocular contents are removed and a silicone sphere inserted through a scleral incision. The ISP procedure should be avoided in cases of severe corneal disease, intraocular infection (endophthalmitis), or neoplasia. ISP surgery is relatively

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SECTION  XII  Ophthalmologic Diseases

BOX 251-3  Available Surgical Options for Visual and Blind Eyes in Dogs Surgical Options for a Visual Eye Laser cyclophotocoagulation Cyclocryotherapy Endoscopic cyclophotocoagulation (with or without lens removal) Gonioimplant placement Frontal glaucoma shunt placement Combination of laser therapy or cyclocryotherapy plus glaucoma shunt placement

Figure 251-4  Cosmetic postoperative appearance of an intrascleral silicone prosthesis placed in a 6-year-old Maltese with blinding glaucoma. Note the subtle wrinkling of the corneal endothelium. (Courtesy Dr. Anne Gemensky Metzler.)

rapid and typically associated with few complications. Bilateral ISP surgery can be performed in dogs that have lost vision in both eyes because of chronic glaucoma. In most cases a very cosmetic result is achieved with a gray to black color of the eye (Figure 251-4). Possible complications associated with ISP surgery include corneal ulcer formation due to poor blinking ability, extrusion of  the implant, infection, placement of an inadequately sized implant, development of keratoconjunctivitis sicca, unrecognized intraocular neoplasia, and inadequate evisceration of the intraocular contents. Enucleation, or eye removal, is a technique preferred by many ophthalmologists in glaucoma cases. Ocular pain is relieved, and tissue is readily available for histopathologic analysis. Many owners, however, may be resistant to the idea of a one-eyed pet. Postoperative bleeding, cyst formation (due to inadequate removal of any epithelial or glandular tissue), and a sunken orbital pocket are potential complications associated with enucleation. Intraocular injections of a toxic chemical to destroy the ciliary body also can be performed in a blind eye. Injections of gentamicin (or, less commonly, cidofovir) are used. The advantage of this technique is that the procedure is rapid, can be performed under sedation or deep topical or peribulbar anesthesia, and results in effective destruction of the ciliary body. The eye must be blinded already before this procedure is performed because this toxic intraocular injection will surely result in blindness due to retinal toxicity. The disadvantages of gentamicin injections are the relatively uncertain cosmesis of the globe, frequent development of a shrunken globe (phthisis bulbi), potential recurrence of glaucoma, and possibility of injection into an eye with an undiagnosed intraocular tumor.

Surgical Options for a Blind Eye in a Dog with   Chronic Glaucoma Evisceration with placement of an intrascleral prosthesis Enucleation Laser therapy (transscleral or endoscopic) Cryotherapy Intravitreal gentamicin or cidofovir injection

Thus the choices for glaucoma therapy are numerous and are determined by the treatment goals, the equipment available, the surgeon’s training, and surgeon and owner preferences (Box 251-3).

References and Suggested Reading Bras TD et al: Diode endolaser cyclophotocoagulation in canine and feline glaucoma, Vet Ophthalmol 8(6):449, 2005. Cook CS et al: Diode laser transscleral cyclophotocoagulation for the treatment of glaucoma in dogs: results of six and twelve month follow-up, Vet Comp Ophthalmol 7:148, 1997. Cullen CL: Cullen frontal sinus valved glaucoma shunt: preliminary findings in dogs with primary glaucoma, Vet Ophthalmol 7:311, 2004. Gelatt KN, Brooks DE, Källberg ME: The canine glaucomas. In Gelatt KN, editor: Veterinary ophthalmology, ed 4, Ames, IA, 2007, Blackwell Publishing, p 753. Hardman C, Stanley RG: Diode laser transscleral cyclophotocoagulation for the treatment of primary glaucoma in 18 dogs: a retrospective study, Vet Ophthalmol 4:209, 2001. Johnsen DA, Maggs DJ, Kass PH: Evaluation of risk factors for development of secondary glaucoma in dogs: 156 cases (19992004), J Am Vet Med Assoc 229:1270, 2006. Lutz EL, Sapienza JS: Diode endoscopic cyclophotocoagulation in pseudophakic and aphakic dogs with secondary glaucoma, Vet Ophthalmol 11(6):423, 2008. Reinstein SL, Rankin AJ, Allbaugh R: Canine glaucoma: medical and surgical options, Compend Contin Educ Vet 31:454, 2009. Sapienza JS, van der Woerdt A: Combined transscleral diode laser cyclophotocoagulation and Ahmed gonioimplantation in dogs with primary glaucoma: 51 cases (1996-2004), Vet Ophthalmol 8:121, 2005. Westermeyer HD, Hendrix DV, Ward DA: Long-term evaluation of Ahmed gonioimplants in dogs with primary glaucoma: nine cases (2000-2008), J Am Vet Med Assoc 238:610, 2011.

CHAPTER 

252 

Feline Glaucoma AMY J. RANKIN, Manhattan, Kansas

G

laucoma is one of the most frustrating conditions to treat in veterinary ophthalmology. In most cases, despite intensive therapy, the disease process continues and eventually leads to loss of vision. Glaucoma is a group of diseases that have an abnormally elevated intraocular pressure (IOP) as a common feature. The elevated IOP may cause irreversible damage to the retina and optic nerve and lead to blindness. Clinical symptoms in cats often are subtle, and many cats are not brought for treatment until late in the course of the disease when the eye is already permanently blind. The normal IOP range in cats has been reported to be between 15 and 25 mm Hg (mean, ~20 mm Hg). IOP is generated by aqueous humor production and outflow, which normally are in equilibrium. The elevated IOP in glaucoma is due to reduced outflow of aqueous humor rather than overproduction of aqueous humor. Glaucoma can be categorized as congenital, primary, or secondary. Congenital glaucoma is very uncommon in cats. It is due to abnormalities in the aqueous humor outflow pathway and generally occurs in very young patients (20%, calculated as standard deviation/mean). The Tono-Pen is very accurate in the normal range of IOPs but tends to overestimate IOP in the low range and underestimate IOP in the high range. Ideally readings with a coefficient of variation of 5% or less should be recorded as the IOP for that patient. The TonoVet measures the rebound action of a magnetic probe as it contacts the corneal surface and bounces back. One of the advantages of the TonoVet tonometer is that it does not require the use of a topical anesthetic. The instrument should be held upright while taking measurements. The mean IOP reading obtained with the rebound tonometer (TonoVet) has been found to be 2 to 3 mm Hg higher than that measured with the applanation tonometer (Tono-Pen VET) in cats. Although a difference of 2 to 3 mm Hg is not clinically significant, it highlights the importance of using the same tonometer for follow-up examinations in the same patient. IOP can be elevated artificially in cats without any ophthalmic abnormalities, which indicates that a single abnormal IOP measurement in the absence of other ophthalmic abnormalities may be insufficient for a diagnosis of glaucoma in cats. Artificially high IOP readings can occur in fractious or nervous cats. Excessive pressure on the globe, eyelids, or neck also can increase IOP readings artificially. Cats that have IOP readings of 25 mm Hg or more or a difference in IOP between the two eyes of 12 mm Hg or more but that do not show any ophthalmic abnormalities or changes in the optic nerve head may have a falsely high IOP. Tonometry should be repeated in these cats within a few weeks, and if the elevation in  IOP persists, referral to an ophthalmologist for a more

CHAPTER  252  Feline Glaucoma thorough examination may be warranted before antiglaucoma therapy is initiated. Because secondary glaucoma is much more common than primary glaucoma it is important to diagnose the cause of glaucoma (e.g., uveitis or neoplasia) and address the underlying issue. In cases of uveitis, topical antiinflammatory therapy and specific antimicrobial agents when an infectious cause has been identified are recommended (see Chapter 250). Antiglaucoma medications can be used at the same time as topical antiinflammatories. In cases of intraocular neoplasia, enucleation and histopathologic examination of the eye is recommended. If an intraocular tumor is suspected, thoracic and abdominal radiography and abdominal ultrasonography should be discussed with the owner before surgery is undertaken to remove the eye. The goals of glaucoma therapy are to preserve vision and alleviate discomfort. The therapeutic plan depends on the cause of the glaucoma and the patient’s visual status.

Medical Treatment Hyperosmotic Agents The administration of hyperosmotic agents is indicated only in the treatment of acute glaucoma. Since the majority of cats have chronic glaucoma these medications very rarely are indicated. Mannitol can be administered over a 20- to 30-minute period at a dosage of 1 g/kg IV. Water or fluids should be withheld for 4 hours and then slowly reintroduced. Mannitol should not be administered to cats with heart failure, known cardiomyopathy, or renal impairment.

Carbonic Anhydrase Inhibitors Systemic and topical carbonic anhydrase inhibitors (CAIs) are available. CAIs work by decreasing the production of aqueous humor. The administration of oral CAIs can be associated with anorexia, gastrointestinal disturbances, increased respiratory rate secondary to metabolic acidosis, hypokalemia, blood dyscrasias, and neurologic abnormalities. Cats appear to be more susceptible to the adverse effects of oral CAIs than other species, and oral CAIs should not be used in cats. Because of the adverse effects associated with systemic CAIs topical formulations have been developed. The topical ophthalmic CAIs currently available commercially are dorzolamide hydrochloride 2% solution (Trusopt and generic) and brinzolamide 1% suspension (Azopt). Experimental evaluation of the use of dorzolamide 2% in normal cats showed a significant decrease in IOP compared with pretreatment values (Rainbow and Dziezyc, 2003; Dietrich et al, 2007; Rankin et al, 2011); however, the magnitude of effect of dorzolamide on IOP in normotensive cats may not be an accurate representation of the effect of this medication in cats with glaucoma. Dogs with glaucoma typically have a greater decrease in IOP than normotensive dogs when treated with topical and systemic CAIs. Cats with glaucoma are likely to have a

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more dramatic response to topical CAIs than normal cats, so the practitioner should not be dissuaded from the use of this important class of medications. A recent study demonstrated a dramatic decrease in IOP in cats with primary congenital glaucoma that were treated three times daily with topical dorzolamide 2% solution (Sigle et al, 2011). The most common adverse effect with the use of topical CAIs is irritation after instillation, which is more common with dorzolamide than with brinzolamide. A solution of dorzolamide 2% and timolol 0.5% is commercially available but does not appear to lower IOP more than dorzolamide alone three times daily in cats. Also, because of the possible absorption of the medication and the small body size of cats, a β-blocker should be used with caution. Topical carbonic anhydrase inhibitors should be administered every 8 to 12 hours.

β-Blockers Betaxolol is a selective β1-antagonist and timolol is a nonselective β-antagonist. Both of these medications are available in 0.25% and 0.5% ophthalmic solutions. Topical administration of timolol 0.5% to normotensive cats causes a significant (22%) decrease in IOP. A significant miosis also is observed. After topical application of an ophthalmic medication, a portion of the medication is absorbed systemically through the conjunctiva or  the nasal or oral mucosa after the medication passes through the nasolacrimal system. Although serum levels of drugs that are applied topically to the eye generally are low, there can be systemic side effects. β-Blockers may cause undesirable cardiac effects, including bradycardia, syncope, or reduced myocardial contractility. In addition to adverse cardiac effects, blockade of β2-receptors by nonselective β-blockers could theoretically lead to respiratory complications, and these drugs should not be used in cats with a history of asthma. Because of the small body size of cats, topical β-blockers should be used with caution in cats, and the 0.25% ophthalmic solution should be administered every 12 to 24 hours.

α-Agonists Apraclonidine is an α2-agonist. Although it causes a significant decrease in IOP in normotensive cats, it should not be used because of the severe adverse effects associated with its administration, including decreased heart rate and vomiting.

Cholinergic Agents Topical pilocarpine 2%, a direct-acting parasympathomimetic agent, has been reported to decrease IOP in normotensive cats. Parasympathomimetic medications are contraindicated in cases of uveitis because they may increase the permeability of the blood-aqueous barrier. Pilocarpine may be very irritating topically and also has the potential for serious systemic adverse effects, and should not be used in cats to treat glaucoma. Demecarium bromide is an indirect-acting parasympathomimetic that is available from compounding pharmacies in 0.125% and 0.25% solutions. Topically applied demecarium

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bromide can reach systemic concentrations high enough to result in toxicosis (diarrhea, salivation, and vomiting) and also should be avoided in cats.

Prostaglandin Analogs Prostaglandin analogs are the newest antiglaucoma medications available. They are believed to lower IOP primarily by increasing uveoscleral outflow of aqueous humor via their action on iris and ciliary body musculature.  In addition, there is evidence to suggest that prostaglandin analogs also have an effect on the conventional outflow pathway and decrease the production of aqueous humor. Topical application of prostaglandins decreases IOP in cats, but unfortunately the commercially available prostaglandin analogs, including latanoprost, bimatoprost, and unoprostone, do not consistently reduce IOP in cats. Although these medications cause significant miosis, they do not consistently decrease IOP and therefore are not recommended for the treatment of feline glaucoma.

Surgical Treatment If medical therapy can no longer control the IOP, surgery may be indicated. In visual eyes, cyclocryotherapy and cyclophotocoagulation are options to decrease the production of aqueous humor. Cyclocryotherapy uses either nitrous oxide or liquid nitrogen applied to the sclera to cause cryonecrosis of the ciliary body. Complications associated with cyclocryotherapy include inflammation inside the eye, retinal detachment, and cataract formation. Cyclophotocoagulation is destruction of the ciliary body using either a diode or neodymium:yttriumaluminum-garnet (Nd:YAG) laser and generally is considered to be associated with fewer complications than cyclocryotherapy. The laser energy can be delivered to the eye either through the sclera (transscleral cyclophotocoagulation) or through an intraocular endolaser that applies the laser energy directly to the ciliary body. Complications include postoperative increases in IOP, corneal ulcers, cataract, hyphema, and retinal detachment.

Endoscopic cyclophotocoagulation offers a fairly high rate of success in IOP control and vision preservation. In permanently blind eyes with glaucoma, a palliative surgical procedure is recommended to alleviate pain. In general, discomfort is not associated with an IOP of less than 25 mm Hg. Enucleation is recommended for painful blind eyes. If an intraocular tumor or uveitis is suspected, the globe should be submitted to a veterinary pathologist for histopathologic evaluation. Placement of an orbital prosthesis is not recommended in cats because of the high complication rate (40%) seen in this species. Evisceration and placement of an intraocular prosthesis is another option for cats that do not have an intraocular tumor or intraocular infection, but cats are more likely than dogs to have complications associated with the prosthesis. Chemical ablation of the ciliary body epithelium with an intravitreal injection of gentamicin is not recommended in cats because of the potential for inducing an intraocular sarcoma.

References and Suggested Reading Czederpiltz JMC et al: Putative aqueous humor misdirection syndrome as a cause of glaucoma in cats: 32 cases (1997-2003),  J Am Vet Med Assoc 227(9):1434, 2005. Dietrich UM et al: Effects of topical 2% dorzolamide hydrochloride alone and in combination with 0.5% timolol maleate on intraocular pressure in normal feline eyes, Vet Ophthalmol 10(Suppl 1):95, 2007. Peiffer R, Wilcock B: Histopathologic study of uveitis in cats: 139 cases, J Am Vet Med Assoc 198:135, 1991. Powell CC, Lappin MR: Causes of feline uveitis, Comp Contin Ed Pract Vet 23(2):128, 2001a. Powell CC, Lappin MR: Diagnosis and treatment of feline uveitis, Comp Contin Ed Pract Vet 23(3):258, 2001b. Rainbow M, Dziezyc J: Effects of twice daily application of 2% dorzolamide on intraocular pressure in normal cats, Vet Ophthalmol 6:147, 2003. Rankin A, Crumley W, Allbaugh R: Effects of ocular administration of ophthalmic 2% dorzolamide hydrochloride solution on aqueous humor flow rate and intraocular pressure in clinically normal cats, Am J Vet Res 73:1074, 2011. Sigle K et al: The effect of dorzolamide 2% on circadian intraocular pressure in cats with primary congenital glaucoma, Vet Ophthalmol 14:48, 2011.

CHAPTER 

253 

Disorders of the Lens DAVID A. WILKIE, Columbus, Ohio

T

he crystalline lens is an avascular, transparent, biconvex structure that serves, along with the cornea, to refract and focus an image on the retina. During embryogenesis, lens development is supported anteriorly by the pupillary membrane vasculature and posteriorly by the hyaloid vasculature. Abnormalities of these vascular structures may be associated with congenital lens malformations or cataracts. The lens is supported by zonular fibers that originate at the ciliary body and insert at the lens equator. The zonules facilitate accommodation, which is controlled by the musculature of the ciliary body. Loss of zonular attachment results in lens instability and lens luxation. The lens is divided into nuclear, cortical, and capsular regions. The lens nucleus is located centrally and is formed during embryogenesis. Abnormalities of the nucleus typically are congenital, but not all congenital lens abnormalities involve the nucleus. The lens cortex surrounds the nucleus and can be divided into anterior, posterior, and equatorial regions. The lens epithelial cells are located just under the anterior lens capsule. The epithelial cells undergo migration and replication and, at the lens equator, elongate anteriorly and posteriorly to form new lens cortical fibers, are displaced centrally, and join other lens fibers anteriorly and posteriorly at the regions known as the lens sutures. It is the regular arrangement of lens fibers that allows transparency. Changes in lens fiber arrangement or composition result in an opacity, termed a cataract. Insults to the lens epithelium may result in cell death, posterior cell migration, or epithelialmesenchymal cell transformation, all of which contribute to cataractogenesis. New lens fibers are added throughout life, but the lens is restricted in the size to which it can grow. As a result, rather than increase in size, the lens increases in density and the central lens becomes compressed. This results in lenticular sclerosis, a zone of change in transparency between the central and peripheral lens. Clinically this becomes apparent at the age of 6 years in most dogs and cats and increases with age (Figure 253-1). The lens is surrounded by a capsule comprised of the basement membrane of the lens epithelial cells. The anterior lens capsule (50 to 75 µm) is thicker than the posterior capsule (5 µm). The capsule is a semipermeable membrane allowing nutritional substances and metabolic waste materials to pass while serving to isolate the antigenic lens protein. In hypermature cataracts, lens proteins can break down, leak across the capsule, and result in lens-induced uveitis. With traumatic or spontaneous rupture of the lens capsule, lens proteins enter the

anterior chamber in large quantity, resulting in phacoclastic uveitis. As an avascular structure, the lens relies on the aqueous humor for nutrition and waste removal. Abnormalities of the aqueous humor, as seen in uveitis, may alter lens metabolism and result in cataract formation. Abnormalities or changes of the lens include lenticular sclerosis, congenital malformations, cataract, lens instability, and trauma to the lens and its capsule.

Congenital Lens Anomalies Congenital abnormalities of the lens may be solitary or part of multiple ocular anomalies and include variations in lens shape, size, location, or transparency. They may be inherited or result from toxic, infectious, nutritional, or other insults during embryogenesis. The most common congenital lenticular abnormalities are microphakia, lens coloboma, spherophakia, posterior lenticonus, cataract, and ectopia lentis. These may be associated with microphthalmia, persistent pupillary membranes, persistent hyaloid, persistent tunica vasculosa lentis, anterior segment dysgenesis, retinal dysplasia, retinal detachment, or other ocular malformations. When a congenital ocular abnormality is present, a complete dilated ophthalmic examination of both eyes should be performed. If no obvious cause is apparent, the abnormality should be presumed to be inherited, and affected animals should not be used for breeding. In addition, parents and littermates should be examined whenever possible. Follow-up examination of affected animals should be performed to monitor for progression of cataract or glaucoma. When significant cataracts are present, surgical removal may be an option, but placement of an intraocular lens may be difficult or impossible in cases of microphakic lenses or microphthalmic eyes. Additionally, these eyes are at increased risk of postoperative glaucoma and retinal detachment compared with the eyes of routine cataract patients.

Cataract A cataract is defined as an opacity of the lens or its capsule regardless of size. Cataracts are classified by age of onset, location, severity, and cause (Table 253-1). Cataracts may be congenital (present at birth), juvenile (appearing at 6 years of age). Cataract locations are described as nuclear, cortical (anterior, posterior, equatorial), capsular, and axial versus peripheral. With respect 1181

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SECTION  XII  Ophthalmologic Diseases

TABLE 253-1  Classification of Cataracts Age of onset

Congenital (present at birth) Developmental Juvenile (6 yr)

Severity

Incipient Immature Mature Hypermature Morgagnian

Cause

Inherited Associated with other congenital ocular abnormalities Metabolic disease—diabetes mellitus Trauma Retinal degeneration Inflammatory disease—uveitis Toxins or drugs Radiation Electric shock

Location

Figure 253-2  Incipient axial posterior cortical cataract involving the posterior suture in a 2-year-old Labrador retriever.

Capsular—anterior, posterior Cortical—anterior, posterior, equatorial Nuclear Equatorial vs. axial

Figure 253-3  Immature cataract involving the posterior, ante-

rior, and equatorial cortex in a 2-year-old golden retriever. The equatorial involvement shows cortical vacuoles suggestive of more recent and rapid cataract progression.

Figure 253-1  Lenticular sclerosis (arrows) of the axial lens in an 11-year-old Labrador retriever.

to severity and the amount of lens affected by a cataract, the terms used are incipient (does not affect vision significantly; Figure 253-2), immature (interferes with vision but does not completely prevent it; Figure 253-3), mature (obscures an image entirely; Figure 253-4), and hypermature (liquefactive degeneration of the lens proteins has occurred). Liquefaction of lens protein results in lensinduced uveitis that may lead to globe hypotony, iris hyperpigmentation, aqueous flare, miosis, synechia, keratic precipitates, lens instability, secondary glaucoma, vitreous degeneration, or retinal detachment (Figure 2535). Hypermature cataracts are characterized clinically by irregularity of the lens surface, a deeper anterior chamber,

Figure 253-4  Mature intumescent (swollen) cataract with suture clefting (arrows) secondary to diabetes mellitus.

CHAPTER  253  Disorders of the Lens

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Figure 253-7  Spontaneous lens capsule rupture secondary to Figure 253-5  Hypermature cataract with secondary lens-

induced uveitis. The uveitis has resulted in posterior synechia, dyscoria, and keratitic precipitates.

Figure 253-6  Hypermature morgagnian cataract. Because the majority of the cataractous lens cortex has been resorbed, the remaining lens nucleus has settled ventrally in the capsular bag.

capsule wrinkling, and mineralization. Hypermature cataracts occasionally may undergo substantial or complete resorption in which the cortex liquefies and the nucleus shifts and are then termed morgagnian cataracts (Figure 253-6). In some of these cases, the patient may regain vision as the cataract resorbs, although retinal detachment often occurs during rapid resorption. Most canine cataracts are inherited or caused by diabetes mellitus. Inherited cataracts are seen in most breeds of dogs and in mixed-breed dogs. Inherited cataracts may be congenital or acquired and vary by breed in age of onset, location, severity, and progression. Affected animals should not be used for breeding regardless of the severity of the cataract. Metabolic causes of cataracts include diabetes mellitus and, less commonly, hypocalcemia. In dogs affected with diabetes mellitus, 50% will develop cataracts within 170 days of diagnosis of diabetes and 80%

diabetes mellitus. The lens capsule has ruptured equatorially with retraction of the anterior lens capsule (arrow) and exposure of the lens cortex.

will have cataracts by 470 days. Diabetic cataracts begin with vacuoles or “bubbles” in the equator of the lens that progress, often rapidly, to swelling and rupture of lens fibers with subsequent complete opacification and clefting of the lens fibers at the suture junctions due to fluid accumulation (see Figure 253-4). Diabetic cataracts result when the enzyme aldose reductase catalyzes the reduction of glucose to sorbitol. The intracellular accumulation of sorbitol in the lens leads to an osmotic shift and swelling and disruption of lens fibers. Due to rapid and dramatic swelling of the lens, subsequent spontaneous lens capsule rupture has been described in dogs with diabetes mellitus as well as in nondiabetic dogs with rapidly progressive cataracts (Figure 253-7). Spontaneous lens capsule rupture is both a medical and a surgical emergency, with phacoclastic uveitis expected within days of the rupture. Additional causes of cataracts in dogs include trauma, uveitis, retinal degeneration, nutritional deficiencies, electrical shock, and radiation. Feline cataracts most commonly occur secondary to anterior uveitis. Inherited cataracts have been described in cats, but cataracts secondary to diabetes are not typically seen in the cat. The treatment of cataracts depends on the impact of the lesion on vision, the overall health and age of the patient, the presence of concurrent ocular abnormalities, and the owner’s wishes and financial status. Cataracts that are incipient should be monitored for progression and generally do not require any additional treatment. Cataracts that are progressive, immature, mature, or hypermature should be considered as potential surgical candidates. With the introduction of intraocular lens implants, cataract surgery also can be offered in cases of unilateral cataract to restore binocular emmetropia. There is no medical treatment for cataracts that has any clinical benefit for vision restoration. Veterinarians and dog owners should not fall prey to the various holistic and dietary supplemental treatments sold to “cure” cataracts. Although proper nutrition may play a role in cataract prevention, once a cataract has occurred, the change in

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SECTION  XII  Ophthalmologic Diseases

lens protein is irreversible. Hypermature cataracts are associated with an increased risk not only of lens-induced uveitis but also of secondary glaucoma, retinal detachment, lens capsular wrinkling and opacification, and lens instability. Therefore careful monitoring and prompt referral of patients with cataracts are imperative to ensure the best postoperative results and prognosis. For patients unable to be referred, the veterinarian should consider long-term monitoring for glaucoma and uveitis and use of a topical antiinflammatory drug to decrease secondary complications.

Lens-Induced Uveitis Lens-induced or phacolytic uveitis (LIU) commonly is seen in dogs with cataracts, with one study suggesting a prevalence as high as 71% (Paulsen et al, 1985). It has been suggested that all stages of cataract are accompanied by some degree of LIU. Clinical signs of LIU include low intraocular pressure, conjunctival hyperemia and episcleral injection, aqueous flare, iris hyperpigmentation, ectropion uveae, keratic precipitates, delayed or incomplete pharmacologic mydriasis, and synechia. Although early retrospective studies suggested that preexisting LIU significantly reduced the long-term success of cataract surgery, this does not appear to be as significant with current surgical techniques. However, prompt recognition and treatment of LIU is imperative to ensure the best long-term prognosis for vision and ocular health. In general, pretreatment with topical or systemic antiinflammatory therapy (Table 253-2) for a period of a few days to weeks followed by phacoemulsification is the most appropriate means to manage LIU and avoid long-term sequelae. The consequences of uncontrolled LIU include secondary glaucoma, synechia, corneal edema, retinal detachment, lens luxation, vitreous degeneration, and phthisis bulbi.

TABLE 253-2  Antiinflammatory Treatment Options for LensInduced Uveitis before Cataract Surgery Route of Administration

Drug Class

Drug and Dosage

Topical

Corticosteroid

Prednisolone acetate 1% q6-12h Dexamethasone 0.1% q6-12h Diclofenac 0.1% q6-12h Ketorolac 0.4% q6-12h Flurbiprofen 0.03% q6-12h Nepafenac 0.1% q12h Atropine 1% q12-24h

NSAIDs

Mydriatic Oral

Corticosteroid NSAIDs

Prednisone 0.5 mg/kg q12h PO Carprofen 2.2 mg/kg   q12h PO Meloxicam 0.2 mg/kg once PO, then 0.1 mg/kg   q24h PO

NSAIDs, Nonsteroidal antiinflammatory drugs; PO, orally.

Cataract Surgery Cataract surgery has changed dramatically in recent  years with regard to surgical technique, ocular pharmacology, and the availability of antiinflammatory agents, viscoelastic agents, and phacoemulsification; the most recent advancement is intraocular lens (IOL) implantation for dogs and cats. Despite these dramatic changes, cataract surgery remains a procedure for which a  successful outcome depends on meticulous attention to detail, surgeon skill and experience, appropriate patient selection, and diligent postoperative treatment and monitoring. Cataract surgery is considered to be an elective procedure since many animals adapt well to vision loss. It must be remembered, however, that if the owner elects not to perform cataract surgery, the patient still must be monitored long term for lens-induced complications such as LIU, secondary glaucoma, retinal detachment, and lens luxation. Younger animals with cataracts that do not undergo surgery may experience spontaneous resorption of the cataract and regain aphakic vision if the retina does not detach during resorption. In a study of 44 dogs with cataracts, eyes that received no medical or surgical treatment had a much greater risk of a poor outcome such as chronic ocular pain, secondary glaucoma, lens luxation, or enucleation or globe evisceration compared with eyes that were treated with antiinflammatory agents and those in which phacoemulsification was performed (Lim et al, 2011). Surgical outcome was better for immature cataracts than for mature and hypermature cataracts. Recent studies have suggested that dogs with significant cataracts that remain unoperated have a 20% risk of developing glaucoma in at least one eye, whereas the glaucoma risk following cataract surgery is 7% to 9% (Gelatt and MacKay, 2004). The conclusions are that early surgical intervention is associated with the highest success rate and that animals that do not undergo phacoemulsification should be managed with a topical antiinflammatory medication and monitored for the development of secondary glaucoma. If surgery is not performed, topical nonsteroidal antiinflammatories or a topical corticosteroid should be administered every 12 to 24 hours for life (or until the cataract has completely resorbed), and an ophthalmic examination should be performed every 6 to 9 months. Before cataract surgery is undertaken a complete ophthalmic examination is required (see Chapter 242). In addition, ocular ultrasonography and electroretinography are performed to ensure that there are no abnormalities of the posterior segment, including vitreous degeneration, retinal detachment, or retinal degeneration. If LIU is present, it should be treated and controlled before surgery. The intraocular pressure should be measured to rule out early secondary glaucoma. A complete physical examination as well as a complete blood count, serum chemistry panel, and urinalysis are indicated to ensure that the animal is healthy enough to undergo general anesthesia. Cataract surgery requires extensive equipment and training to become proficient and is considered a referral procedure. Clients with affected animals who are

CHAPTER  253  Disorders of the Lens considering surgery should be referred early in the disease course to allow the veterinary ophthalmologist to visualize the posterior segment before the cataract becomes mature. Early surgical intervention before the cataract becomes hypermature and LIU begins results in a more favorable outcome. Rapidly progressive cataracts in dogs with diabetes mellitus can be considered somewhat of an emergency, and such patients should be referred promptly because these cataracts can result in severe LIU and spontaneous lens capsule rupture. The success rate of cataract surgery in restoring longterm vision when performed using phacoemulsification and IOL implantation generally is considered to be 85% to 90%. Certain breeds of dogs are at increased risk of specific postoperative complications. Specifically, these complications include retinal detachment in the bichon frise and Shih Tzu, postoperative intraocular hypertension and glaucoma in the Labrador retriever and Boston terrier, and glaucoma in those breeds with a risk of primary glaucoma such as the American cocker spaniel and miniature poodle. The current accepted standard of care for cataract surgery in small animals is phacoemulsification and IOL implantation. Phacoemulsification is carried out under general anesthesia and is performed through a small incision with minimal tissue trauma and restoration of emmetropia through implantation of an IOL specifically designed for the canine or feline eye (Figure 253-8). Without placement of an IOL, the eye is left 14 diopters hyperopic (far-sighted), and vision is significantly abnormal. Before surgery, topical mydriatics and topical and systemic antiinflammatories and antibiotics are used according to surgeon preference. If cataracts are bilateral, most surgeons choose to operate on both eyes during a single procedure. This minimizes cost, requires only one anesthesia induction, simplifies the postoperative management, and avoids leaving a cataract that may result in LIU and its associated complications. Exercise restriction and use of an Elizabethan collar are required for the first 10 to 14 days following surgery.

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Topical and systemic antiinflammatories and antibiotics are prescribed according to surgeon preference. Medications are gradually tapered and may be discontinued, and the period between follow-up examinations is extended. After the immediate postoperative period of 4 to 6 months, it generally is recommended that annual or semiannual ophthalmic examinations be performed by a veterinary ophthalmologist. These examinations are to monitor for uveitis, retinal detachment, secondary glaucoma, keratoconjunctivitis sicca, and other complications that may affect the long-term success of cataract surgery. Early diagnosis of these complications, should they occur, can result in successful medical or surgical management and vision preservation. Postoperative medications are adjusted on an individual animal basis, but some animals require some level of lifelong topical antiinflammatory therapy. This is especially true for dogs with diabetes mellitus. The most common long-term complication of cataract surgery and IOL implantation in veterinary ophthalmology is posterior capsule opacification. Currently this occurs with varying severity in 100% of canine and feline patients. It results when residual lens epithelial cells undergo epithelial-mesenchymal transformation, migrate, and proliferate on the anterior and posterior lens capsule. It is more severe in young animals and may occur even before cataract surgery in cases of hypermature cataracts. Fortunately, it is rarely of clinical significance with respect to the animal’s ability to navigate and function normally following surgery. Methods to limit or decrease posterior capsule opacification through IOL design, surgical technique, and pharmacologic intervention are currently under investigation. When seeing a cataract patient after surgery, the primary care veterinarian should include evaluation of menace and pupillary light responses, measurement of tear production and intraocular pressure, and examination of the anterior and posterior segments of the eye as part of an annual wellness examination.

Lens Instability

Figure 253-8  Acrivet 60V acrylic intraocular lens seen in the

lens capsule. Fibrosis of the edge of the anterior lens capsule opening is noted, but the lens optic and visual axis remain clear.

Lens instability can occur as a primary abnormality or develop secondary to hypermature cataract, chronic LIU, trauma, or glaucoma. Primary lens luxation (PLL) is breed associated and is considered common in as many as 8 to 10 terrier breeds and the Australian cattle dog, border collie, and shar-pei. Primary lens instability typically appears between the ages of 2 and 6 years and, although often asymmetric at presentation, typically is a bilateral disease. The mode of inheritance is autosomal recessive, and a genetic test is commercially available for the canine PLL mutation. DNA results suggest that in some breeds, such as the miniature bull terrier in the United Kingdom, up to 40% of breed members may be carriers. Unstable lenses may remain in the posterior chamber or may luxate into the anterior or vitreous chambers. Lens instability or lens subluxation may be recognized by the presence of an aphakic crescent (Figure 253-9), lens trembling (phacodonesis), iris trembling (iridodonesis), corneal edema, vitreous in the anterior chamber, and visualization of the lens in the anterior (Figure 253-10) or

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SECTION  XII  Ophthalmologic Diseases

Figure 253-9  Mature cataract in a subluxated lens. The lens is

unstable and has shifted ventrally, which results in an aphakic crescent (arrow).

Figure 253-11  A complete posterior lens luxation of a cataractous lens in a canine eye.

Figure 253-10  Complete anterior lens luxation in a feline eye.

vitreous chamber (Figure 253-11) A dog with an anteriorly luxated lens may be brought to the veterinarian because of acute onset of corneal edema and blepharospasm. If the corneal edema is not severe, the lens may be visualized in the anterior chamber by viewing the globe from the lateral side. Initial assessment and management consists of measurement of the intraocular pressure, assessment of vision status, and determination of the location of the lens. If the lens is located anteriorly, the use of topical miotic agents is contraindicated, and prompt referral is the most appropriate treatment. If the intraocular pressure is elevated and the lens is anterior, topical and oral carbonic anhydrase inhibitors and systemic osmotic agents such as mannitol may be used to lower intraocular pressure (see Chapter 251). If the lens is located posterior to the iris and is unstable or luxated, topical miotic agents may be used to trap the lens and avoid anterior luxation. Topical miotic agents

include the prostaglandin analogs (latanoprost [Xalatan], travoprost [Travatan], bimatoprost [Lumigan]), which induce potent miosis and can be used every 12 hours indefinitely, and the parasympathomimetic drugs (demecarium bromide 0.125% and pilocarpine 2%). The miotic agents also serve to lower intraocular pressure and so have the advantage of managing both the lens instability and possible secondary glaucoma. In the author’s opinion, topical latanoprost 0.005% every 12 hours is the most effective topical therapy for a posterior lens luxation. Referral of an animal with posterior lens luxation to a veterinary ophthalmologist is advised. If the lens instability is considered to be primary, examination of the contralateral eye is essential because it is also at risk. There is considerable diversity of opinion among veterinary ophthalmologists regarding when unstable lenses should be removed. The most conservative approach is to use topical miotic agents to prevent anterior luxation and to perform surgery only when the lens luxates anteriorly. Once the lens has luxated completely, removal often requires an intracapsular surgical technique (intracapsular lens extraction) that uses a 160-degree incision and can be associated with significant postoperative complications (glaucoma, retinal detachment). Recent studies have revealed that the prognosis for vision after intracapsular lens extraction is poor if glaucoma is present at the time of surgery. The mechanisms by which unstable lenses cause glaucoma have not been identified, but some believe glaucoma begins early in the course of lens instability and then rapidly becomes irreversible. As a result, some advocate that unstable lenses be removed as soon as the instability is detected. DNA testing for PLL combined with early surgical intervention for unstable lenses should be considered in an effort to improve long-term outcomes. The technique for removal of an anteriorly luxated or unstable lens depends on the degree of instability, the

CHAPTER  253  Disorders of the Lens equipment available, the health of the vitreous, and surgeon preference. In general, if the lens is stable enough to allow phacoemulsification, this should be the preferred method of extraction. This method allows the use  of small-incision techniques and has been shown to produce significantly better outcomes than intracapsular lens extraction. In addition, after phacoemulsification, implantation of an IOL into the capsular bag may be possible in some cases. For lens instability of more than 160 degrees or complete lens luxation, a sulcus-sutured IOL may be placed in selected cases to restore emmetropia. With the concurrent use of endoscopic cyclophotocoagulation, the incidence of postoperative glaucoma may be reduced.

Trauma Ocular trauma can be divided into sharp and blunt. Blunt trauma typically results in an explosive type of rupture of the fibrous tunic, and the globe usually is not visual or able to be salvaged. Sharp trauma, such as puncture with a cat claw, results in laceration of the fibrous tunic and, if penetrating, may involve the lens and its capsule. After laceration of the lens capsule, a cataract will occur. Phacoclastic uveitis may develop if the lens capsule laceration is large enough so that sufficient exposure of lens proteins occurs. When a rupture of the lens capsule is suspected or diagnosed, prompt referral for corneal repair and lens removal is indicated. Systemic and topical nonsteroidal antiinflammatories and antibiotics should be prescribed until surgery can be performed. Although small lens capsule lacerations may seal themselves, which results in a focal cataract without phacoclastic uveitis, this is the exception and referral still is indicated.

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References and Suggested Reading Beam S, Correa MT, Davidson MG: A retrospective-cohort study on the development of cataracts in dogs with diabetes mellitus: 200 cases, Vet Ophthalmol 2:169, 1999. Binder DR, Herring IP, Gerhard T: Outcomes of nonsurgical management and efficacy of demecarium bromide treatment for primary lens instability in dogs: 34 cases (1990-2004), J Am Vet Med Assoc 231:89, 2007. Biros DJ et al: Development of glaucoma after cataract surgery in dogs: 220 cases (1987-1998), J Am Vet Med Assoc 216:1780, 2000. Bras ID et al: Posterior capsular opacification in diabetic and nondiabetic canine patients following cataract surgery, Vet Ophthalmol 9:317, 2006. Gould D et al: ADAMTS17 mutation associated with primary lens luxation is widespread among breeds, Vet Ophthalmol 14:378, 2011. Gelatt KN, MacKay EO: Secondary glaucoma in the dog in North America, Vet Ophthalmol 7:245, 2004. Gelatt KN, Wilkie DA: Surgical procedures of the lens and cataract. In Gelatt KN, Gelatt JP, editors: Veterinary ophthalmic surgery, St Louis, 2011, Saunders, p 305. Lim CC et al: Cataracts in 44 dogs (77 eyes): a comparison of outcomes for no treatment, topical medical management, or phacoemulsification with intraocular lens implantation, Can Vet J 52:283, 2011. Paulson ME et al: The effect of lens induced uveitis on the success of extracapsular cataract extraction: a retrospective study of 65 lens removals in the dog, J Am Anim Hosp Assoc 22:49, 1985. Sigle KJ, Nasisse MP: Long-term complications after phacoemulsification for cataract removal in dogs: 172 cases (1995-2002), J Am Vet Med Assoc 228:74, 2005. Wilkie DA et al: Canine cataracts, diabetes mellitus and spontaneous lens capsule rupture: a retrospective study of 18 dogs, Vet Ophthalmol 9:328, 2006. Wilkie DA, Colitz CMH: Surgery of the canine lens. In Gelatt KN, editor: Veterinary ophthalmology, ed 4, Ames, IA, 2007, Blackwell Publishing, p 888.

CHAPTER 

254 

Canine Retinopathies SIMON M. PETERSEN-JONES, East Lansing, Michigan

R

etinopathies in dogs may be identified because of a loss of vision or an altered external appearance of the eyes. Many cases are detected only during a careful ophthalmoscopic examination (Figure 254-1) as part of a general physical examination or at a screening clinic (e.g., a Canine Eye Registration Foundation examination). This chapter considers hereditary and acquired diseases of the canine retina.

Hereditary Retinal Dystrophies Retinal Dysplasia Retinal dysplasia is a group of conditions that involve abnormal development of the retina. Retinal dysplasia is classified by both cause and severity. Categorized by cause, retinal dysplasias include acquired lesions, which may result from insults such as in utero infection or irradiation, and hereditary lesions. Complete or total retinal dysplasia is the most severe form and is characterized by blindness due to detachment or congenital nonattachment of the retina. Concurrent congenital abnormalities such as microphthalmos and cataract may be present. Nonocular congenital anomalies, such as skeletal dwarfism, also may be observed with complete or total retinal dysplasia. An example is oculoskeletal dysplasia, also referred to as dwarfism with retinal dysplasia. In the Labrador retriever and Samoyed breeds the causal gene mutations for dwarfism with retinal dysplasia have been identified. A less severe retinal dysplasia known as geographic retinal dysplasia is seen in many breeds of dog (see Figure 254-1, C). The tapetal retina dorsal to the optic nerve head is affected most frequently. Affected regions may be focally detached or there may be regions of retinal thinning with subsequent pigmentation, which produces an appearance similar to that of a chorioretinal scar. Unless the geographic lesions are very extensive or a complete retinal detachment develops, vision is not noticeably affected. A third form of retinal dysplasia is known as multifocal retinal dysplasia. In this form the lesions may appear as circular dots, linear streaks, or V- or Y-shaped streaks, most commonly in the tapetal fundus. Typically there is a duplication of the photoreceptor layer within the lesions, which also are called rosettes because of their appearance in histologic sections. The lesions usually have a different color from the surrounding normal fundus and may appear hyporeflective (due to thickening of abnormal retinal tissue). The affected retina also may degenerate, which leaves a hyperreflective spot or streak. Multifocal 1188

retinal dysplasia typically does not have any detectable effect on vision.

Canine Multifocal Retinopathy Canine multifocal retinopathy (cmr) is an autosomalrecessive condition caused by mutations in the canine BEST1 gene (cBEST1). Three different mutations have been identified in cBEST1 in different breeds of dog causing cmr1, cmr2, and cmr3. Mastiff breeds are affected with cmr1, the Coton de Tulear breed with cmr2, and the Lapponian herder with cmr3. Dogs affected with cmr develop multiple small bullous retinal detachments that have tan-colored subretinal fluid. These first develop in young dogs and then may remain unchanged for years. The cmr3 form may have a somewhat later onset than cmr1 and cmr2, with lesions developing at about 1 year of age. Histologically, the lesions show focal loss of photoreceptors, and the underlying retinal pigment epithelium is abnormal. Currently there is no treatment for the condition, although gene therapy is being investigated experimentally. Genetic tests for cmr1, cmr2, and cmr3 have been developed.

Progressive Retinal Atrophy Progressive retinal atrophy (PRA) is a group of conditions that have a similar clinical presentation, although the age of onset and rate of progression can vary considerably by breed. The majority of forms are inherited in an autosomalrecessive fashion, although dominant and X-linked PRAs have been identified. There are forms of PRA that are breed specific (the causal mutation has been identified in only a single breed), others that occur only in closely related breeds, and one important form that is caused by a mutation in the progressive rod-cone degeneration gene (PRCD) that occurs in many different breeds. In attempts to categorize the different forms, PRA has been divided into categories based on age of onset and the pathologic changes that occur in the retina of affected dogs. Thus there are early, middle-aged, and late-onset forms and forms with descriptive names such as rod dysplasia, rodcone dysplasia (types 1, 2, and 3), early retinal degeneration, and progressive rod-cone degeneration. Advances in molecular genetics have allowed the underlying gene mutation of several forms to be identified. This allows classification on a molecular basis so that the disorder is described  as PRA due to a particular mutation in a certain gene (Table 254-1). Classically, PRA results in an initial deterioration of vision in dim light followed by a progressive loss of

CHAPTER  254  Canine Retinopathies

A

1189

B

D

C Figure 254-1  A, Wide-angle view of a fundus of a normal adult dog. B, Wide-angle view of a

fundus of a Cardigan Welsh corgi with progressive retinal atrophy. The tapetal fundus is hyperreflective due to retinal thinning and the retinal vasculature is attenuated. C, Fundus of a springer spaniel with geographic retinal dysplasia lesions. The lesions have an altered tapetal color and the larger ones have a pigmented center. D, Wide-angle view of a fundus of an elderly cat with hypertensive retinopathy. There are multiple spots of hemorrhage in the central retina. Some tapetal hyperreflectivity is present due to retinal thinning.

TABLE 254-1  Examples of the Different Classifications for Four Forms of Progressive Retinal Atrophy (PRA) Classification by Inheritance

Classification by Age of Onset

Classification by Pathologic Features

Classification by Genetic Mutation

Irish setter

Autosomal-recessive PRA

Early-onset PRA

Rod-cone dysplasia type 1 (RCD1)

Rod cyclic GMP phosphodiesterase β subunit (PDE6B)

Collie

Autosomal-recessive PRA

Early-onset PRA

Rod-cone dysplasia type 2 (RCD2)

Retinal degeneration 3 (RD3)

Cardigan Welsh corgi

Autosomal-recessive PRA

Early-onset PRA

Rod-cone dysplasia type 3 (RCD3)

Rod cyclic GMP phosphodiesterase α subunit (PDE6A)

Poodle, Labrador retriever, cocker spaniel, plus many other breeds

Autosomal-recessive PRA

Mid- to late-onset PRA

Progressive rod-cone degeneration (PRCD)

Progressive rod-cone degeneration (PRCD)

Breed

GMP, Guanosine monophosphate.

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SECTION  XII  Ophthalmologic Diseases

daytime vision and ultimate blindness. Owners also may notice that the pupils are unusually dilated and there may be increased “eye shine” due to a combination of the pupillary dilation and increased tapetal reflectivity. Cataract formation commonly accompanies PRA and may be the initial presenting complaint. Ophthalmoscopic signs of PRA include progressive development of a generalized hyperreflectivity of the tapetal fundus, which is a result of retinal thinning (see Figure 254-1, B). Retinal vasculature becomes progressively attenuated, and atrophy involving the optic nerve head also develops. Pigmentary changes (patchy increase and decrease in pigmentation) in the nontapetal fundus also may become apparent. Electroretinography, a diagnostic method used to measure the retinal electrical response to light stimulation, can be used for the early diagnosis of many forms of PRA and also for assessment of retinal function when ophthalmoscopic examination is not possible because of cataract. DNA tests now are available for many breeds.

Cone-Rod Dystrophy The term cone-rod dystrophy (CRD) is used for retinal degenerative conditions in which the cone photoreceptors are affected earlier or more severely than the rod photoreceptors. This is in contrast to “classical” PRA in which rods are affected initially or more severely in the early stages of the condition compared with cones. The ophthalmoscopic changes in CRD may be very similar to those in PRA (tapetal hyperreflectivity, retinal vascular attenuation, optic nerve atrophy). Electroretinography is useful in differentiating the two conditions. DNA testing is available for many breeds.

Retinal Pigment Epithelial Dystrophy Retinal pigment epithelial dystrophy (RPED) originally was called central progressive retinal atrophy. The condition is characterized by the accumulation of light brown pigment spots across the tapetal fundus. Experimental vitamin E deficiency and vitamin E deficiency caused by very poor diet have been described in dogs and result in a retinal dystrophy that appears very similar to RPED, which has led to speculation that RPED may be associated with vitamin E deficiency. Anecdotal evidence from the United Kingdom indicates that the incidence of RPED decreased dramatically when owners improved the quality of the diet that typically was fed. This direct and indirect evidence suggests that systemic or local abnormalities in vitamin E metabolism or transport may play a role in the development of some forms of RPED.

Congenital Stationary Night Blindness/ Retinal Dystrophy of Briards Congenital stationary night blindness (retinal dystrophy of briards) is an autosomal-recessive trait of the briard. Affected dogs have markedly reduced visual sensitivity so that when the light level is reduced from full room light they become effectively blind. Although the condition initially was considered a stationary (nonprogressive) night blindness, in fact daytime vision also is affected to

a variable extent and the condition does progress slowly over several years, which makes the name a misnomer. The condition is caused by a mutation in the RPE65 gene. A mutation in the same gene in humans is responsible for an important cause of blindness called Leber’s congenital amaurosis type II. The RPE65 gene product is expressed in the retinal pigment epithelium of the eye and is an important enzyme in the retinoid (visual) cycle. RPE65 deficiency is associated with very slow degeneration of the photoreceptors in affected dogs.

Achromatopsia Achromatopsia (also day blindness or hemeralopia) is a term used to describe conditions that result in a lack of, or loss of, cone function. Affected dogs have visual impairment in bright light with restoration of normal vision in dim lighting conditions. Pupil size in bright light varies from pinpoint to normal to mydriatic. Achromatopsia in the Alaskan malamute and German shorthaired pointer have been shown to be caused by different mutations in the CNGB3 gene, which is inherited in an autosomal-recessive fashion.

Treatment of Hereditary Retinal Dystrophies Currently there are no proven therapies for retinal dystrophy that are in common clinical use. Dogs have proven to be important models for several human retinopathies, and significant developments have occurred through the study of canine patients. In applied veterinary medicine, the focus currently is on DNA-based testing for diseasecausing gene mutations and selective breeding to eliminate those conditions. In the future, some of the novel treatment approaches developed in natural or experimental dog models of human retinopathy may become available to treat canine veterinary patients.

Treatments Applicable before Complete Photoreceptor Loss Dietary Supplementation Large clinical trials of dietary supplementation in human patients with retinal dystrophies such as retinitis pigmentosa have shown some positive effects of supplementation. The effects of dietary supplementation on retinal dystrophies in companion animals have not been the subject of well-designed clinical trials. Despite this lack of scientific proof, dietary supplements are being marketed for this use. There is a real need for carefully controlled large clinical trials examining dietary supplementation as a way of slowing retinal degeneration in conditions such as PRA. This paucity of hard evidence to support dietary supplementation in dogs with retinal dystrophies makes it impossible to give advice based on anything more than anecdotal evidence. Supplementation therefore should be advised with care and excessive supplementation of fatsoluble vitamins avoided so as not to risk toxicity effects. Although RPED has strong similarities to vitamin E deficiency and vitamin E supplementation in affected dogs may seem a logical approach, clinical trials to 

CHAPTER  254  Canine Retinopathies investigate such supplementation as a method of treatment have not been reported. There is anecdotal evidence that ensuring that at-risk dogs receive a diet adequate in vitamin E and antioxidants reduces the incidence of RPED. The results from the clinical trials of human patients with retinitis pigmentosa mentioned earlier showed that vitamin E supplementation actually had a deleterious effect, which suggests that supplementation is not without risk. Disease-Specific Gene Therapy Recent advances in gene therapy have given scientists and practitioners alike a glimpse of the future possibilities of this novel treatment modality. Gene supplementation therapy in the RPE65-mutant briard dog has provided spectacular restoration and subsequent maintenance of visual function. One important feature of the retinal dystrophy in the dog with RPE65 mutation is that although the visual deficits are present from the time of retinal maturation, the retinal cells degenerate only very slowly. This disconnect between function and structure provides a large window of opportunity to correct the genetic defect while photoreceptors remain and thus to restore vision. Modified adeno-associated viruses used to introduce a normal copy of the RPE65 gene were injected into the subretinal space (between the photoreceptors and retinal pigment epithelial cells) and delivered the normal gene to the retinal pigment epithelium, which allowed restoration of visual function. These studies in RPE65mutant dogs led to human clinical trials of similar gene therapy. Unfortunately, humans appear to have fewer surviving photoreceptors, so the success of gene therapy in the human trials to date has not been as spectacular as it is in dogs. Unfortunately, the situation in many other retinal dystrophies is not as favorable for gene supplementation therapy. The loss of vision in a number of retinal dystrophies is the result of the death of photoreceptors, with vision deteriorating as the number of remaining functional photoreceptors dwindles. For gene supplementation to be successful, it would need to be applied before too many photoreceptors are lost. This would require the early identification of animals that are destined to  go blind because of a retinal dystrophy and then provision of treatment early in the disease process. Because there are many different genes that can lead to a retinal dystrophy when mutated, this approach also would require the construction of a new therapeutic viral vector for each gene. Each unique construct would be able  to treat only disease resulting from a mutation of  that gene. Further complicating successful gene therapy is the variation in the genetics of each dystrophy. Most of the conditions that would be amenable to gene supplementation therapy are recessively inherited and are caused by a lack of normal gene product. Carrier animals with only one functional copy of the gene instead of two have a reduced amount of the gene product, but this is still enough to allow for retinal function. Dominantly inherited retinal dystrophies result when having only one functional copy of the gene is not sufficient for normal function or when the mutated gene product is produced

1191

but has a deleterious effect. Simple gene supplementation therapy is unlikely to be successful in these cases. Generic Gene Therapy In gene supplementation therapy (adding a normal copy of a mutated gene) each gene therapy vector is suitable for use in only a small number of patients because the vector is specific to the particular breed mutation. A more generic treatment that could slow or prevent vision loss in a wide range of retinal dystrophies would be more attractive, particularly for commercialization. Research looking at factors to prevent photoreceptor cell death, including the introduction of therapeutic genes expressing growth factors, cell survival factors, and antiapoptosis factors, is under way. Growth Factors Therapy involving the delivery of growth factors to the retina has been developed and is being tested in human clinical trials. One approach that has been investigated extensively is the use of intravitreal implants of encapsulated cells altered to produce a particular therapeutic protein, such as ciliary neurotrophic factor. The therapeutic protein is produced by the modified cells in the device, leaks from the capsule, and reaches the retina following diffusion across the vitreous. This approach has been shown to preserve photoreceptors in many different animal models, including models with severe forms  of PRA.

Treatments Applicable after Photoreceptors Have Died Once retinal degeneration has advanced to the stage that the photoreceptor cells have died, therapeutic approaches that introduce a new copy of the defective gene or proteins that stop or slow down photoreceptor loss are no longer effective, and a different therapeutic approach is required. Three main approaches currently are being investigated: transplantation of retinal progenitor cells that can develop into replacement photoreceptors, introduction of light-sensitive channel proteins into the remaining cells of the inner retina, and implantation of an electrical microarray to act as an artificial retina. Transplantation Injection of progenitor photoreceptors into eyes with photoreceptor degeneration currently is being investigated in animal models. The most promising results so far have come from injection of progenitor cells rather than stem cells. These progenitor cells have been manipulated to commit them to becoming photoreceptors before they are injected into the subretinal space. Introduction of Light-Responsive Channel Proteins Another approach to restoration of vision involves the use of gene therapy to introduce a light-responsive channel protein into the cell membranes of remaining inner retinal neurons. Inner retinal neurons are still present in retinal dystrophies long after the photoreceptors have degenerated. The channel proteins allow these remaining neurons to create a difference in electrical

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SECTION  XII  Ophthalmologic Diseases

potential across their membranes upon light stimulation. This results in the transmission of a neurologic message to the brain for conscious perception. This approach already has been shown to restore some light-driven responses in mice blinded because of retinal dystrophies. Artificial Retina An electrical microchip can be implanted into the eye and used to stimulate the remaining inner retinal neurons that it contacts. A camera is then used to send information to the microchip, creating a pattern of stimulation on the retina that is subsequently processed in the visual centers of the brain. This approach currently is being evaluated in human clinical trials.

Acquired Retinal Dystrophies Diabetic Retinopathy Diabetic retinopathy in humans is a very important problem, with proliferative retinal neovascularization and resultant hemorrhage developing in some patients and potentially causing vision loss. Diabetic dogs do develop retinal vascular changes and retinal hemorrhage, and microaneurysms are observed in some animals. A retrospective study of 52 diabetic dogs recorded retinal hemorrhages or microaneurysms in 21%, whereas in control animals the incidence was 0.6% (Landry et al, 2004). Fortunately, therapeutic intervention beyond adequate regulation of the diabetes generally is not necessary to control diabetic retinopathy in canine patients.

Hypertensive Retinopathy Systemic hypertension can result in retinal changes ranging from arteriolar constriction and dilation (aneurysms) to retinal edema, retinal detachment, and retinal and preretinal hemorrhage (see Figure 254-1, D). The more severe changes may be vision threatening. Systemic blood pressure always should be measured when these signs are observed funduscopically. Control of the systemic blood pressure is key in the stabilization of the retinal changes (see Chapter 169). Prompt reduction of hypertension and maintenance of normal blood pressure can allow a detached retina to reattach and potentially restore vision.

Sudden Acquired Retinal Degeneration Syndrome Sudden acquired retinal degeneration syndrome (SARDS) is a unique canine retinopathy that results in the sudden onset of vision loss. Typically, middle-aged dogs are affected. There may be a history of polydipsia and

polyphagia. On examination the dogs are blind, but the pupillary light reflexes may be normal, delayed, or absent in association with mydriasis. Fundus examination reveals no retinal abnormalities. The main differential diagnosis for blindness with no apparent cause detectable on ophthalmoscopic examination is central blindness. An electroretinogram allows differentiation between SARDS and central blindness. In SARDS no electrical responses can be recorded from the retina in response to light stimulation, whereas in the initial stages central causes of blindness do not have a major effect on the electroretinogram. The cause of SARDS is not understood, and there does not appear to be an effective treatment.

Senile Retinal Degeneration It is recognized that vision deteriorates with age. In elderly animals retinal thinning may become apparent; it is particularly evident in the peripheral retina and on ophthalmoscopic examination can be seen most readily as hyperreflectivity of the peripheral tapetal region.

References and Suggested Reading Acland GM et al: Gene therapy restores vision in a canine model of childhood blindness, Nat Genet 28:92, 2001. Gearhart PM, Gearhart CC, Petersen-Jones SM: A novel method for objective vision testing in canine models of inherited retinal disease, Invest Ophthalmol Vis Sci 49:3568, 2008. Guziewicz KE et al: Bestrophin gene mutations cause canine multifocal retinopathy: a novel animal model for best disease, Invest Ophthalmol Vis Sci 48:1959, 2007. Hurn SD, Hardman C, Stanley RG: Day-blindness in three dogs: clinical and electroretinographic findings, Vet Ophthalmol 6:127, 2003. Komaromy AM et al: Gene therapy rescues cone function in congenital achromatopsia, Hum Mol Genet 19:2581, 2010. Landry MP, Herring IP, Panciera DL: Funduscopic findings following cataract extraction by means of phacoemulsification in diabetic dogs: 52 cases (1993-2003), J Am Vet Med Assoc 225:709, 2004. McLellan GJ et al: Clinical and pathological observations in English cocker spaniels with primary metabolic vitamin E deficiency and retinal pigment epithelial dystrophy, Vet Rec 153:287, 2003. Tao W et al: Encapsulated cell-based delivery of CNTF reduces photoreceptor degeneration in animal models of retinitis pigmentosa, Invest Ophthalmol Vis Sci 43:3292, 2002. Wrigstad A, Narfström K, Nilsson SE: Slowly progressive changes of the retina and retinal pigment epithelium in Briard dogs with hereditary retinal dystrophy. A morphological study, Doc Ophthalmol 87:337, 1994. Zangerl B et al: Identical mutation in a novel retinal gene causes progressive rod-cone degeneration in dogs and retinitis pigmentosa in humans, Genomics 88:551, 2006. Zangerl B et al: Assessment of canine BEST1 variations identifies new mutations and establishes an independent bestrophinopathy model (cmr3), Mol Vis 16:2791, 2010.

CHAPTER 

255 

Feline Retinopathies KATHERN E. MYRNA, Athens, Georgia

E

xamination of the feline retina is an important part of a thorough systemic evaluation. Any cat with a pupillary abnormality, a presenting complaint of vision loss, a systemic illness of unknown origin, or a cardiac abnormality should undergo a complete retinal examination. Proper retinal evaluation can help the practitioner to focus the diagnostic search as well as monitor response to therapy. This chapter reviews the most common causes of retinal lesions in the feline and  presents a diagnostic approach to retinal changes. Figure 255-1 provides a diagnostic algorithm for feline retinal disease. The biggest obstacle to understanding retinal disease is the difficulty inherent in fundic examination. The fundus is defined as the visible structures in the posterior half of the eye and includes five overlapping layers of tissue with varying degrees of transparency. The fundus is composed of the sclera, the choroid, the tapetum, the retinal pigmented epithelium, and the neurovascular retina. The posterior blood-eye barrier is formed by the nonfenestrated capillaries of the neurovascular retina and the tight junctions between retinal pigmented epithelium cells, and acts to prevent substances in the bloodstream from entering the eye. Pathologic conditions result in a breakdown of this barrier, which can allow offending substances, including inflammatory cells, infectious organisms, or blood, to collect within and under the retina. These alterations in the layers of the fundus result in the characteristic changes in the appearance of the retina. The first key to effective fundic evaluation is an understanding of the normal retinal appearance. Performing routine retinal examinations and using an ophthalmic atlas will help to establish a thorough recognition of normal variation. When retinal disease is detected, it is first important to differentiate active from inactive disease. When cells or fluid sit between the retina and the tapetum the tapetal reflection is blocked, which leads to a murky or blurry image. Thus active retinal lesions often are hyporeflective and fuzzy with irregular borders. Atrophy of the retina results in vascular attenuation and retinal thinning, which allows greater tapetal reflection. Thus inactive lesions are hyperreflective with sharp margins. Inactive lesions also may be associated with pigment clumping, leading to foci of hyperpigmentation within or adjacent to a hyperreflective lesion.

Hypertensive Retinopathy Hypertensive retinopathy is perhaps the most common and clinically important retinopathy in the cat. It should be considered in all cases of acute blindness in older cats.

Hypertensive retinopathy has been used as a broad term to include both hypertensive retinopathy and choroidopathy. The retinal arteries autoregulate in response to increased systemic blood pressure. This results in vasoconstriction, which in turn leads to hypertrophy of the smooth muscle layer of the arteriole and ultimately to focal necrosis and rupture of the vessel. These focal ruptures produce multifocal areas of retinal edema or hemorrhage. As more vessel damage occurs, serum and blood continue to leak, which leads to complete retinal detachment and blindness. Additionally, the choroid does not autoregulate, and as the blood pressure increases, there is a substantial degree of choriocapillaris serum leakage resulting in serum collection beneath the retina and exudative retinal detachment. The incidence of ocular signs in hypertensive cats  is about 40% to 60%, and ocular signs are the most common form of target organ dysfunction associated with systemic hypertension. Hypertensive retinopathy is identified most often in cats older than 10 years of age with systolic blood pressures greater than 168 mm Hg when measured by an oscillometric technique (Sansom et al, 2004). The presence of ocular changes is an indication to start antihypertensive therapy even if blood pressure measurements do not consistently meet the criteria for hypertension.

Diagnosis Clinical signs of hypertensive retinopathy can be unilateral but are typically bilateral. Presenting complaints include blindness, vision loss, or progressively dilated pupils. Hypertensive retinopathy also may have a subclinical presentation, noted only during routine examination of the fundus or during examination of cats with high blood pressure or those evaluated for a gallop sound or heart murmur. Serous retinal detachment often can be diagnosed with a penlight from arm’s distance. Retroillumination of the eye is achieved by holding a light at arm’s length from the patient. A normal eye should show bright yellow-green tapetal reflection in the pupil, although a blue eye may have a red pupil due to a lack of tapetum. Retinal detachment results in a dampening of that reflection caused by the presence of fluid between the retina and the tapetum. The proximity of the retina to the lens also sometimes allows the retinal vessels to be seen directly through the pupil. Retinal examination is difficult with retinal detachment, and the entire fundus may seem blurry. Focal areas of detachment are blurry and hyporeflective and are sometimes associated with hemorrhage beneath, within, or above the retina. Hyphema or vitreal hemorrhage also may be observed. 1193

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SECTION  XII  Ophthalmologic Diseases

Is the patient able to see? No

Yes

Does the retina look normal?

Is the fundus hyperreflective or hyporeflective? Hyperreflective

Hyporeflective

Is the hyperreflectivity focal or diffuse? Diffuse Retinal degeneration

Focal Inactive lesion

Yes

Is the hyporeflectivity focal or diffuse? Diffuse Retinal detachment

Consider brain or optic nerve disease (CT or MRI)

Focal Chorioretinitis

No Is the fundus hyperreflective or hyporeflective?

Hyperreflective Hyporeflective End-stage retinal degeneration

Retinal detachment hypertensive retinopathy

Rule/ outs -Taurine deficiency -Inherited retinal degeneration -Enrofloxacin toxicity

Chorioretinal scar retinal folds

Figure 255-1  Diagnostic algorithm for the evaluation of feline retinopathies.

Treatment and Prognosis Treatment of hypertensive retinopathy is focused solely on control of the systemic hypertension. No topical medications are indicated to treat the ocular component. Amlodipine has been demonstrated to be particularly effective in the resolution of systemic hypertension and hypertensive retinopathy (Maggio et al, 2000). Current recommendations for the treatment of systemic hypertension can be found in Chapter 169, but cats with hypertensive retinopathy should be evaluated for underlying systemic disease, including renal failure, hyperthyroidism, and the more uncommon condition of hyperaldosteronism (Conn’s syndrome). The prognosis for vision varies depending on the duration of the retinal detachment, with experimental models showing a return to function if the retina has been detached for 2 weeks or less. Unfortunately, because of cats’ ability to adjust to vision loss, the retina typically is detached long before the patient is seen by a clinician. Although resolution of the hypertension usually results in reattachment of the retina, continued retinal degeneration is likely to occur. Thus some cats who are visual at presentation or regain vision immediately after treatment may continue to go blind despite adequate control of blood pressure.

Retinal Degeneration The term retinal degeneration is a broad description for all disease states that result in progressive atrophy of the retina. There are nutritional, toxic, and inherited causes

of retinal degeneration that can be challenging to differentiate. The clinical signs of retinal degeneration include progressive vision loss, dilated pupils, and a poor or incomplete pupillary light reflex. Fundic examination reveals diffuse bilateral retinal vascular attenuation and tapetal hyperreflectivity. Unfortunately, there is no way to differentiate the cause of retinal degeneration based  on its appearance once the disease has progressed to  clinical blindness. Thus all possible causes should be considered.

Taurine Retinopathy Taurine is an essential amino acid for the cat and must be ingested in the diet to maintain health. Since the description of taurine deficiency and its associated retinopathy in 1975, commercial diets routinely have been supplemented with taurine. This has greatly decreased the incidence of the disease; however, deficiencies can be found in strays, patients fed homemade or canine-only diets, and occasionally in patients with seemingly appropriate diets. Diagnosis Taurine deficiency manifests initially as a pathognomonic lesion in the area centralis of the retina (see Figure 255-1). The area centralis is located superior and lateral to the optic disc and is characterized by a high concentration of photoreceptors. The taurine deficiency causes a focal retinal atrophy and a football-shaped area of hyperreflectivity. This proceeds to a band of hyperreflectivity extending across the visual streak. The retinal degeneration will

CHAPTER  255  Feline Retinopathies progress to complete retinal atrophy without dietary modification. The presence of bilateral oval lesions or diffuse retinal degeneration is an indication to assess whole blood taurine levels. If the patient is found to have a taurine deficiency, a cardiac workup is recommended because the deficiency also is associated with dilated cardiomyopathy. Treatment and Prognosis If diagnosed early, taurine deficiency retinal degeneration can be halted but not reversed by restoring normal levels of taurine. Owners should be counseled to feed a commercial diet or to supplement their homemade diets with proper levels of taurine. Cats also can be given 125 to 250 mg of taurine twice daily PO. Although the precise time to retinal response is unknown, it can take 2 to 3 months before cardiac response is seen, and it is likely that retinal effects follow a similar timeline.

Enrofloxacin Toxic Retinopathy Enrofloxacin toxicity first was identified in the mid-1990s when the dosing recommendations for cats were altered. After individual reports of rapid vision loss after systemic enrofloxacin administration, the toxicity was discovered to be dose related. Signs of retinal damage can be found in cats administered 25 mg/kg or more, with 50-mg/kg dosing resulting in retinal changes within days (Ford et al, 2007). The mechanism of toxicity is proposed to be a defect in a drug transporter gene that leads to accumulations of photoreactive fluoroquinolones; these subsequently generate toxic free radicals when exposed to light, which leads to photoreceptor cell death. Diagnosis Diagnosis is based on the presence of typical ocular signs combined with a history of high-dose enrofloxacin administration. The first clinical sign is the presence of dilated pupils, which is usually seen within several days of the enrofloxacin administration. Initially, increased granularity is appreciated in the area centralis, dorsotemporal to the optic disc. As in taurine deficiency retinopathy, this lesion progresses to include the horizontal visual streak. Eventually, vascular attenuation and diffuse tapetal hyperreflectivity characteristic of end-stage retinal degeneration are observed. Treatment and Prognosis At this time there is no treatment for enrofloxacin toxicity, and its resultant blindness is irreversible. However, early identification of the toxicity and discontinuation of the drug can preserve some vision. Although the toxicity is dose related, there are reported risk factors. These include rapid intravenous infusion of the drug, prolonged administration of the drug, and increased age of the patient. Given the severity of the retinal damage, enrofloxacin should be reserved for treatment of severe diseases, and dosages never should exceed 5 mg/kg q24h PO. Additional caution should be exercised when administering the drug intravenously and when choosing treatment for older cats. Although the toxicity is best understood for enrofloxacin, all fluoroquinolones hold the potential

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to cause retinal toxicity. Current studies have demonstrated higher safety thresholds with more recent generations of the drug including the recently released pradofloxacin.

Inherited Retinal Degeneration The incidence of heritable retinal degeneration is significantly lower in cats than in dogs (see Chapter 254), and such disorders fall under the broad designation of progressive retinal atrophy (PRA). Abyssinian and Somali cats with PRA have been studied extensively, and two forms of the disease have been identified. The early-onset form is inherited as an autosomal-dominant trait and results in vision loss by 7 weeks of age. The late-onset PRA is an autosomal-recessive trait and results in vision loss by 3 to 5 years of age. The genetic basis for these degenerative disorders is known, and genetic testing is available. The single-nucleotide mutation in the CEP290 gene discovered in Abyssinians with late-onset PRA (rdAc) also has been found in many other breeds. Siamese cats show a significantly increased incidence of this mutation, which may account for the anecdotal reports of PRA in Siamese and Siamese crossbreeds (Menotti-Raymond et al, 2010). An early-onset PRA has been reported in a domestic shorthaired cat and a Persian cat, although the prevalence of this disease appears to be low. This disease entity (Rdy) is associated with a single base deletion in the CRX gene. Genetic testing is available for the early-onset PRA affecting Abyssinians and Somali cats (Rdy genotype) and the late-onset form (rdAc genotype) from the University of California at Davis. Diagnosis Diagnosis of inherited PRA in the cat is based on a combination of compatible clinical signs and signalment. The presence of bilaterally symmetric retinal vascular attenuation and diffuse hyperreflectivity in a 3- to 7-year-old cat of the appropriate breed should raise the index of suspicion for an inherited PRA. A diagnosis can be made by ruling out all other causes of retinal degeneration, including enrofloxacin toxicity and taurine deficiency, as well as testing for the rdAc genotype. Treatment and Prognosis There is no therapy to slow or reverse PRA. The rate of retinal degeneration is variable. Abyssinians and Somalis with early-onset PRA will lose vision by 7 weeks of age, and those with the late-onset form will be blind by 3 to 5 years of age. Although the inheritance is not understood in all breeds, it is prudent to recommend against breeding any cat with a suspected PRA. Blind cats generally have a high quality of life, although they should be confined inside to minimize the chance of accidents.

Chorioretinitis Chorioretinitis is a term for inflammation that originates in the choroid and spreads to the adjacent retina. Chorioretinitis occurs with a breakdown of the blood-eye barrier and the introduction of infectious organisms, inflammatory cells, or exudate into the subretinal space

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or the retina itself. Because many disease processes can disrupt the blood-eye barrier, the causes of chorioretinitis are quite varied, and infection with any hematogenously disseminated pathogen could potentially result in chorioretinitis.

resolution of the inflammation, the areas will atrophy, which results in focal areas of hyperreflectivity with pigment clumping.

Diagnosis

The last category of retinal change is that of inactive disease. This includes both chorioretinal scars and the congenital defect retinal dysplasia. All inactive retinal lesions are characterized by hyperreflectivity, and many are associated with clumps of pigment. Retinal dysplasia has a characteristic appearance of multifocal, linear, curving lesions with a central line of pigment surrounded by hyperreflectivity. In cats neonatal infection with panleukopenia or feline leukemia virus is a known cause of retinal dysplasia. Because these lesions are inactive and nonprogressive, no treatment is needed. Chorioretinal scars typically are circular rather than vermiform and are less regular in size. The impact of many chorioretinal scars on vision is unknown, but in this author’s experience, a clinical visual defect never has been detected with these lesions.

Chorioretinitis is characterized by multifocal areas of active retinal inflammation. These areas have poorly defined or fuzzy borders and decreased reflectivity. Depending on the cellular makeup of the lesions, they can have a gray, white, yellow, or tan appearance. Severe chorioretinitis can result in complete retinal detachment. Once chorioretinitis has been identified, the focus should be on determination of the underlying cause. Potential causes of chorioretinitis in the cat are similar to the causes of uveitis (Chapter 250) and include systemic mycoses (cryptococcosis, blastomycosis, histoplasmosis, coccidiomycosis, systemic aspergillosis), feline infectious peritonitis (typically the dry form), and toxoplasmosis, as well as primary choroidal neoplasia. This list is not exhaustive but includes the most likely causes of chorioretinitis in the cat. Diagnostic workup should include a full physical examination, routine blood work, and urinalysis. Further diagnostic tests such as infectious disease titers, examination of lymph node aspirates, and imaging should be guided by the history and geographic location as well as the presence of concurrent clinical signs.

Treatment and Prognosis Treatment is focused on the underlying cause of the chorioretinal lesions. Prognosis is good if the underlying disease can be identified and treated. However, chorioretinitis is more likely to result in permanent vision loss  than other forms of intraocular inflammation. After

Inactive Retinal Lesions

References and Suggested Reading Ford MM et al: Ocular and systemic manifestations after oral administration of a high dose of enrofloxacin in cats, Am J Vet Res 68:190, 2007. Maggio F et al: Ocular lesions associated with systemic hypertension in cats: 69 cases (1985-1998), J Am Vet Med Assoc 217:695, 2000. Menotti-Raymond M et al: Widespread retinal degenerative disease mutation (rdAc) discovered among a large number of popular cat breeds, Vet J 186:32, 2010. Sansom J, Rogers K, Wood JL: Blood pressure assessment in healthy cats and cats with hypertensive retinopathy, Am J Vet Res 65:245, 2004. Stepien R: Feline systemic hypertension diagnosis and management, J Feline Med Surg 13:35, 2011.

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Orbital Disease RALPH E. HAMOR, Urbana-Champaign, Illinois

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rbital disease in dogs and cats can be caused by a variety of pathologic processes. Accurate assessment of the patient is essential for the selection of appropriate diagnostic studies and therapy. Orbital disease generally can be divided into those processes that lead to exophthalmos (protrusion of a normal-sized globe from the orbit) due to space-occupying disease, enophthalmos (recession of the globe within the orbit) due to decreased orbital contents, or strabismus (deviation of the globe within the orbit) (Box 256-1). The diagnostic challenge lies in the fact that clinical signs of orbital disease are evident only indirectly and involve changes in a wide variety of orbital tissues and surrounding structures.

Orbital Anatomy Dogs and cats have an incomplete bony orbit. The orbit consists of the frontal, lacrimal, zygomatic, sphenoid, maxillary, and palatine bones. The lateral orbital wall is completed by a collagenous orbital ligament that attaches the frontal process of the zygomatic bone to the zygomatic process of the frontal bone. The masseter muscle completes the orbit posterolaterally, whereas the zygomatic salivary gland and medial pterygoid muscle fill the floor of the orbit. Most of the extraocular muscles arise from the posterior and medial aspect of the orbit to form a cone as they attach to the anterior aspect of the globe. The lacrimal gland is located dorsolaterally beneath the frontal bone in the lacrimal fossa. The frontal sinus is located dorsal to the orbit, and the maxillary sinus is rostral and ventral to the orbit. The ventral floor of the orbit is directly adjacent to the oral cavity as well as the roots of the upper premolar and molar teeth. The orbital cavity also contains the second, third, and fourth cranial nerves; the ophthalmic branch of the fifth cranial nerve; the sixth cranial nerve; numerous arteries and veins; and smooth muscle, and is surrounded by periorbital tissue. The orbit is most shallow and directed more laterally in brachycephalic breeds and is most deep and directed more medially in dolichocephalic breeds, with the orbit in mesaticephalic breeds lying somewhere in between.

Clinical Signs of Orbital Disease Pathologic processes affecting the orbit involve one or more of three anatomic compartments: (1) within the extraocular muscle cone, (2) outside the cone but inside the periorbital tissue, and (3) inside the orbit but outside the periorbital tissue. Orbital disorders are characterized by clinical signs that alter the function, appearance, 

or position of the globe, eyelids, or ocular adnexal structures. The orbit is a confined space with little capacity for its contents to expand. Primary and secondary clinical signs of orbital disease are the hallmark of orbital disorders. Primary clinical signs include exophthalmos, enophthalmos, and strabismus. Secondary clinical signs include chemosis, swelling of the eyelids and periorbital tissue, elevation of the third eyelid, pain upon opening the mouth, lagophthalmos (incomplete eyelid closure), exposure keratitis, visual impairment, abnormal pupillary light reflexes, scleral indentation, mild to moderate increase in intraocular pressure (only with extreme exophthalmos), and facial asymmetry. One of the challenges in the diagnosis of orbital disease is the accurate interpretation of clinical signs. It is crucial for the clinician to differentiate buphthalmos (enlargement of the globe) from exophthalmos. Exophthalmos is a clinical sign of orbital disease, whereas buphthalmos is secondary to chronic glaucoma. Measuring the horizontal corneal diameter (from limbus to limbus) may be useful in differentiating buphthalmos from exophthalmos. The horizontal corneal diameters of the two globes should differ by 1 mm or less. Ultrasonography also can be used to measure the axial globe length. When assessing axial globe length, the operator should ensure that the ultrasound probe is positioned in the center of the globe so that the image is captured through the thickest section of the lens.

Diagnostic Approach A thorough history taking and physical examination are prerequisites for the diagnostic workup of orbital disease. When orbital disease is suspected, initial examination should include palpation of the eye and periocular structures, retropulsion of the globe, and careful examination of the oral cavity. The sizes of the palpebral fissures should be compared, the orbit should be palpated, the position of the eyelids and third eyelid should be observed, the location and mobility of the globe within the orbit should be assessed, and the presence of any ocular discharge should be noted. The globe generally can be retropulsed if there are no space-occupying lesions in the orbit. Retropulsion of the globe is performed through closed eyelids by placing an index finger on the upper eyelid of each eye and gently pressing or pushing the globe caudally within the orbit. Brachycephalic breeds may have quite shallow orbits, and the amplitude of retropulsion may be decreased even in normal orbits. 1197

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BOX 256-1  Orbital Diseases Causing Exophthalmos, Enophthalmos, and Strabismus Exophthalmos Abscess (bacterial, fungal) Cellulitis Neoplasia Zygomatic mucocele Varix or vascular anomaly Hemorrhage secondary to trauma Coagulopathy Masticatory myositis Extraocular polymyositis Relative exophthalmos (brachycephalic breeds) Proptosis Craniomandibular osteopathy

Enophthalmos Relative enophthalmos (dolichocephalic breeds) Phthisis bulbi Microphthalmia Pain Horner’s syndrome Chronic inflammation Atrophy of orbital tissues Starvation or dehydration Orbital fracture

Strabismus Neoplasia Proptosis Relative strabismus (brachycephalic breeds) Masticatory myositis Zygomatic mucocele Lacrimal cyst Hydrocephalus Orbital fracture

Digital pressure should never be used to assess intraocular pressure. Exophthalmic globes feel “hard” because of the resistance to retropulsion secondary to a spaceoccupying lesion within the orbit. When an exophthalmic globe is diagnosed incorrectly as glaucomatous because the globe feels hard, an incorrect differential diagnostic list and therapeutic plan will be formulated. In general, exophthalmic globes have normal intraocular pressure until the globe is quite exophthalmic, which causes the globe to be pressed against the eyelid margin. In these cases, the globe generally is not buphthalmic and does not have other clinical signs consistent with chronic glaucoma, including diffuse corneal edema, a dilated and unresponsive pupil, lens subluxation, retinal atrophy, and optic nerve cupping. Once orbital disease is suspected, the most important clinical diagnostic test is to check for the presence or absence of resistance to opening the mouth. Pain upon opening or attempting to open the mouth as the coronoid process of the mandible impinges on the orbital tissues is indicative of retrobulbar inflammation. This test should be executed slowly, carefully, and gently because patients with orbital inflammation can have significant pain. A thorough oral examination should be performed. Sedation or general anesthesia may be necessary. Lack of pain upon opening the mouth more often is consistent with orbital neoplasia. Orbital neoplasia generally causes less orbital inflammation for a similar degree of exophthalmos. Some orbital neoplastic diseases may produce significant orbital inflammation, and some cases of orbital inflammation may not cause pain when the mouth is opened; however, evidence of pain on opening the mouth is more common in orbital inflammatory disease. Inappetence may be reported by the owner in association with oral pain.

sinonasal disease, and hematogenous dissemination of infection or neoplasia. In some cases, an underlying cause may not be identifiable. The canine and feline orbit lacks a bony floor, which leaves it vulnerable to penetrating injury or puncture if the patient chews a bone or a stick. Foreign bodies often are implicated as the cause of orbital cellulitis but rarely are identified definitively. The onset of clinical signs generally is rapid. These signs may include exophthalmos, fever, pain upon opening the mouth, and chemosis. A soft, fluctuant swelling or hyperemia may be present caudal to the last molar. Tooth root abscesses of the fourth premolar can erupt through the skin causing a draining tract ventral to the orbit. Diagnostic evaluation for orbital cellulitis or abscess should include a complete physical examination, a complete blood count, and a thorough oral examination. Dental radiography may be indicated to rule out dental disease. Skull radiographs may demonstrate radiodense foreign bodies, show evidence of extension of inflammation from adjacent sinuses, or reveal orbital fractures. Orbital ultrasonography may demonstrate diffuse  hyperechogenicity posterior to the globe or a discrete hypoechoic mass. Ultrasonography of the fellow normal orbit may be useful for comparison and aid in the identification of subtle lesions. Advanced imaging (including magnetic resonance imaging [MRI] and computed tomography [CT]) provides the most detailed and accurate images of the orbit and retrobulbar tissue. CT generally is considered to be the imaging modality of choice for orbital disease. Fine-needle aspirates for cytologic evaluation or culture and sensitivity testing may be obtained from the retrobulbar space through the conjunctiva, skin, or oral cavity. Ultrasonographic or CT guidance may be useful to improve localization when aspiration is performed.

Exophthalmos

Treatment of Orbital Cellulitis or Abscess Therapy consists of establishing surgical drainage under general anesthesia, performing local irrigation, and administering systemic antibiotics. Before any of these procedures is performed, the operator should ensure that the cuff of the endotracheal tube is well inflated to

Orbital Cellulitis or Abscess The causes of orbital cellulitis include trauma, penetrating foreign body, extension of tooth root abscess or

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prevent aspiration of any exudates. The mucosa should be incised behind the last upper molar using a No. 10 or No. 15 Bard-Parker scalpel blade and a closed blunt mosquito hemostat should be inserted to enlarge the opening. The closed hemostat then should be opened gently to create a tract to allow drainage. Purulent material may not be immediately evident after establishment of a drainage tract. Samples should be procured for aerobic and aerobic culture and sensitivity testing if purulent material is obtained. The tract then may be flushed gently with dilute 1 : 10 povidone-iodine solution. Systemic antibiotics should be administered after drainage has been established. Mixed aerobic and anaerobic bacterial infections occur most commonly in the dog and cat, and cephalosporins, extended-spectrum penicillins, potentiated penicillins, and carbapenems are recommended for initial antimicrobial treatment of orbital abscesses in dogs and cats (Wang et al, 2009). Administration of systemic nonsteroidal antiinflammatories and analgesics, including oral opioids such as tramadol hydrochloride, also is recommended until clinical signs resolve. Antiinflammatory dosages of oral corticosteroids may also be effective; however, immunosuppressive dosages should be avoided. The patient should be evaluated carefully for the ability to completely close the lids over the globe. Many patients with exophthalmos develop secondary exposure keratitis from lagophthalmos. Corneal ulceration may occur in lagophthalmic patients. All patients with exophthalmos should be evaluated carefully for the presence of a corneal ulceration. Topical lubricating ointments should be applied every 2 to 6 hours to prevent desiccation of the ocular surface. A temporary tarsorrhaphy may be necessary if the exophthalmos is severe or prolonged.

biopsy is useful in establishing a diagnosis. In some cases, surgical orbital exploration may be necessary to obtain tissue for histopathologic analysis. Orbital exploration is best performed by a surgeon familiar with orbital anatomy and vasculature.

Orbital Neoplasia

Extraocular Polymyositis

Orbital neoplasia is an important cause of exophthalmos in canine and feline patients (see Chapters 257 and 258). The clinical signs are similar to those of orbital cellulitis, but the onset of signs generally is less acute. Pain upon opening the mouth is not observed frequently, and fever or leukocytosis usually is absent. The most common clinical sign is slowly progressive unilateral exophthalmos. Patients with orbital neoplasia also are much more likely to have strabismus, which may assist in localization of the orbital mass. A patient with a tumor in the ventronasal aspect of the orbit often has dorsotemporal strabismus because the mass shifts the normal position of the globe away from the location of the orbital mass. As in orbital cellulitis, the intraocular pressure of the globe usually is within the normal range unless the exophthalmos is so severe that the eyelids are compressing the globe. Diagnostic evaluation for orbital neoplasia should include a complete physical examination and systemic staging (complete blood work, three-view thoracic radiography, and abdominal ultrasonography). An oral examination also is warranted because in rare cases orbital neoplasia erodes or invades the ventral floor of the orbit. Orbital ultrasonography may be helpful, but more advanced imaging (MRI or CT) provides the most diagnostically useful information. Fine-needle aspiration or

Extraocular polymyositis is an autoimmune inflammatory disease that is confined to the extraocular muscles. The syndrome is described most commonly in young large-breed dogs; golden retrievers are overrepresented. Clinical signs include acute-onset bilateral exophthalmos and mild chemosis. Because the exophthalmos is directly along the visual axis, affected animals have 360 degrees of scleral exposure. In rare cases, massive swelling of the extraocular muscles may compress the optic nerve and cause a visual deficit. Diagnosis is made primarily by observation of the characteristic clinical signs. Findings of advanced imaging (MRI or CT) and biopsy of the extraocular muscles, which reveals infiltration of the muscle by lymphocytes and histiocytes, are supportive of the diagnosis. Treatment is similar to that for masticatory muscle myositis.

Masticatory Muscle Myositis Masticatory muscle myositis is a canine autoimmune inflammatory disease. It commonly occurs in German shepherds, golden retrievers, and weimaraner dogs. This condition involves the muscles of mastication (masseter, temporalis, and sometimes pterygoid). Clinical signs include exophthalmos, blepharedema, protrusion of the third eyelid, and pain upon opening the mouth. Upon palpation, the involved masticatory muscles typically are hard and painful. Episodes of inflammation may last 10 to 21 days and commonly recur. Persistently affected dogs may be unable to open the mouth (trismus) and demonstrate atrophy or fibrosis of the temporalis and masseter muscles. Diagnosis generally is made by observation of characteristic clinical signs and is confirmed by histopathologic evaluation. Peripheral eosinophilia is present inconsistently. Autoantibodies against type IIM myofibers have been identified in affected dogs (also see Chapter 240). Biopsy of the temporalis muscle demonstrates eosinophilic infiltration and type IIM myofiber antigen-antibody complexes. The mainstay of treatment is systemic corticosteroids (immunosuppressive dosage initially, with the dosage then slowly tapered over 4 to 6 weeks). Oral azathioprine also may be used for long-term therapy. During episodes of inflammation, patients can be encouraged to eat by providing frequent soft meals.

Cystic Orbital Disease Exophthalmos may occur secondary to zygomatic or lacrimal mucoceles. Zygomatic mucocele is most common and may occur spontaneously or secondary to trauma. Mucoceles generally are nonpainful and may cause protrusion of the oral mucous membrane behind the last upper molar or protrusion of a mass beneath the

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conjunctiva in the inferior temporal or nasal conjunctival fornix. Ultrasonography may reveal a cystic mass in the orbit. Aspiration of the cyst generally reveals thick, stringy, clear to straw-colored fluid that forms mucoid strands when placed between the thumb and forefinger. Advanced imaging of the orbit may be useful. Treatment is generally surgical removal, but some patients respond to systemic broad-spectrum antibiotics and antiinflammatory agents.

Enophthalmos Enophthalmos occurs when the globe becomes displaced posteriorly within the orbit. The globe may be normal sized or smaller than normal. Causes of enophthalmos  in a normal-sized globe include age-related loss of  periorbital and orbital muscle mass and fat leading to symmetric enophthalmos. Horner’s syndrome causes enophthalmos secondary to loss of sympathetic innervation of the orbit (see Web Chapter 80). Enophthalmos also may occur when the globe is retracted actively by the retractor bulbi muscle. This is observed most commonly in patients with a painful ocular surface or intraocular disease. Microphthalmos is a unilateral or bilateral congenital lesion in which the globe is smaller than normal. Microphthalmos must be differentiated from phthisis bulbi (shrinking of a previously normal-sized globe), which occurs secondary to chronic and severe uveitis. In addition to enophthalmos, clinical signs may include passive elevation of the third eyelid and secondary entropion of the lower lateral eyelid. Identification of the cause of enophthalmos is the most important component of treating enophthalmos. Age-related orbital tissue atrophy does not need treatment, but enophthalmos may be a clinical sign of serious intraocular disease that needs accurate identification and intervention.

Trauma Traumatic lesions of the orbit include proptosis and fracture. Proptosis is discussed in Web Chapter 78. Orbital fractures usually are caused by some traumatic event and may be associated with proptosis of the globe, especially in nonbrachycephalic breeds. Diagnosis of

orbital fractures frequently can be made by palpation. Small nondisplaced fractures may be difficult to see radiographically. CT may be useful in such cases. Clinical signs include pain, periorbital swelling and contusions, crepitus, facial asymmetry, exophthalmos or enophthalmos, and corneal disease. Careful assessment of globe motility is indicated because bony fragments may lead to entrapment of extraocular muscles. A helpful maneuver to perform, when possible, is to move the head side to side as well as up and down while following the movement of both globes. The globes should move together and symmetrically. In a sedated or anesthetized patient, motility of the globe can be assessed by gently grasping the sclera with toothed forceps. The normal globe can be used for comparison. Visual prognosis  is poor when extraocular muscles are entrapped in fractured bone. Bony fragments can be removed, especially if they are protruding into the orbit. Large displaced fractures can be repaired or removed surgically. Consultation with an experienced orthopedic or ophthalmic surgeon is recommended. Although the patient may heal with some facial asymmetry and enophthalmos, most patients retain vision. It is not uncommon for the zygomatic arch to be fractured completely with significant head trauma. Complete removal or reconstruction may be necessary.

References and Suggested Reading Allgower I et al: Extraocular muscle myositis and restrictive strabismus in 10 dogs, Vet Ophthalmol 3:21, 2000. Armour MD et al: A review of orbital and intracranial magnetic resonance imaging in 79 canine and 13 feline patients (20042010), Vet Ophthalmol 14:215, 2011. Miller PE: Orbit. In Maggs DJ, Miller PE, Ofri R, editors: Slatter’s fundamentals of veterinary ophthalmology, ed 4, St Louis, 2008, Saunders, p 352. Ramsey DT et al: Comparative value of diagnostic imaging techniques in a cat with exophthalmos, Vet Comp Ophthalmol 4:198, 1994. Ramsey DT et al: Ophthalmic manifestations and complications of dental disease in dogs and cats, J Am Anim Hosp Assoc 32:215, 1996. Wang AL, Ledbetter EC, Kern TJ: Orbital abscess bacterial isolates in in vitro antimicrobial susceptibility patterns in dogs and cats, Vet Ophthalmol 12:91, 2009.

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Canine Ocular Neoplasia SANDRA M. NGUYEN, Sydney, Australia AMBER LABELLE, Urbana-Champaign, Illinois

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cular neoplasia is relatively uncommon compared with neoplasia affecting other body systems; however, it is the second most common cause of enucleation. Early detection of ophthalmic neoplasia is important for optimal treatment outcome. Ophthalmic disease, particularly uveitis, can be the first sign of systemic neoplasia, and multicentric neoplasia can involve the eye, which makes an ocular examination desirable in all canine oncology patients. These relationships emphasize the importance of a complete physical examination in all cases of canine uveitis. Additionally, owners may be less willing to pursue oncologic treatment in blind pets, which underscores the importance of early detection and aggressive treatment of ocular neoplasia.

General Diagnostic Approach In general, a working diagnosis should be made based on ophthalmic and physical examination findings and results of fine-needle aspiration (FNA) or biopsy. Appropriate staging tests can be selected based on these results. For orbital tumors, computed tomography (CT) and magnetic resonance imaging (MRI) are very helpful in determining the local extent of disease and planning surgical and radiation treatment. For tumors involving the globe, ocular ultrasonography is useful for identifying and localizing masses obscured by corneal, aqueous, or lens opacity and for those located in the posterior segment. Ocular ultrasonography also is useful for guiding FNA, and highresolution ultrasonography can be used to assess the extent of tumors in the cornea, sclera, and iris. Thoracic radiography and lymph node aspiration should be performed to detect metastatic disease, with recognition that the overall metastatic rate for most malignant ocular neoplasms is low. The eye also may be a site of metastatic or multicentric neoplasia (as in the case of lymphoma), so the initial diagnosis will influence the subsequent diagnostic and treatment decisions. For eyelid lesions, which typically are benign, early diagnosis is the key to complete resolution without the need for complicated surgical reconstruction. One third of the eyelid margin length can be excised without impairing eyelid function. As for other skin lesions, cytologic analysis, examination of skin scrapings, and FNA are straightforward diagnostic procedures for periocular masses. The eye must be protected or retropulsed whenever a needle or blade is directed toward the globe, so chemical restraint often is indicated to prevent ocular trauma during the procedure.

For conjunctival lesions, most diagnostic procedures can be performed using topical anesthesia (proparacaine hydrochloride 0.5% solution) and gentle manual restraint. A sample of a conjunctival lesion for cytologic analysis can be obtained with the blunt end of a scalpel blade, a cytobrush, or a Kimura spatula. Biopsy of the conjunctiva also can be performed using topical anesthesia. The conjunctiva adjacent to the lesion should be grasped using small, toothed forceps and gently elevated, and then the lesion should be snipped free with small scissors. The sample then can be gently spread onto a tongue depressor for fixation. Alternatively, the sample can be placed directly into a histopathologic tissue cassette. Closure of conjunctival defects smaller than 4 mm in diameter is unnecessary. Although biopsy may be more invasive, it provides more information than cytologic analysis alone and may prove essential to obtaining a diagnosis. Subconjunctival or episcleral masses most often are inflammatory, but differentiating these from a neoplastic mass can be a diagnostic challenge. Biopsy of an episcleral mass may warrant referral to an ophthalmologist to avoid inadvertent penetration of the globe. Examination of the third eyelid also can be performed with topical anesthesia. Nontoothed forceps may be used to grasp the leading margin and elevate the third eyelid, which allows the palpebral and bulbar surfaces to be visualized and palpated directly. Biopsy of the third eyelid conjunctiva may be performed as described earlier. For larger lesions for which excisional biopsy or removal of the entire third eyelid may be warranted, general anesthesia may be required. Because the development of keratoconjunctivitis sicca is a possible complication of complete third eyelid excision, it is important to ensure that informed consent is obtained before this procedure is performed. Aqueous paracentesis is performed infrequently on visual eyes because it requires general anesthesia; carries a (low) risk of bacterial endophthalmitis, profuse iridal hemorrhage, or retinal detachment; and reliably induces transient uveitis. Aqueous humor cytologic evaluation is most sensitive for the diagnosis of lymphoma, if the diagnosis cannot be made by sampling other tissues. Vitreocentesis is most useful in cases of exudative or solid posterior segment masses in blind globes. For blind eyes, aqueous humor cytologic analysis or vitreal aspirate examination may yield a diagnosis before enucleation that may improve surgical planning, but enucleation is preferred in nonvisual eyes affected with neoplasia. For orbital masses, FNA, collection of culture specimens, and Tru-Cut biopsy can be performed through the 1201

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conjunctiva, periocular skin, or oral cavity behind the last molar. Tru-Cut biopsy is best performed under sedation or anesthesia in conjunction with ultrasonography or CT to avoid damage to the globe. Plain radiographs are useful mostly for identifying dental or nasal disease or osteolysis; CT or MRI is far superior for evaluating the soft tissues of the orbit and globe as well as for assessing involvement of orbital bone and sinuses. Orbital mucoceles and abscesses tend to have a more cavitary appearance than orbital tumors on ultrasonographic, CT, or MRI scans. Signalment, history, and examination findings help further with differential diagnoses. For instance, dental disease and neoplasia are more common causes of orbital disease in older patients. Abscesses tend to arise more quickly and to elicit more pain than tumors. Application of topical lubricants or performance of a temporary tarsorrhaphy often is needed in cases of severe exophthalmos to protect the cornea while a definitive diagnosis is being made and therapy is implemented. Histopathologic diagnosis of ophthalmic neoplasia can be complicated by the idiosyncrasies of ophthalmic anatomy and tumor physiology, species differences, the mount of inflammation present within a tumor, the orientation of the tissue, and the experience of the veterinary pathologist. Submitting a detailed history as well as drawings and photographs of the lesion in situ, inking the margins of adnexal tumors, and marking the scleral location of intraocular tumors with suture after enucleation are recommended to assist the pathologist in making the most accurate and informative diagnosis. When an enucleated globe is submitted for histopathologic analysis, fixation in a volume of formalin 10 times that of the globe is optimal for adequate fixation of intraocular tissue. A 25-gauge needle may be used to inject approximately 0.5 ml of formalin through the sclera posterior to the equator of the globe to improve fixation of the intraocular structures.

Primary Ocular Neoplasia Adnexa and Conjunctiva The most common canine eyelid neoplasms are meibomian gland adenoma and epithelioma (Figure 257-1) These tumors are benign but locally expansive, arising from the sebaceous glands and glandular epithelium, respectively. They typically occur in older dogs, have an irregularly textured to cobblestone surface, and can be seen protruding from the meibomian gland orifice as a pink, gray, or black mass at the eyelid margin. If the tumor remains within the meibomian gland it may cause obstruction of the gland orifice, resulting in accumulation of the glandular lipid secretions within the duct. When rupture of the gland ensues, marked granulomatous inflammation may develop in response to the release of inflammatory lipid products into the surrounding tissues. This secondary inflammation may give a small meibomian gland adenoma a falsely large appearance and can be quite uncomfortable for the patient. Meibomian gland adenomas and epitheliomas also can cause significant corneal irritation, and although these rarely are a direct cause of

Figure 257-1  Meibomian gland adenoma in the lower central and upper lateral eyelid of a mixed-breed dog.

corneal ulceration, they may prevent epithelialization and delay corneal wound healing when an ulcer is present. Squamous papillomas, which arise from the eyelids and periocular skin, have a clinical appearance and behavior similar to those of tumors of meibomian gland origin and also are frequent in older dogs. Squamous papillomas in younger dogs are more likely of viral origin and usually regress spontaneously without any treatment. Benign eyelid melanomas also are common in older dogs and typically are broad-based pigmented masses adjacent to but not usually involving the eyelid margin. Pedunculated forms rarely occur. Surgical resection is the treatment of choice for most canine eyelid tumors. Surgical options include fullthickness eyelid resection, carbon dioxide laser ablation, and surgical debulking with cryoablation. When fullthickness eyelid resection is performed, it is imperative to achieve perfect reapposition of the eyelid margin to ensure normal eyelid function and long-term corneal health. Surgical debulking with cryoablation is an alternative to full-thickness eyelid resection that does not require general anesthesia in most patients. It can be performed under sedation (e.g., dexmedetomidine 375 to 500 µg/m2 IV and butorphanol 0.1 mg/kg IV) and local anesthesia (0.5 ml of lidocaine 2% infiltrated into the base of  the neoplasm). After an open-closed chalazion clamp is placed over the eyelid and tumor, small scissors are used to excise all neoplastic tissue visibly extruding from the meibomian gland orifice. Gentle digital pressure may be applied to the palpebral conjunctiva to extrude any glandular contents. If the tumor can be visualized through the palpebral conjunctiva, a No. 15 Bard-Parker scalpel blade can be used to sharply excise the overlying conjunctiva to the level of the tumor, which allows débridement with a 3- or 4-mm curette or sharp excision using Stevens tenotomy scissors. It is important not to incise the eyelid margin using this debulking approach and to ensure that any incisions extend only through the palpebral conjunctiva. After the majority of the tumor material has been removed, cryoablation can be performed using liquid nitrogen in a dispensing canister with a flat probe attached (Figure 257-2). The size of the ice ball generated provides

CHAPTER  257  Canine Ocular Neoplasia

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Figure 257-2  Intraoperative photograph demonstrating the

use of an open-closed chalazion clamp to isolate a meibomian gland adenoma of the upper eyelid. A cryoprobe has been applied directly to the palpebral conjunctiva overlying the base of the tumor.

Figure 257-3  Biologically high-grade, histologically low-grade

an estimate of the depth of cryopenetration. Use of two complete freeze-thaw cycles is recommended. The size of the tip selected for the cryoablation unit should approximate the size of the base of the tumor. Postoperatively, patients should be treated for 5 to 7 days with a broadspectrum ophthalmic antibiotic ointment. Swelling and epidermal depigmentation occur commonly at the site of cryoablation, but repigmentation may be expected within weeks to months. In rare cases depigmentation remains at the eyelid margin, which may be a concern in patients for which cosmesis is important. Histiocytomas appear as firm, well-circumscribed, pink or red, raised cutaneous masses that may involve the periocular skin in young dogs. Spontaneous regression occurs within 6 weeks in most cases. FNA usually is  sufficient to confirm the diagnosis. If spontaneous  regression does not occur, complete surgical excision is recommended. Mesenchymal hamartomas are an infrequently reported benign tumor of the canine eyelid for which complete surgical excision is expected to be curative. Primary malignant neoplasms of the canine adnexa include melanoma, adenocarcinoma, mast cell tumor, histiocytic sarcoma, hemangiosarcoma, basal cell carcinoma, squamous cell carcinoma, lymphoma, and fibrosarcoma (Figure 257-3). The majority of these tumors are locally invasive, and complete surgical excision is required to achieve a good outcome. It is also important to evaluate the patient and stage the tumor to ensure that the tumor is indeed primary and to assess for the presence of metastasis or multicentric disease, particularly with lymphoma, mast cell tumor, and histiocytic sarcoma. Cytologic or histopathologic evaluation is recommended before definitive surgery to confirm the diagnosis and assist in surgical planning. Enucleation is necessary in cases of very large eyelid tumors when achievement of adequate surgical margins makes surgical resection and repair impossible.

Neoplasia of the third eyelid is uncommon. Reported neoplasms include adenoma, adenocarcinoma, squamous cell carcinoma, mast cell tumor, melanoma, lymphoma, hemangioma, hemangiosarcoma, plasmacytoma, and papilloma. Clinical signs of third eyelid disease include elevation of the third eyelid, enophthalmos or exophthalmos, deviation of the globe, and a visible mass effect within the body of the nictitans. Conjunctivitis may occur as a secondary finding. It is important to differentiate third eyelid neoplasia from a glandular cyst or prolapsed gland of the third eyelid (also known as cherry eye). Removal of the third eyelid generally is not recommended because of the contributions the gland makes to the aqueous portion of the tear film; however, surgical resection may be curative for neoplasia of the third eyelid, and the subsequent keratoconjunctivitis sicca can be managed medically in most cases. Adenocarcinoma is the most frequently reported neoplasm of the third eyelid; local recurrence or metastasis is uncommon because complete surgical resection is expected to be curative. If the tumor extends into the orbit, exenteration may be necessary to achieve complete excision. Advanced diagnostic imaging, such as CT or MRI, may be useful in surgical planning when the tumor extends to the base of the nictitans or when orbital involvement is suspected. Because of the intimate anatomic relationship of the eyelid and conjunctiva, primary conjunctival neoplasia can be quite difficult to differentiate from eyelid neoplasia. Determining the tissue of origin is particularly important for conjunctival melanoma, which has a significantly higher rate of local recurrence and potential to metastasize than melanoma of the periocular skin. Other reported neoplasms of the conjunctiva include squamous cell carcinoma, mast cell tumor, hemangioma, hemangiosarcoma, papilloma, lymphoma, and histiocytic sarcoma. Neoplastic conjunctival masses must be differentiated from nonneoplastic diseases such as episcleritis, parasitic granuloma, cysts, and subconjunctival fat prolapse. Most

fibrosarcoma arising from the lower lid of a young golden retriever. The tumor has caused significant deviation of the globe and subsequent corneal rupture.

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conjunctival neoplasms are amenable to surgical excision, potentially followed by cryoablation or beta irradiation of the margins. Conjunctival melanomas may have a higher rate of recurrence, and wide surgical excision is indicated for these neoplasms. Enucleation or exenteration may be required in some cases. Papillomas, which are found more frequently in young dogs, may regress spontaneously.

Sclera, Limbus, and Cornea Neoplasia of the canine cornea and sclera are uncommon. Theoretically, all types of epithelial neoplasms could arise from their surfaces; however, squamous cell carcinoma and limbal melanoma are the most common and clinically important tumors. Squamous cell carcinoma may affect the conjunctiva, limbus, corneal surface, or some combination thereof. Chronic keratitis is a risk factor for the development of squamous cell carcinoma. Some authors have proposed that the long-term use of immunomodulatory agents such as cyclosporine or tacrolimus may be a risk factor for the development of squamous cell carcinoma; however, controlled studies are lacking. Squamous cell carcinoma appears clinically as a pink, raised mass with an irregular or ulcerated surface, and in younger dogs, it should be differentiated from a viral papilloma, which may have a similar appearance. Cytologic analysis may be useful for distinguishing the two neoplasms. Keratectomy is curative in most cases, and adjunctive treatment with beta irradiation, carbon dioxide laser ablation, or cryoablation may decrease the incidence of local recurrence. Limbal melanomas are recognized easily by their clinical appearance as a black, smooth, circular mass at the limbus. They may invade into the cornea, iridocorneal angle, and anterior chamber. The German shepherd and Labrador retriever are predisposed. In young dogs the tumor may grow rapidly and invasively; surgical intervention is indicated in these cases. In older dogs, the tumors tend to grow very slowly and may not require treatment, although diligent monitoring with careful sequential measurements is indicated. Limbal melanomas must be differentiated from anterior uveal melanomas because uveal melanomas have a greater potential for destruction of intraocular tissues and vision loss, and therefore necessitate earlier intervention and possibly enucleation. Potential surgical interventions include full-thickness resection with grafting procedures to restore the integrity of the sclera and limbus and debulking followed by cryoablation, photoablation, or beta irradiation. Referral to an ophthalmologist is indicated in cases of limbal melanoma or squamous cell carcinoma.

Uvea Uveal melanoma or melanocytoma is the most common intraocular neoplasm in the dog and must be differentiated from a uveal cyst. Uveal cysts arise from the posterior pigmented iris epithelium, tend to be round and translucent, and may be free floating within the anterior chamber or connected to the pupillary margin by a thin stalk. A neoplastic lesion also must be differentiated from

Figure 257-4  Melanocytoma located between the 9 o’clock

and 12 o’clock positions in the iris of a Bernese mountain dog. The mass is causing dyscoria.

an iris nevus, which is the equivalent to a freckle on the skin; an iris nevus is a pigmented, flat, benign, and inactive lesion that is not expected to undergo neoplastic transformation. Anterior uveal melanoma and melanocytoma vary in clinical appearance from dark brown or black, flat or slightly raised lesions on the face of the iris, to large masses expanding or effacing the iris, to partially hidden but expansile masses of the ciliary body (Figure 257-4). Anterior uveal melanocytic neoplasms typically are locally invasive and expansive and may lead to intraocular inflammation, secondary glaucoma, and retinal detachment. These long-term complications frequently necessitate enucleation. When a slightly raised, well-circumscribed pigmented mass is present on the anterior surface of the iris, diode or neodymium:yttriumaluminum-garnet (Nd-YAG) laser may be effective in arresting the growth of the lesion and eliminate the need for enucleation. Surgical resection by sector iridectomy may be a curative therapy for smaller lesions but is accompanied by significant risk of complications, including intraocular hemorrhage, endophthalmitis, and retinal detachment. Posterior uveal (choroidal) melanoma and melanocytoma are less common and necessitate enucleation in the majority of cases. Most uveal melanocytic neoplasms in the dog are benign with no potential for metastasis, which makes recommending enucleation challenging for a visual and comfortable globe. Unfortunately, it is nearly impossible to differentiate a benign from a malignant tumor clinically, and histopathologic evaluation is essential for  confirming the diagnosis. Referral to a veterinary ophthalmologist is warranted to determine treatment options and prognosis in individual cases. For melanomas that are expected to be biologically aggressive based on presentation and histopathologic features, the canine melanoma vaccine may be used after local control of the tumor is achieved, although peer-reviewed studies documenting its efficacy in this location are lacking. Iridociliary adenoma is the second most common primary intraocular tumor in the dog (Figure 257-5). These tumors appear pink to pink-red and are seen as

CHAPTER  257  Canine Ocular Neoplasia

Figure 257-5  Ciliary body adenoma visible in the pupil of a

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mixed-breed dog. The mass has a significant cystic component and appears translucent at its most temporal aspect.

Figure 257-6  Enophthalmos, strabismus, and elevation of the

well-circumscribed masses through the pupil and behind the iris. They arise from the ciliary body but may also involve the iris. Occasionally, iridociliary adenomas may appear pigmented, which makes them difficult to differentiate from an intraocular melanocytic neoplasm. In the early stages, iridociliary tumors are not associated with intraocular inflammation. As they increase in size, secondary intraocular disease such as uveitis, secondary glaucoma, hyphema, and retinal detachment are common. These secondary complications are the most likely reasons for enucleation. Surgical resection can be attempted and is most likely to be successful early in the disease process. Transscleral laser ablation may be effective in shrinking or slowing the growth of iridociliary neoplasms. Referral to an ophthalmologist is recommended for these surgical interventions. Iridociliary adenocarcinomas are less common and rarely metastasize. It is difficult to differentiate an iridociliary adenoma from an adenocarcinoma based on clinical presentation. Spindle cell tumor of blue-eyed dogs is a mesenchymal neoplasm found in dogs with a blue or heterochromic iris. The tumor appears as an expansile mass within the iris leaflet and can extend into the ciliary body. Melanocytoma, melanoma, iridociliary epithelial neoplasia, and metastatic neoplasia are differential diagnoses for tumors with this clinical appearance. Enucleation and histopathologic analysis are required for definitive diagnosis. The tumor is considered benign, and metastasis is very rarely reported. Immunohistochemically, the tumor appears similar to a schwannoma; however, the cell type of origin has not been elucidated. Because it is difficult to distinguish this tumor clinically from metastatic neoplasia, enucleation is indicated.

Clinically the tumor appears as a pink or pink-white mass protruding into the vitreous cavity from the optic nerve or retina, and often it is associated with vision loss and mydriasis. Intraocular hemorrhage frequently is seen with these tumors, which makes intraocular visualization difficult. Ocular ultrasonography is invaluable in these cases. Although such tumors rarely metastasize, local extension from the optic nerve toward the brain is common. When such extension is present, the prognosis is significantly poorer. Radiation therapy is likely to be an effective adjunctive treatment for a glioma patient after enucleation with incomplete excision, although the efficacy of this modality for tumors in this location is not well documented in the literature. Medulloepitheliomas, although uncommon in the dog, can present as pink masses in the anterior chamber or can arise from the retina. These tumors are congenital and originate from neuroectodermal tissue. Enucleation is recommended. Meningioma is the most common tumor of the canine optic nerve. Meningiomas are divided into two categories: intraocular and retrobulbar-orbital. The intraocular form has a clinical appearance similar to that of gliomas and typically is visible on fundic examination. Exophthalmos, mydriasis, and vision loss are more common with the orbital form of meningioma. This tumor can arise from the central nervous system (CNS) with secondary extension along the optic nerve or may originate from the retrobulbar optic nerve sheath and extend both into the globe and toward the CNS. Surgical resection may be curative; however, local recurrence with extension into the CNS is common, although metastasis is rare. Radiation is likely to be an effective adjunctive therapy. Although primary orbital neoplasia has a low frequency in the canine population, it is one of the most common diseases of the canine orbit (Figure 257-6). All orbital tissues may give rise to neoplasia. Reported tumors include osteosarcoma, fibrosarcoma, squamous cell carcinoma, chondrosarcoma, and meningioma. Advanced imaging, including MRI and CT, is important for assessing local disease in these patients and aids in surgical planning. Exenteration most often is the treatment of choice;

Retina, Optic Nerve, and Orbit The retina is an extremely uncommon site of primary neoplasia. Gliomas, which are further subcategorized into astrocytomas, oligodendrogliomas, ependymomas, and oligoastrocytomas, are the only reported primary retinal neoplasms. The optic nerve frequently is involved.

nictitating membrane in a dog with an orbital mass.

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Figure 257-7  Iris bombé, dyscoria, and diffuse infiltration in the iris of an older golden retriever with multicentric lymphoma.

however, achieving complete excision of the tumor can be challenging in some cases. Follow-up radiation usually is indicated to ensure adequate local control.

Secondary Ocular Neoplasia Secondary canine neoplasms more commonly involve the intraocular structures than the ocular surface. Although any neoplasm can metastasize to the eye and periocular tissues, certain tumor types are overrepresented. Lymphoma is the most common secondary ocular neoplasm (Figure 257-7). Sudden onset of blindness or hyphema may be the first clinical sign noted in a dog with lymphoma. Involvement of the highly vascular uveal tract often is associated with uveitis. Gross masses within the iris may be present concurrently with uveitis. In addition to systemic chemotherapy for lymphoma, topical antiinflammatory therapy is warranted whenever uveitis is present. Topical ophthalmic steroid preparations such as prednisolone acetate 1% suspension should be administered every 4 to 8 hours until signs of uveitis are controlled. Topical ophthalmic atropine 1% solution may be useful in managing the pain associated with ciliary body muscle spasm that accompanies uveitis as well as preventing posterior synechia. Secondary glaucoma is an occasional complication and unfortunately is difficult to treat in isolation; achieving a systemic remission often manages the ocular component of disease. In some cases secondary glaucoma may be controlled with the judicious use of topical carbonic anhydrase inhibitor/β-blocker combinations. Topical prostaglandin analog therapy should be avoided if possible in cases of secondary

glaucoma associated with uveitis because of the potential for formation of posterior synechiae and exacerbation of the uveitis. A complete ophthalmic examination should be a regular component of reevaluation in a patient with lymphoma because ocular signs may be the first evidence that the disease is coming out of remission. Ocular lesions also may be observed in dogs with multiple myeloma. Retinal hemorrhages, increased retinal vascular caliber and vascular tortuosity, retinal detachment, anterior uveitis, iridal hemorrhages, and secondary glaucoma may be evident. Hyperviscosity syndrome likely plays a role in the etiopathogenesis of these clinical signs. Prognosis for vision can be good with systemic therapy if remission is achieved. Tumor extension from the oral, nasal, or sinus cavity into the retrobulbar space can cause exophthalmos, increased resistance to retropulsion of the globe, and ocular or nasal discharges. Squamous cell carcinoma is most commonly implicated, although primary nasal adenocarcinoma also commonly causes retrobulbar or orbital disease. Advanced imaging can confirm the suspected secondary involvement and help define the primary tumor. Any hematogenously disseminating tumor can produce metastasis within the globe or orbit; however, with the exception of lymphoma, ocular involvement is not a common feature of any single neoplasm.

References and Suggested Reading Boroffka SA et al: Assessment of ultrasonography and computed tomography for the evaluation of unilateral orbital disease in dogs, J Am Vet Med Assoc 230:671, 2007. Dreyfus J, Schobert CS, Dubielzig RR: Superficial corneal squamous cell carcinoma occurring in dogs with chronic keratitis, Vet Ophthalmol 14:161, 2011. Fife M et al: Canine conjunctival mast cell tumors: a retrospective study, Vet Ophthalmol 14:153, 2011. Giuliano EA et al: A matched observational study of canine survival with primary intraocular melanocytic neoplasia, Vet Ophthalmol 2:185, 1999. Kern TJ: Orbital neoplasia in 23 dogs, J Am Vet Med Assoc 186:489, 1985. Krohne SG et al: Prevalence of ocular involvement in dogs with multicentric lymphoma: prospective evaluation of 94 cases, Vet Comp Ophthalmol 4:127, 1994. Naranjo C, Schobert C, Dubielzig R: Canine ocular gliomas: a retrospective study, Vet Ophthalmol 11:356, 2008. Pirie CG et al: Canine conjunctival hemangioma and hemangiosarcoma: a retrospective evaluation of 108 cases (19892004), Vet Ophthalmol 9:215, 2006. Roberts SM, Severin GA, Lavach JD: Prevalence and treatment of palpebral neoplasms in the dog: 200 cases (1975-1983), J Am Vet Med Assoc 189:1355, 1986. Zarfoss MK et al: Uveal spindle cell tumor of blue-eyed dogs: an immunohistochemical study, Vet Pathol 44:276, 2007.

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Feline Ocular Neoplasia SANDRA M. NGUYEN, Sydney, Australia AMBER LABELLE, Urbana-Champaign, Illinois

O

cular neoplasia is less common in the cat than in the dog, but the proportion of primary tumors that are malignant is much higher. For appropriate therapeutic intervention, it is important to distinguish primary tumors from secondary neoplasms. Staging of disease also is important, and the concepts applicable to the cat are discussed in the chapter on canine ocular neoplasia (see Chapter 257) in this section. Treatment of many ocular neoplasms is surgical, and complications of surgery, including scarring, can lead to a number of problems of the globe or adnexa. Thus optimal surgical outcomes are most likely when the procedure is performed by a specialist in ophthalmic surgery. Additionally, other treatments may involve advanced oncologic therapies that can be obtained only by referral.

Primary Ocular Neoplasia Adnexa Feline eyelid neoplasms are less common and more likely to be malignant than similar neoplasms in dogs. Virtually any epidermal or dermal tumor may affect the eyelid. The most commonly reported neoplasm is squamous cell carcinoma. Other tumors include fibrosarcoma, adenocarcinoma or adenoma, mast cell tumor, basal cell tumor, fibroma, papilloma, hemangiosarcoma, and melanoma. Large eyelid tumors require extensive reconstructive surgery after resection, which may deter owners from pursuing treatment. Because malignant eyelid tumors can result in death or euthanasia of the cat, it is best to examine and treat these tumors early in the course of disease. Squamous cell carcinomas may appear as ulcerated or proliferative, pink, cobblestone masses. They are more common in older cats with lightly pigmented (pink) eyelid margins. Exposure to ultraviolet light is a significant risk factor for the development of squamous cell carcinoma. Squamous cell carcinoma is locally invasive and tends to metastasize late in the course of disease. The treatment of choice is complete surgical excision, although this may be challenging with large or multifocal lesions. Adjunctive therapies, including beta irradiation (using a strontium 90 probe) or cryotherapy can successfully induce remission in some patients with small tumors. If complete surgical excision is unattainable and adjunctive therapies are not available, enucleation or exenteration may be necessary. Piroxicam 0.3 mg/kg q48h PO is an empirical treatment for some cats with squamous cell carcinoma, but the patient must be closely

monitored for nephrotoxicity and gastrointestinal ulceration as well as for efficacy. Feline periocular peripheral nerve sheath tumor appears clinically as a firm intradermal mass with little to no alopecia or surface ulceration. Surgical resection with wide margins is recommended, and reconstructive surgery may be required to maintain eyelid function. Enucleation, with creation of rotational flaps to cover the orbital wound, may be necessary to prevent recurrence. Apocrine gland hidrocystomas are an unusual type of benign neoplasia seen most commonly in aged brachycephalic cats. The clinical appearance is that of multiple 2- to 8-mm smooth, round, darkly pigmented masses that contain a brown serous fluid. Although the masses are benign, their rupture may be associated with ocular discomfort. Surgical excision alone is associated with recurrence. Topical application of trichloroacetic acid and cryoablation have been reported to be more effective therapies in preventing reappearance. Neoplasia uncommonly affects the feline nictitans. Clinical signs include elevation of the nictitans, mass effect with deviation of the globe, conjunctivitis, and enophthalmos or exophthalmos. The most commonly reported tumor is squamous cell carcinoma, which may be a local extension from an eyelid or palpebral conjunctival lesion. Other reported tumors include adenocarcinoma, mast cell tumor, hemangiosarcoma, fibrosarcoma, lymphoma, and melanoma. Care must be taken to differentiate prolapse of the gland of the nictitans (also called cherry eye), a relatively uncommon condition in cats except for the Burmese and Bombay breeds, from neoplasia of the nictitans. Surgical excision is indicated for most neoplasms, with exenteration necessary when adequate surgical margins cannot be achieved with the globe in situ.

Cornea and Conjunctiva Primary corneal neoplasia is uncommon in the cat. The limbus is the most frequently affected region of the cornea. Limbal or epibulbar melanoma is the most commonly recognized tumor of the feline limbus. Limbal melanomas arise from the pigmented melanocytes of the limbus and sclera. The clinical appearance is that of a black, smooth, well-circumscribed mass that may be observed to invade the cornea and sclera. Gonioscopy is useful to detect extension into the iridocorneal angle, and high-resolution (35- to 50-MHz) ultrasonography may be necessary to determine the extent of intraocular involvement. Because limbal melanomas in cats generally are 1207

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benign and nonpainful, monitoring alone is indicated in most cases. If progression is noted, treatment options include surgical debulking and adjunctive treatment of the tumor bed (diode laser ablation, cryoablation, beta irradiation) or full-thickness surgical excision with grafting to restore scleral integrity. Digital photographs and detailed measurements are useful for detecting subtle changes in size and shape. Although distant metastasis of limbal melanoma has been reported, it is rare. Other primary corneal tumors include squamous cell carcinoma, hemangiosarcoma, fibrous histiocytoma, and lymphoma. All would be expected to arise at the limbus and usually involve corneal neovascularization. Careful clinical examination and diagnostic cytologic examination or biopsy are required to differentiate these uncommon corneal neoplasms from the more common feline corneal diseases of eosinophilic keratitis or feline herpesvirus 1–associated keratoconjunctivitis. Keratectomy with adjunctive radiation therapy or cryotherapy is indicated for these primary corneal neoplasms. Unlike limbal melanomas, conjunctival melanomas are more likely to be malignant and are associated with a higher rate of metastasis. Golden to brown granular pigmentation of the temporal bulbar conjunctiva, palpebral conjunctiva, and eyelid margin is a common ocular finding in cats with an orange coat and must not be confused with a conjunctival melanoma. Conjunctival melanomas typically are dark brown or black and raised. The palpebral, bulbar, or nictitans conjunctiva may be affected. Although excision and adjunctive treatment, including irradiation or cryoablation, may be effective in treating local disease, widespread metastasis still may result within weeks to months. Local recurrence may follow simple excision. Primary conjunctival hemangiomas and hemangiosarcomas are diagnosed rarely. Their biologic behavior is locally aggressive with rare metastasis. Complete excision is recommended. A single report of B-cell lymphoma with the clinical manifestation of palpebral conjunctival masses suggests that the conjunctiva may be primarily involved in rare cases of lymphoma.

Figure 258-1  Benign iris nevus located temporal to the pupillary margin in a young domestic shorthair cat.

Figure 258-2  Darkly pigmented multifocal iris lesions consistent with feline diffuse iris melanoma.

Uvea Feline diffuse iris melanoma (FDIM) is a clinical syndrome that encompasses a spectrum of iris lesions. A nevus is a focal, flat, benign, pigmented iris lesion that remains unchanged over the course of a patient’s life and is unassociated with other intraocular disease (Figure 258-1). FDIM must be differentiated from an iris nevus as well as from diffuse iris hyperpigmentation resulting from chronic uveitis. An FDIM lesion can be distinguished from a nevus by its typically darker pigmentation (dark brown to black), raised surface with loss of normal iris architecture, and “velvety” appearance (Figures 258-2 and 258-3). The tumors are more likely to be associated with secondary uveal or pupillary changes, pigment dispersion into the aqueous humor, and secondary glaucoma. Magnification is helpful when scrutinizing the iris surface and differentiating a benign nevus from lesions of FDIM. Frequently the diagnosis is not straightforward, and referral to an ophthalmologist may be helpful. Gonioscopy may

Figure 258-3  Diffuse iris thickening with loss of normal archi-

tecture and velvety pigmentation of the iris consistent with feline diffuse iris melanoma.

CHAPTER  258  Feline Ocular Neoplasia be useful to examine the iridocorneal angle for the presence of pigment. Determining when a pigmented iridal lesion has undergone malignant transformation to a neoplasm is a major clinical challenge. A focal pigmented lesion associated with some dyscoria but no significant uveitis or secondary glaucoma presents a significant dilemma to the clinician. Once clinical changes suggestive of malignancy (dyscoria, uveitis, pigment dispersion, or glaucoma) are documented, complete staging (based on results of local lymph node aspiration, thoracic radiography, and abdominal ultrasonography) followed by enucleation is recommended. Alternatives to enucleation include laser (neodymium : yttrium-aluminum-garnet [Nd : YAG] or diode) ablation of iridal lesions and, rarely, surgical excision of FDIM, but to date there is little documentation on the long-term benefit of these treatments. Although enucleation does provide tissue for histopathologic interpretation, iris biopsy has not proven useful clinically for making treatment decisions. Histopathologic features such as iris stromal invasion and a high mitotic rate may be poor prognostic indicators. When metastasis occurs, regional lymph nodes, lung, liver, and spleen are affected most frequently. Uveal melanomas in cats rarely may arise in the choroid. These lesions carry a poorer prognosis because their posterior location means detection occurs relatively late in the disease process. Early enucleation, particularly when performed before the development of secondary glaucoma, is the best-known treatment strategy for survival. Feline posttraumatic sarcoma (FPTS) is a poorly understood neoplasm unique to the cat. Trauma to the eye is hypothesized to result in liberation of lens epithelium from the lens capsule. The cells subsequently undergo neoplastic transformation and give rise to several types of neoplasms, including fibrosarcoma, anaplastic sarcoma, osteosarcoma, and a round cell variant of FPTS. The time between trauma and onset of clinically apparent neoplasia is widely variable, ranging from months to years. Any patient with traumatic lens capsule rupture, penetrating corneal trauma, chronic lens-induced uveitis, or a penetrating scleral wound should be considered at risk for future development of FPTS. The neoplasm typically lines the globe and may cause its expansion, which may be particularly noticeable to owners in cases in which the globe has undergone phthisis bulbi (decrease in globe size associated with chronic inflammation) and subsequently begins to expand to “normal” size. The tumor will extend up the optic nerve and can invade the brain, so that early detection and enucleation are critical for a successful outcome. Enucleation of blind chronically inflamed or previously traumatized feline eyes should be considered to prevent the development of FPTS. Tumors of the feline ciliary body include iridociliary adenoma and iridociliary adenocarcinoma. The tumor appears clinically as a pink or white mass protruding from the region of the ciliary body and often is visible within the pupil. The tumor may be pigmented in rare cases. Dyscoria may result from impingement of large masses on the pupillary margin. If the mass is associated  with uveitis or secondary glaucoma, enucleation is

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recommended. Small lesions may be surgically resectable. Metastasis is reported infrequently.

Optic Nerve and Orbit Primary neoplasia of the feline optic nerve is uncommon; however, orbital neoplasms may involve the optic nerve secondarily. Clinical signs of orbital disease in cats include exophthalmos, decreased eye movements, increased resistance to retropulsion, strabismus, pain on opening of the mouth, elevation of the nictitans, enophthalmos, ocular discharge, conjunctival hyperemia, mydriasis, and blindness. Reported primary orbital tumors include fibrosarcoma, hemangioma, carcinoma, plasmacytoma, retrobulbar teratoma, meningioma, melanoma, and osteosarcoma. Careful clinical examination and advanced imaging, including computed tomography or magnetic resonance imaging, with ultrasonically guided fine-needle aspiration or biopsy is indicated. Feline restrictive orbital myofibroblastic sarcoma is a newly recognized feline orbital neoplasm. It is most often bilateral with infiltration of the orbital and periocular connective tissue. Clinical signs include inability to blink, restriction of globe movement, and exposure keratitis. Involvement of the oral cavity (gingivitis and gingival infiltration) is common. Middle-aged cats are affected most often. Attempts at treatment, including oral immunosuppressive therapy, local antiinflammatory therapy, and radiation therapy, generally have been unsuccessful. Enucleation may be palliative in some cases but has  not been demonstrated to prevent involvement of the fellow eye.

Secondary Ocular Neoplasia The uveal tract is the most common site of metastatic neoplasia (Figure 258-4). Its vascular nature makes the uvea a logical site for hematogenous metastasis. Lymphoma is the most frequently recognized feline uveal tumor to involve the eye. Lymphoma may appear as a discrete mass in the iris or may be associated with

Figure 258-4  Focal mass in the nasal iris associated with uveitis, rubeosis iridis, keratic precipitates, and dyscoria in a domestic shorthair cat with a metastatic intraocular carcinoma.

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generalized uveitis, iritis, rubeosis iridis, miosis, aqueous flare, keratic precipitates, and secondary glaucoma. Choroidal lesions may include intraretinal hemorrhage, retinal detachment, and subretinal masses. Uveitis may be the first clinical sign of lymphoma, which underscores the importance of performing a complete physical examination and systemic workup in all feline patients with uveitis. Aqueous paracentesis may be useful for collecting neoplastic cells to make a definitive diagnosis when sampling of other organs is not feasible. Topical steroids (dexamethasone 0.1% or prednisolone acetate 1% solution q6-12h) are most effective in controlling inflammation. Adding a topical nonsteroidal antiinflammatory drug (flurbiprofen 0.03% or diclofenac 0.1% solution) may increase the antiinflammatory effect in severe cases. Topical atropine 1% solution q12-24h can alleviate painful ciliary body muscle spasm and decrease the formation of posterior synechiae by causing mydriasis. Systemic chemotherapy in conjunction with local treatment of uveitis is most effective in treating the ocular manifestations of lymphoma. Primary bronchogenic carcinoma is associated with a syndrome of angioinvasive pulmonary carcinoma in which tumor cells invade and cause infarction in the choroidal vasculature, which results in ischemic chorioretinopathy. The clinical manifestations include vision loss, wedge-shaped black or tan lesions of the tapetal fundus associated with tapetal necrosis, multifocal serous retinal exudate, and retinal vascular attenuation. Patients are invariably blind and may be affected unilaterally or bilaterally. The distal extremities of these patients similarly are affected by infarcted lesions. Successful treatment has not been reported. The feline orbit is affected more commonly by secondary neoplasms than by primary neoplasms. Extension of neoplasia from nearby anatomic structures such as the oral and nasal cavity often is implicated in orbital disease, including squamous cell carcinoma, adenocarcinoma,

and lymphoma. The conjunctiva and third eyelid also may become involved in a secondary orbital neoplasm. Advanced imaging such as computerized tomography  is invaluable in cases of orbital neoplasia for distinguishing a primary from a secondary lesion; this permits image-guided aspiration or biopsy and more accurate assessment of prognosis. Unfortunately, visual and comfortable globes may need to be sacrificed via exenteration when orbital access is essential for treatment. In some cases of nasal lymphoma, radiation therapy or chemotherapy may be globe sparing.

References and Suggested Reading Bell CM, Schwarz T, Dubielzig RR: Diagnostic features of feline restrictive orbital myofibroblastic sarcoma, Vet Pathol 48:742, 2011. Cantaloube B, Raymond-Letron I, Regnier A: Multiple eyelid apocrine hidrocystomas in two Persian cats, Vet Ophthalmol 7:121, 2004. Cassotis NJ et al: Angioinvasive pulmonary carcinoma with posterior segment metastasis in four cats, Vet Ophthalmol 2:125, 1999. Gilger BC et al: Orbital neoplasms in cats: 21 cases (1974-1990), J Am Vet Med Assoc 201:1083, 1992. Hoffman A et al: Feline periocular peripheral nerve sheath tumor: a case series, Vet Ophthalmol 8:153, 2005. Holt E et al: Extranodal conjunctival Hodgkin’s-like lymphoma in a cat, Vet Ophthalmol 9:141, 2006. Newkirk KM, Rohrbach BW: A retrospective study of eyelid tumors from 43 cats, Vet Pathol 46:916, 2009. Pirie CG, Dubielzig RR: Feline conjunctival hemangioma and hemangiosarcoma: a retrospective evaluation of eight cases (1993-2004), Vet Ophthalmol 9:227, 2006. Schobert CS, Labelle P, Dubielzig RR: Feline conjunctival melanoma: histopathological characteristics and clinical outcomes, Vet Ophthalmol 13:43, 2010. Zeiss CJ, Johnson EM, Dubielzig RR: Feline intraocular tumors may arise from transformation of lens epithelium, Vet Pathol 40:355, 2003.

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75 

Diseases of the Eyelids and Periocular Skin CATHERINE A. OUTERBRIDGE, Davis, California STEVEN R. HOLLINGSWORTH, Davis, California

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he eyelids and periocular skin can be affected by a wide variety of dermatologic diseases. Inflammation of the eyelids is called blepharitis, and many affected animals also have dermatitis elsewhere. In addition, the eyelid margin is a mucocutaneous junction, and the skin diseases that target mucocutaneous junctions often involve the eyelids. This chapter considers some of the more commonly seen medical conditions that can affect the eyelids or periocular skin of dogs and cats.

Infectious Blepharitis Bacterial Blepharitis The most common reason for bacterial blepharitis is infections caused by Staphylococcus spp. Bacterial infection of the eyelids often is secondary to another condition that alters the cutaneous microenvironment and favors bacterial colonization. Hypersensitivity or allergic reactions (e.g., atopic dermatitis or cutaneous adverse food reactions) can cause the animal to self-traumatize the area, which predisposes to secondary infection. Facialfold pyoderma occurs in certain breeds, particularly those that are brachycephalic. If the folds are close to the eyelids, moisture accumulation and bacterial colonization may occur within the skinfolds and extend to the eyelids. Mucocutaneous pyoderma also can develop secondary to a “drainage board” effect at the medial canthi in dogs with chronic epiphora. Clinical signs of bacterial blepharitis include erythema, swelling, depigmentation, alopecia, and variable degrees of ulceration and crusting. There may be pruritus, particularly if bacterial blepharitis is secondary to underlying allergic disease. There also may be concurrent mucopurulent ocular discharge. Treatment should include appropriate systemic and topical antibiotics and identification of any underlying predisposing skin or ophthalmic disease. In some dogs, surgical removal of facial skinfolds may be beneficial or curative. Bacterial infection of the various glands within the eyelid is termed hordeolum. Such infections, usually involving Staphylococcus spp., are thought to originate from the ocular surface flora. Infection of the glands of Zeis or Moll is termed external hordeolum or stye. Similar involvement of the meibomian glands is referred to as internal hordeolum. Both of these conditions are observed more frequently in young dogs and may represent an

immunologic incompetency during the juvenile period. The clinical presentation of both conditions is similar, consisting of swollen, inflamed, and painful eyelid margins. The course often is self-limiting but may be shortened with application of hot compresses along with administration of broad-spectrum topical ophthalmic and systemic antibiotics. A chalazion results when meibomian secretions thicken, obstruct the duct, and cause the buildup of secretory material in the gland. This eventually leads to glandular rupture and lipogranuloma formation. Clinically chalazia present as firm, noninflamed nodules within the eyelid. When viewed through the palpebral conjunctiva, they appear as aggregates of yellow material. Treatment involves incision of the overlying palpebral conjunctiva and curettage of the granulomatous material. Postoperative treatment is topical application of an ophthalmic antibiotic-steroid ointment for 7 to 14 days.

Fungal Blepharitis The most common fungal organisms identified in the dog or cat with dermatophytosis are Microsporum canis, Micro­ sporum gypseum, and Trichophyton mentagrophytes. These fungal organisms are adapted to colonize hair and cornified layers of the skin, where they digest keratin protein. Most animals must be exposed to a minimum infective dose of dermatophyte spores before an infection can become established. This dose varies, and development of infection is influenced by the individual animal’s overall health and immunologic status. Dermatophytosis in dogs often results in localized lesions, most commonly affecting the face, feet, or tail. Dogs often are brought in with the classical circular alopecia with scale, crust, and follicular papules. A kerion is a localized inflammatory lesion secondary to a dermatophyte infection and presents clinically as a wellcircumscribed nodular lesion of furunculosis, often located on the face or distal extremity. Dermatophyte lesions in cats are more pleomorphic. Classic lesions include one or more areas of partial alopecia, with scaling and crusting most commonly noted on the head or forelimbs. Facial lesions often are asymmetric. Dermatophytosis may result in lesions that resemble miliary dermatitis. The clinical appearance of skin lesions is unreliable as the sole criterion for diagnosis of dermatophytosis, and e363

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additional tests are required (see Chapter 105). A Wood lamp examination can be helpful in some cases, but positive fluorescence occurs in only 50% of M. canis infections, and other dermatophyte species of veterinary significance do not fluoresce at all. Definitive diagnosis of dermatophytosis requires a fungal culture and identification of the organism. Culture samples can be obtained from hairs plucked from suspicious lesions based on clinical appearance or from fluorescence-positive areas identified with a Wood lamp. Topical therapy long has been advocated for the treatment of dermatophytosis. However, numerous studies have shown that topical therapies alone are less effective than systemic therapy. Lime sulfur and enilconazole are the two most effective antifungal topical therapies. Systemic antifungal therapy has been demonstrated to decrease both the duration and severity of dermatophytosis. Itraconazole (10 mg/kg) is now preferred systemic therapy for treatment of dermatophytosis. Ketoconazole (10 mg/kg), fluconazole (10 mg/kg), griseofulvin, and terbinafine are other antifungal agents with activity against dermatophytes. Malassezia pachydermatis is a normal commensal inhabitant of the skin and external ear canal in dogs and cats. The organism may cause dermatitis as a result of inflammatory or hypersensitivity reactions to yeast antigens by the host. Most dogs with Malassezia dermatitis have concurrent skin diseases. Dogs with allergic dermatitis often have increased numbers of Malassezia colonizing their skin, and when they are treated appropriately with antifungal therapies, both the overall appearance of the skin and the degree of pruritus improve. About 40% of allergic dogs with Malassezia dermatitis also have concurrent superficial pyoderma. Cats with allergic dermatitis also may be predisposed to Malassezia dermatitis. The diagnosis of generalized Malassezia infection in a cat is reported to be linked strongly to concurrent serious systemic disease: diabetes mellitus, positive retroviral status, and systemic neoplasia. Malassezia dermatitis is diagnosed on the basis of cytologic documentation of increased numbers of the yeast organism. Malassezia organisms are lipophilic, and isolation by fungal culture often requires the addition of olive oil to the medium. The authors have seen localized Malassezia dermatitis in the periocular region in dogs who were being treated with topical ophthalmic medications in a lipid base. Topical treatment (miconazole, ketoconazole) may be effective, but in cases of chronic or generalized infection systemic therapy with 5 mg/kg of ketoconazole, fluconazole, or itraconazole daily may be necessary. Griseofulvin has no activity against Malassezia.

Parasitic Blepharitis Parasitic blepharitis most commonly is caused by infestation with Demodex mites. Demodex canis is the most commonly identified Demodex mite in dogs, but there also is a long-bodied mite, Demodex injai, and short-bodied mite, Demodex cornei. The most common form of demodicosis is localized disease, which is seen most frequently in animals younger than 10 months of age. Clinically dogs have focal areas of alopecia, erythema, and scaling, often

involving the face and feet. Generalized demodicosis covers larger areas of the body and is more common in certain breeds such as the Staffordshire terrier, Chinese shar-pei, English bulldog, Boston terrier, boxer, and pug. Clinically there can be marked areas of alopecia and erythema. Complete alopecia of the eyelids and periocular regions develops in some dogs. A cause for generalized demodicosis in adult dogs, such as immunosuppression resulting from underlying disease or a history of longterm corticosteroid use, is found in about 50% of cases. Concurrent bacterial folliculitis or deep pyoderma almost always is present in generalized demodicosis and should be treated appropriately. Feline generalized demodicosis due to Demodex cati also often is associated with underlying systemic disease. Demodex gatoi is a short-bodied mite that lives in the stratum corneum and can be a cause of contagious pruritus in cats. Diagnosis of demodicosis is based on identification of the mite on deep skin scrapings or hair pluckings. Multiple life stages and eggs also may be identified. For localized demodicosis no treatment is needed; it should resolve spontaneously as the dog matures. Dogs with generalized disease should be spayed because the disease may be exacerbated by estrus, and predisposition to disease likely is a heritable trait. Generalized demodicosis can be treated with total body dips with amitraz, which is the only licensed therapy for canine demodicosis. Off-label systemic therapy with ivermectin (0.4 to 0.6 mg/kg daily), milbemycin (1 to 2 mg/kg daily), or moxidectin (0.4 mg/kg) can be effective for generalized demodicosis (see Chapter 99 for details regarding dosing frequency). The clinician must ensure that the patient is negative for heartworm microfilaria before treatment. Ivermectin or moxidectin should never be used in breeds known or suspected to be sensitive to this drug. Dogs can be tested for carriage of the ABCB1-1 mutation (previously called the multidrug resis­ tance gene [MDR1]) that conveys sensitivity to ivermectin toxicity. Regardless of which treatment is used, therapy should be continued for 1 month past the second consecutive monthly skin scraping in which mites are not detected.

Feline Herpetic Ulcerative Dermatitis Feline herpesvirus 1 (FHV-1) is a common pathogen of domestic cats worldwide that is associated with acute and chronic rhinitis, numerous ocular diseases, stomatitis, and ulcerative facial and nasal dermatitis. Cats with herpetic dermatitis develop ulcerative skin lesions most commonly on the dorsal muzzle and nasal planum, but lesions can involve the medial canthus and periocular regions. Pruritus is variable. Cats may not have any other concurrent signs of FHV-1 infection. Diagnosis is based on compatible histopathologic findings on skin biopsy specimens from representative lesions. The presence of intranuclear viral inclusions in cells obtained from the face of a cat with marked ulcerative dermatitis is diagnostic. Eosinophilic inflammation also may be evident in affected tissues. If viral inclusions are not found, polymerase chain reaction (PCR) assay for FHV-1 or immunohistochemical testing for the virus can

WEB CHAPTER  75  Diseases of the Eyelids and Periocular Skin be performed on formalin-fixed tissue samples taken from skin biopsy specimens. In one study a negative PCR result had a 100% negative predictive value. Treatments for herpetic ulcerative dermatitis can include subcutaneous interferon-α at 1 million U/m2 or systemic antiviral drugs such as famciclovir. Secondary bacterial dermatitis may develop; thus appropriate systemic antibiotics may be warranted initially.

Allergic Blepharitis Causes of allergic eyelid disease include atopic dermatitis and cutaneous adverse food reaction (food allergy). Immune-mediated skin disorders also can affect the eyelids (see later in this chapter).

Atopic Dermatitis Atopic dermatitis is a pruritic, inflammatory, allergic skin disease that occurs in genetically predisposed animals (see Chapter 90). The prevalence of canine atopic dermatitis has been estimated to be up to 10%. Breeds predisposed to atopic dermatitis tend to vary geographically. In general, boxers, retriever breeds, and terrier breeds are overrepresented among dogs affected with this disease. Most dogs show clinical signs of atopic dermatitis between 1 and 3 years of age, and initially the clinical signs often are seasonal. The most common clinical manifestation is pruritus, particularly involving the face and including the ears, feet, axillae, and ventrum. Dogs self-traumatize pruritic areas, which results in alopecia, erythema, and excoriations. Lichenification and hyperpigmentation can develop in chronic lesions. Atopic dermatitis is diagnosed on the basis of appropriate signalment, history, and clinical findings and the exclusion of all other causes of pruritic skin disease. Treatment is aimed at decreasing the individual dog’s pruritic threshold. This often involves the elimination of any secondary bacterial and Malassezia infections; identification of any other concurrent allergic skin diseases; and judicious and prudent use of antihistamines, corticosteroids (topical and systemic), allergen-specific immunotherapy, and cyclosporine in various combinations (see Chapters 91 and 92).

Cutaneous Adverse Food Reaction (Food Allergy) A cutaneous adverse food reaction (food allergy) is presumed to be a hypersensitivity reaction to ingested allergens. Food allergy occurs in both dogs and cats, and clinically affected animals demonstrate nonseasonal pruritus that results in lesions caused by self-trauma including erosions, ulcerations, excoriations with varying degrees of alopecia, lichenification, and hyperpigmentation or erythema. The face, ears, extremities (feet), and ventrum are affected most commonly. Otitis externa also is a common feature of canine food allergy. Food allergy is diagnosed based on a compatible history and clinical signs as well as confirmation of improvement with consumption of a strict elimination

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diet containing a novel protein and relapse on challenge provocation with the original diet (see Chapter 96).

Metabolic-Nutritional Blepharitis Zinc-Responsive Dermatosis Zinc-responsive dermatosis is a metabolic skin disease that often involves the periocular region in affected dogs. Arctic breeds such as Siberian huskies and Alaskan malamutes are affected most commonly, but the disorder can be observed in other breeds. Two syndromes of zincresponsive dermatosis are recognized in dogs. Syndrome I has been identified in Siberian huskies, Alaskan malamutes, and occasionally other breeds. These dogs are speculated to have a genetic defect in the intestinal absorption or metabolism of zinc. Dogs with this disease manifest signs even when fed well-balanced diets. Syndrome II occurs in rapidly growing puppies that often are being fed a poor-quality dog food or are being oversupplemented with calcium. These juvenile dogs are thought to have a relative zinc deficiency caused by a combination of low zinc intake and the zinc-binding effects of calcium or phytate in the diet. Dogs affected by syndrome I typically have scaling, crusting, and alopecic lesions near mucocutaneous junctions, elbows, and footpad margins. Dogs affected by syndrome II are young large-breed dogs that have generalized crusting, plaques with extensive crusting or adherent scaling, and fissuring of the footpads. Diagnosis is based on appropriate signalment and dietary history, the presence of typical cutaneous lesions, and histopathologic analysis of skin biopsy specimens that reveals marked follicular and epidermal parakeratotic hyperkeratosis. Many dogs with syndrome II respond simply to feeding of a better-quality diet. Other dogs with syndrome II and all dogs with syndrome I require supplementation with 2 to 3 mg/kg of elemental zinc in the form of zinc sulfate, zinc gluconate, or zinc methionine. To date, differences in clinical response have not appeared to depend on which zinc salt is used. Affected female dogs often respond to lower dosages of zinc after being spayed. Clinical signs typically improve within 4 to 6 weeks. Response to zinc supplementation is dramatic in syndrome II zinc deficiency, and therapy is not needed once the dog has reached maturity. Dogs with syndrome I zinc-responsive dermatosis require ongoing therapy.

Superficial Necrolytic Dermatitis Superficial necrolytic dermatitis (SND) (or hepatocutaneous disease) is an uncommon skin disease (see Chapter 118). It is seen most commonly in older dogs, and there have been rare reports of the disorder in cats. Males appear overrepresented in several studies, and the mean age of affected dogs is 10 years. Elevated serum glucagon levels have been measured in a minority of dogs with SND, and a glucagon-secreting pancreatic tumor has been identified. However, most dogs with SND have a characteristic metabolic hepatopathy. It remains unclear what metabolic pathways may be linking liver or pancreatic disease with these skin lesions.

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Cutaneous lesions include erythema, crusting, exudation, ulceration, and alopecia of the face (often in the periocular and perioral regions), genitalia, and pressure points on the trunk and limbs. There is also a marked hyperkeratosis, fissuring, and ulceration of the footpads that is very suggestive clinically. Secondary cutaneous infection with bacteria, yeast, or dermatophytes, particularly involving the feet, also can be present. The skin disease may precede any systemic signs. Common clinical signs include the characteristic skin lesions, lameness secondary to footpad lesions, inappetence, weight loss, polydipsia, and polyuria. The polydipsia and polyuria typically are associated with concurrent diabetes mellitus, which is present in up to 30% of dogs with SND. Histopathologic findings of a markedly parakeratotic epidermis with striking intercellular and intracellular edema in the upper epidermis and hyperplastic basal cells create the so-called red, white, and blue lesion that is considered diagnostic for this disease. Elevation of liver enzyme levels and hypoalbuminemia are common clinicopathologic changes. Glucosuria and hyperglycemia may be documented if diabetes mellitus is present. Abdominal ultrasonography often reveals a very characteristic honeycomb pattern in the liver consisting of variable-sized hypoechoic regions surrounded by hyperechoic borders. Grossly, livers of affected dogs are multinodular, but they are not typically cirrhotic unless the liver is affected by another disease. A vacuolar hepatopathy with minimal fibrosis (inconsistent with cirrhosis) is histologically evident in most affected dogs. Dogs with SND have dramatic reductions in plasma amino acid concentrations. The hypoaminoacidemia most likely reflects increased hepatic catabolism of amino acids. Prognosis is poor, with mean survival times of 3 months. However, some dogs have survived for over a year with treatment. Palliative therapy with intravenous and oral amino acid supplementation, often with concurrent oral supplementation with zinc and essential fatty acids, has improved cutaneous lesions and overall wellbeing in some dogs. Secondary skin infections also should be treated. If present, diabetes mellitus requires appropriate management. Removal of a glucagonoma was reported to result in resolution of lesions in one dog.

Immune-Mediated Blepharitis Pemphigus Foliaceus Pemphigus foliaceus (PF) often is considered the most common of the autoimmune skin diseases in dogs. The Akita, bearded collie, chow-chow, Newfoundland, schipperke, and Doberman pinscher are predisposed to this disease. The English springer spaniel, Chinese shar-pei, and collie also appear to be at increased risk of developing PF. Mean age of affected animals is between 4 and 5 years, but dogs of any age, breed, or sex can develop PF. Three forms are suggested to occur in the dog; these are differentiated by historical information. Spontaneous PF is most common. Drug-induced PF is clinically indistinguishable from spontaneous PF. Therefore obtaining a drug history (particularly information regarding any

previous antibiotic administration) is critical for all patients with PF. Some cases of PF may occur in patients with a history of chronic, ongoing inflammatory skin disease such as allergic dermatitis. PF is important to consider in patients with chronic dermatologic conditions, particularly those with allergic dermatitis that develop atypical or more severe lesions than in previous episodes. Clinically PF is characterized by pustular and crusting lesions that often involve the face and head. The most commonly affected sites are the dorsal muzzle, nasal planum, pinnae, periocular skin, and paw pads. The nasal planum and haired dorsal muzzle typically are affected concurrently. Truncal lesions often are diffuse, and paw pad lesions vary considerably in their severity. Intraoral lesions never are a feature of PF. Pustules, if present, often are large but may progress quickly to adherent crusts. Lesions may occur in waves, so that the disease may seem to wax and wane in severity. When pustules are present they should be biopsied. Older crusted lesions that no longer are tightly adherent often are not diagnostic. Histologically, subcorneal pustules containing acantholytic cells often span multiple hair follicles. Pustules with acantholysis also can involve follicular epidermis. Neutrophils predominate within the pustules. In humans desmoglein 1 (Dsg 1) is the primary targeted autoantigen in PF. Dsg 1 is an integral protein component of the desmosomes in the superficial layers of the epidermis. Desmosomes are responsible for intercellular cohesion, and when these structures are damaged, acantholysis results. Until recently Dsg 1 was believed also to be the primary autoantigen in PF in the dog. However, recent evidence suggests that other proteins composing the desmosome may be more common autoantigens in PF, and it has just been demonstrated that desmocollin 1 is the major autoantigen in canine PF. PF should be considered when a dog has acquired pustular or crusting disease that is generalized or strongly facial or fails to respond to antibiotics. Differential diagnoses include superficial bacterial folliculitis, superficial pustular dermatophytosis, demodicosis, sebaceous adenitis, and epitheliotropic T-cell lymphoma. The prognosis for PF generally is fair. However, a retrospective study found that 50% of dogs diagnosed with PF were euthanized within 1 year of diagnosis, usually as a result of complications from immunosuppressive drug therapy. Dogs that initially were treated concurrently with staphylocidal antibiotics tended to have a better prognosis. Prednisone or prednisolone monotherapy may not maintain remission of PF as dosages are decreased. Therefore concurrent use of azathioprine, chlorambucil, or other immunosuppressive therapies is recommended to spare the adverse effects of corticosteroids. A small percentage of dogs with PF can be managed using combination therapy with tetracycline and niacinamide. Focally affected areas sometimes respond to topical immunosuppressive therapy.

Pemphigus Erythematosus Pemphigus erythematosus is a very rare crusting autoimmune skin disease. It is considered to be a more benign

WEB CHAPTER  75  Diseases of the Eyelids and Periocular Skin form of PF or a crossover between PF and systemic lupus erythematosus (SLE). The collie and the German shepherd may be breeds at increased risk. Lesions have been proven to be aggravated by light exposure. Lesions are confined to the face and include crusting, alopecia, and erosions of the dorsal muzzle, pinnae, and periocular areas. The nasal planum often is involved with depigmentation, crusting, and erosions. Biopsy specimens from intact pustules or adherent crusts are most diagnostic. Histologically, subcorneal pustules with acantholytic cells (as seen in PF) are present with concurrent interface dermatitis with basal cell damage (as seen in SLE). A definitive diagnosis requires immunologic confirmation via immunohistochemical or immunofluorescent assay and a positive result on an antinuclear antibody test. Differential considerations include facially predominant PF, discoid lupus erythematosus, superficial pustular dermatophytosis, epitheliotropic T-cell lymphoma, uveodermatologic (or Vogt-Koyanagi-Harada–like) syndrome, and SLE.

Systemic Lupus Erythematosus Skin lesions may be present in fewer than 20% of cases of canine SLE. The cutaneous lesions are pleomorphic, with erythema, scaling, crusting, depigmentation, and ulceration that often involve the face, ears, and distal extremities. Panniculitis and oral ulcerations also have been seen. SLE is a progressive disease, and evidence of immunologic involvement in multiple organ systems may not always be evident on the initial presentation. Biopsy specimens should be taken from intact epidermis. The classic histologic lesion of SLE is an interface dermatitis. Immunohistochemical testing reveals a band of positive fluorescence at the basement membrane zone. Polyarthritis, protein-losing nephropathy, neutropenia, thrombocytopenia, hemolytic anemia, and polymyositis all have been reported in association with SLE. A thorough systemic evaluation, including a complete blood cell count, serum biochemical testing, urinalysis, urine protein/creatinine ratio, antinuclear antibody test, arthrocentesis, and cytologic evaluation of joint fluid is warranted in patients suspected of having SLE. Most patients with SLE have an elevated antinuclear antibody level, although this may not always be present. Immunosuppressive therapy is required.

Erythema Multiforme Erythema multiforme (EM) is an uncommon acute eruption of the skin and mucous membranes characterized by erythematous macules and papules, crusting, vesicles, ulcers, and urticarial plaques. Annular target lesions with central pallor may be present. Lesions are seen on the trunk, groin, axillae, ears, mucocutaneous junctions, and oral mucosa. Histologically, individual cell necrosis of keratinocytes—with or without satellitosis—is the most common lesion in EM. EM likely has a multifactorial cause, with drugs, infection, or neoplasia triggering the skin lesions. In about 50% of canine cases an underlying trigger cannot be found. Drug-induced EM minus often is self-limiting once medications are stopped. Severe

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generalized mucocutaneous EM (EM majus) often requires aggressive supportive care, removal of underlying triggers, and immunosuppressive therapy.

Iatrogenic Blepharitis An adverse reaction to topical medications can result in marked eyelid inflammation, with resultant alopecia, erythema, crusting, erosions, and ulcerations. Neomycin is one of the most common topical medications to cause an adverse reaction. If ophthalmic medications cause an adverse reaction, lesions likely will involve the eyelid and possibly the medial canthus owing to a drainage effect. Diagnosis is based on a compatible history of use of topical medication. If an adverse topical reaction is suspected, all topical medication should be discontinued, and the affected area cleaned. If the inflammatory reaction is severe, systemic or topical corticosteroids may be required. Self-trauma can result in marked inflammation, with lesions of alopecia, excoriations, and crusting. Affected animals need to be evaluated for secondary infections with bacteria or yeast, evidence of demodicosis, and the possibility of allergic dermatitis.

Pigmentary Changes Involving the Eyelid Many diseases, if they cause inflammation of the skin, can result in hyperpigmentation or a loss of pigmentation of the cutaneous regions around the eyes. Lentigo simplex of orange cats is a cosmetic dermatologic condition in which intraepidermal melanocyte proliferation occurs, resulting in hypermelanosis in a macular pattern. The lentigines are well-demarcated black macules that occur most commonly along lip margins, nasal planum, and eyelid margins and increase in size and number. Diagnosis is based on compatible signalment and clinical presentation. No treatment is necessary. Vitiligo is an acquired immunologic loss of melanocytes that results in patchy or macular hypopigmentation. Belgian Tervurens, rottweilers, and German shepherds are predisposed. Lesions of leukotrichia or leukoderma typically are seen on the nasal planum, lip margins, eyelid margins, dorsal muzzle, and paw pads. Diagnosis is based on a compatible history, the presence of clinical lesions, and histopathologic analysis. The disease may wax and wane. Because it is asymptomatic and causes only esthetic concerns, no therapy is warranted. Epitheliotropic T-cell lymphoma can result in depigmentation, which often involves mucocutaneous junctions such as the eyelids, nasal planum, and lip margins. It is discussed more fully later in the chapter.

Uveodermatologic (or Vogt-KoyanagiHarada–Like) Syndrome Uveodermatologic syndrome is an uncommon canine immunologic disease that results in granulomatous uveitis and symmetric depigmenting facial skin lesions. Akitas and arctic breeds are at increased risk of the development of uveodermatologic syndrome. Characteristic

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lesions of leukoderma and leukotrichia with variable erythema and crusting involve the nasal planum, lips, eyelids, and periocular regions. Diagnosis is based on appropriate signalment, clinical signs, and characteristic histopathologic findings in representative skin biopsy specimens. Systemic immunosuppression is required for treatment of the dermatitis and uveitis, which often is blinding because of retinal detachment or development of secondary glaucoma (see Chapters 251 and 252).

Neoplastic Blepharitis Meibomian Gland Adenoma Meibomian gland adenoma is the most common adnexal neoplasm in dogs. These neoplasms almost always are benign, with malignancy being manifested only by rapid local growth, not by adjacent tissue invasion or distant metastasis. Although studies have not demonstrated a consistent breed predisposition, occurrence of this neoplasm definitely is associated with advancing age. The clinical signs consist of a nodular swelling within the eyelid and a proliferative, papilloma-like growth extending through the duct opening at the eyelid margin. The neoplasm itself typically does not cause discomfort or significant inflammation but is problematic because of its proximity to the cornea. Signalment and clinical appearance allow a tentative diagnosis, which is confirmed subsequently with histopathologic examination. Numerous effective treatment options are available, including wedge resection, laser ablation, and debulking and curettage with adjunctive cryotherapy.

Papilloma Papillomas also are a relatively common eyelid neoplasm in dogs. Unlike meibomian adenomas, these are found in young dogs. They almost always are self-limiting, and treatment rarely is indicated.

Squamous Cell Carcinoma Squamous cell carcinoma is the most common adnexal neoplasm in cats, although adnexal tumors in general are observed far less frequently in cats than in dogs. Metastasis is a potential problem but usually occurs only late in the disease course. The neoplasm can be locally aggressive, however, and spread to regional lymph nodes is not uncommon. White-haired coats and actinic radiation are thought to be involved in the pathogenesis. The common clinical presentation is an ulcerative, crusty lesion along the margin of the lower eyelid. Surgical excision, radiation therapy, and cryotherapy all are effective. Squamous cell carcinoma or actinic dermatitis occurs in areas that are poorly pigmented and in animals with a history of solar exposure. Lesions initially are erythematous, with crusting that progresses to ulceration. Eyelid margins, nasal planum, dorsal muzzle, and pinnal extremities in white animals are the most common sites for lesions.

Lymphosarcoma Both dogs and cats can have adnexal manifestation of lymphoma, which is characterized by diffuse chemosis and conjunctival hyperemia. Although lymphoma usually is accompanied by other ocular or nonocular signs, biopsy of the conjunctiva can be helpful in providing a diagnosis when it is affected. Epitheliotropic T-cell lymphoma often results in pigment loss with erythema around mucocutaneous junctions such as the eyelid, lip, or philtrum. Other cutaneous lesions can include exfoliative erythroderma and nodular or ulcerative lesions. Diagnosis is made by histopathologic analysis, sometimes with immunohistochemical testing of representative skin biopsy specimens. Systemic therapy with lomustine or retinoids appears to offer the best clinical response.

Mast Cell Tumor Mast cell tumors also can affect both dogs and cats. These tumors usually appear as noninflamed nodules within or under the eyelid skin. They usually are benign in this location. Diagnosis is by fine-needle aspiration or biopsy. Treatment options include surgical excision and radiation therapy.

Miscellaneous Eyelid Diseases Juvenile Sterile Granulomatous Dermatitis and Lymphadenitis/Juvenile Cellulitis (Puppy Strangles) Juvenile sterile granulomatous dermatitis and lymphadenitis is seen almost exclusively in puppies. Dachshunds, golden retrievers, and Labrador retrievers seem to be predisposed. The initial clinical sign is an acute onset of facial swelling affecting the eyelids, muzzle, and lips. Lesions consisting of erythematous papules, pustules, and nodules that rupture and form crusts or fistulae quickly develop. These lesions most commonly develop in the periocular regions, dorsal muzzle, and pinnae. Concurrent lymphadenopathy, lethargy, and fever are common. The disease is very characteristic in its clinical appearance, but generalized demodicosis and primary bacterial infection need to be ruled out with appropriate cytologic sampling. Histopathologic examination of representative skin biopsy specimens may be necessary to make a definitive diagnosis in early lesions. Affected puppies respond quickly to immunosuppressive doses of glucocorticoids, which suggests some underlying immune dysregulation.

Canine Reactive Histiocytosis Canine reactive histiocytosis occurs in either a cutaneous or a systemic form. Both forms target the skin and subcutaneous tissue, but in the systemic form lymph nodes, conjunctiva, sclera, nasal planum and nares, lungs, spleen, and bone marrow also can be involved. Often skin lesions are multiple nonpruritic cutaneous papules, plaques, or nodules that may be alopecic and can

WEB CHAPTER  75  Diseases of the Eyelids and Periocular Skin ulcerate. Lesions occur most commonly on the head, neck, dorsum, perineum, extremities, and scrotum. Diagnosis is based on histopathologic analysis of skin biopsy specimens from representative lesions. Treatment is with immunosuppressive drugs. Cyclosporine and leflunomide have generated the best clinical response in this disease.

Entropion Entropion is defined as an inward rolling of the eyelid margin that subsequently leads to contact of the eyelid skin with the ocular surface. Entropion often is classified as breed related, spastic, or cicatricial. Breed-related entropion usually is apparent as soon as eyelid margins “open” at about 10 to 14 days postpartum and is seen most frequently in dogs. Different breeds often exhibit entropion in different eyelid locations. Mid-sized to large breeds most often have entropion of the lateral aspect of the lower eyelid. Small and toy breeds demonstrate entropion of the medial aspect of the lower lid. All aspects of both eyelid margins usually are involved in shar-peis. Clinical signs of entropion are blepharospasm, epiphora and wetting of the eyelid skin in the affected areas, corneal ulceration, vascularization, and melanosis if the eyelid skin is in contact with the cornea. The appropriate correction is determined by the age of the patient and the eyelid area involved. Dogs younger than 1 year of age should not undergo permanent surgical repairs. Such adolescent patients are managed with topical lubricants or eyelid-tacking procedures until they are old enough for surgery. The most commonly used surgical repair of entropion is the Hotz-Celsus technique. Spastic entropion occurs as a result of ocular surface pain and may or may not be associated with other types of entropion. Because of the potential for spastic entropion, all patients diagnosed with entropion should be evaluated further after the instillation of a topical anesthetic such as proparacaine. Cicatricial entropion is secondary to eyelid laceration or other injury. In some instances the fibrotic tissue responsible can be identified and excised. Alternatively, the Y-to-V blepharoplasty surgical technique may prove beneficial.

Ectropion Ectropion results when the lower eyelid loses contact with the ocular surface. Most instances in dogs are breed related, although this condition can be caused by old age and weakening of the orbicularis oculi muscle. Breeds with “droopy” eyes such as cocker spaniels, bloodhounds, Saint Bernards, and Mastiffs commonly are affected. Frequently the only signs associated with ectropion are a mild mucoid discharge and conjunctivitis. If the condition is severe enough, exposure keratitis can result, with accompanying blepharospasm, corneal ulceration, vascularization, and melanosis.

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Usually no treatment is indicated for ectropion. In mild cases topical lubricants or antibiotic-steroid combination preparations may be used symptomatically. If corneal lesions are present, a laterally placed wedge resection may be used to shorten the lower eyelid and thus improve eyelid conformation.

Distichiasis The meibomian glands are modified hair follicles. In distichiasis some glands fail to differentiate, and the resultant cilia emerge from the ductal openings. This condition occurs in both dogs and cats and is common in some canine breeds, including American cocker spaniels and golden retrievers. Although distichiasis usually does not produce clinical signs, it can lead to blepharospasm, epiphora, and rarely corneal ulceration. Because distichiasis usually is innocuous, manual epilation is advised to confirm that distichia cilia actually are responsible for the patient’s clinical signs before more aggressive therapeutic measures are undertaken. When necessary, distichiasis is treated by epilation with cryotherapy. A variant of distichiasis is ectopic cilia. In this condition the undifferentiated meibomian gland gives rise to a cilium that protrudes through the palpebral conjunctiva. Such cilia usually are located approximately centrally in the upper eyelid and may not emerge from the conjunctiva until about 1 year of age. Once they come in contact with the ocular surface, they cause an acute onset of marked blepharospasm and epiphora. They also may cause vertically linear superficial corneal ulceration. Treatment of ectopic cilia is surgical excision of the palpebral conjunctiva containing the offending cilia and cryotherapy.

Trichiasis Trichiasis occurs when facial hairs from normal locations come in contact with the ocular surface. It occurs most commonly in small brachycephalic dog breeds. These hairs often wick tears onto the face in the medial canthal region but rarely lead to significant irritation. If they are deemed to be problematic, they can be removed with cryotherapy.

References and Suggested Reading Bizikova P, Linder KE, Olivry T: Immunomapping of desmosomal and nondesmosomal adhesion molecules in healthy canine footpad, haired skin and buccal mucosal epithelia: comparison with canine pemphigus foliaceus serum immunoglobulin G staining patterns, Vet Dermatol 22:134, 2011. Holland JL et al: Detection of feline herpesvirus 1 DNA in skin biopsy specimens from cats with or without dermatitis, J Am Vet Med Assoc 229:1442, 2006. Mueller RS: Treatment protocols for demodicosis: an evidencebased review, Vet Dermatol 15:75, 2004. Plant JD, Lund EM, Yang M: A case-control study of the risk factors for canine juvenile-onset generalized demodicosis in the USA, Vet Dermatol 22:95, 2011.

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76 

Canine Retinal Detachment PATRICIA J. SMITH, Fremont, California

Pathogenesis

Causes

A retinal detachment (RD) is a separation of the neurosensory retina from the retinal pigment epithelium. In the normal eye the vitreous, retina, and lens are connected by various physical and chemical mechanisms. RDs may be caused by one of three main mechanisms: exudation (nonrhegmatogenous), retinal tears (rhegmatogenous), or traction pulling on the retina. Complicated RDs are those that involve more than one of these mechanisms (e.g., a retinal tear or hole that results from a vitreous traction band). In small animals most RDs are exudative. The subretinal fluid usually is inflammatory but can be serous in diseases such as systemic hypertension (see Chapter 169). The subretinal fluid typically results from breakdown of the blood-ocular barrier in the retinal and choroidal vasculature. Because the choroidal vascular bed is much larger than the retinal vascular supply, a large amount of subretinal fluid usually indicates diffuse choroidal involvement, as seen in diseases such as chorioretinitis, systemic hypertension, or hyperviscosity. Initially areas of chorioretinitis appear as variably sized focal or multifocal areas of retinal elevation with indistinct borders. These active areas of chorioretinitis alter the course of the overlying retinal blood vessels and obscure or blur the ophthalmoscopic view of the underlying retinal pigment epithelium or tapetum as shown in Web Figure 76-1. Rhegmatogenous RD is associated with the formation of one or more retinal tears or holes. This type of RD is less common than exudative RD in small animals and occurs more frequently in dogs than in cats. The pathogenesis of rhegmatogenous RD involves the presence of an abnormal retina (i.e., thinned as a result of degeneration, age, or other diseases) that is predisposed to formation of tears or holes, combined with an abnormal vitreous, as with vitreous syneresis (liquefaction), traction (from vitreal floaters or postinflammatory debris), or vitreous detachment. The vitreous gel is a homogeneous collagen fibril network with hyaluronic acid molecules filling the interfibrillar spaces. The vitreous is more firmly attached in three locations: the peripheral posterior lens capsule, the vitreous base that overlies the peripheral edge of the retina (the pars plana and ora ciliaris retinae), and the margin of the optic nerve. Since the vitreous hydrogel is attached to the lens and retina, perturbations of the vitreous (e.g., caused by inflammation or surgery) or of the lens can contribute to the development of rhegmatogenous RD by creating retinal traction, which can lead to tear or hole formation. Liquid from the vitreous then moves through the hole or tear into the subretinal space and exacerbates the RD.

Despite the multiple causes of RD, the following three features assist in differentiating or prioritizing the likely causes: (1) the type of RD (exudative, traction, or rhegmatogenous), (2) the nature of any subretinal fluid, and (3) whether the detachments are unilateral or bilateral. Although bilateral RD is strongly suggestive of systemic disease or congenital ocular disease, unilateral detachment does not rule out these causes. Serous subretinal fluid with or without hemorrhage is more common with hypertension, hyperviscosity syndromes, and rickettsial disease. When subretinal fluid is opaque from a marked cellular infiltrate, causes of exudative disease such as lymphosarcoma, idiopathic inflammatory uveodermatologic syndrome, and fungal infections should be considered more likely.

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Trauma Penetrating injuries (e.g., dog bites, projectiles) or foreign bodies may result in retinal tears or induce intraocular hemorrhage, inflammation, or vitreous infection with subsequent exudative or traction RD. Severe blunt trauma with inflammation and hemorrhage also may cause RD, which may be exudative or rhegmatogenous in nature. It is extremely unlikely for a traumatic incident to cause RD in both eyes. The exception is strangulation, which can lead to bilateral exudative (hemorrhagic) RD.

Ocular Anomalies RD may be associated with severe retinal dysplasia, optic nerve colobomas, vitreous abnormalities, and retinal nonattachment (i.e., developmental failure of the two retinal layers to unite). Animals with RD present at or soon after birth and often have concurrent abnormalities such as microphthalmia or cataracts. Detachment may be unilateral or bilateral. Later-onset genetic anomalies such as cataracts or vitreous degeneration may lead to RD. Rhegmatogenous RD also may occur because of vitreous liquefaction or cataract formation, particularly when the cataracts are rapidly forming or hypermature, or when there is lens-induced uveitis. Rhegmatogenous RD may occur as a sequela to cataract surgery (reported incidence, 1% to 4%) or lens luxation or subluxation. Many of the terrier breeds suffer from genetically based primary lens luxation, and retinal tearing and detachment may occur with or without lens surgery in these breeds. Premature and severe vitreal degeneration occurs in the Shih Tzu and can lead to spontaneous retinal tearing and detachment at a young

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may occur. With neoplasms other than lymphoma and myeloma, RD is more likely to be unilateral.

Chorioretinitis/Retinochoroiditis

Web Figure 76-1  Chorioretinitis in a dog caused by blastomy-

cosis. Small areas of active chorioretinitis are associated with focal, low retinal detachments.

age. Affected animals may be blind with bilateral detachments at presentation. These detachments usually occur one eye at a time, and animals are brought to the veterinarian when the second eye develops a detachment. The author also has seen this type of detachment (related to severe vitreal degeneration) in Boston terriers, Italian greyhounds, Yorkshire terriers, Chihuahuas, and poodles. When an RD is evident but there is no history of trauma, cataracts, or lens surgery, a thorough diagnostic workup is indicated to identify predisposing systemic diseases.

Hypertension and Hyperviscosity Systemic hypertension (most often related to renal diseases) and hyperviscosity syndromes (caused by severe hyperlipidemia, hyperglobulinemia, or polycythemia) are relatively frequent causes of RD. These diseases typically damage the vasculature of the choroid and retina, creating hemorrhage in the retina and sometimes in the vitreous. Renal failure with secondary hypertension probably is one of the most common causes of bilateral RD; Cushing’s disease and the adrenal tumor pheochromocytoma also should be considered as potential causes of RD.

Neoplasia The most common neoplastic causes of RD are multiple myeloma (in which hyperproteinemia and hyperviscosity damage retinal and choroidal vasculature) and lymphosarcoma (which may diffusely infiltrate the retina or choroid). Patients with lymphosarcoma also may present with retinal hemorrhage with or without detachment and anterior uveitis. Each of these neoplasms is likely to affect both eyes but can be unilateral. Large neoplastic masses (e.g., ciliary body iridal tumors) or metastatic lesions may induce traction RDs. If neoplastic tissue is subretinal or choroidal, exudative RD around the subretinal mass

The term retinochoroiditis is used to imply that retinal tissue was inflamed primarily with choroidal inflammation occurring secondarily, whereas the reverse is true for the term chorioretinitis. Retinitis or chorioretinitis may cause focal or multifocal RDs. As discussed previously, small areas of inflammation are technically RDs, but this type of lesion is best termed chorioretinitis (see Chapters 254 and 255). When choroidal inflammation is severe and diffuse, large segmental or complete RDs may occur. In the dog chorioretinitis with RD may be caused by bacteremia or septicemia (e.g., leptospirosis, brucellosis), rickettsial agents (ehrlichiosis, Rocky Mountain spotted fever, bartonellosis, anaplasmosis), fungal organisms (aspergillosis, blastomycosis, coccidioidomycosis, histoplasmosis, cryptococcosis, and less commonly infection with Acremonium spp. and geotrichosis), algae (protothecosis), and, rarely today, canine distemper virus. Parasitic inflammation of the choroid and retina is more likely to cause smaller areas of detachment (i.e., multifocal chorioretinitis). Causes include ocular larva migrans (due to strongyles, ascarids, Baylisascaris larvae), toxoplasmosis, leishmaniasis, neosporosis, and possibly babesiosis.

Immune-Mediated Disease Immune-mediated disease can cause vasculitis with or without choroidal inflammation. This can lead to exudative RD or chorioretinitis. In dogs systemic lupus erythematous and uveodermatologic syndrome may result in exudative detachment. Uveodermatologic syndrome is an autoimmune disease directed against melanin. The uvea of pigmented eyes is targeted, which results in severe anterior and posterior uveitis and RDs. Pigmented cells in the skin also are targeted, so that affected animals can have mucocutaneous (and later diffuse) dermatitis with eventual depigmentation. The author sees uveodermatologic syndrome more commonly in Arctic breeds such as Akitas, Siberian huskies, and chow-chows, but it also has been reported in other breeds. Granulomatous meningoencephalitis also may cause RD, usually in the peripapillary region and in association with optic neuritis and other signs of central nervous system disease. Idiopathic RD is diagnosed after thorough investigation rules out all other causes and the ophthalmic history and examination rule out retinal tears. The author diagnoses this type of detachment in dogs (especially giant breeds). It is sometimes called steroid response RD. Idiosyncratic reactions to drugs (e.g., trimethoprim/sulfa) and ethylene glycol toxicity may induce RD and multifocal chorioretinitis.

Toxicity Toxic chorioretinitis can lead to multifocal RD and possibly generalized RD due to damage of the blood-ocular barrier. This can be caused by drugs (e.g., diphenylthiocarbazone) or the ingestion of external toxins. There have

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been reports of dogs developing multifocal areas of retinal edema after ingesting horse feces that contain ivermectin used for deworming.

Diagnosis A thorough history should determine if any of the following might be relevant: trauma, swimming in ponds (Prototheca infection), feeding of or knowledge of consumption of raw fish (salmon poisoning) or mammalian carcasses (Salmonella or parasitic infection), exposure to ticks, or travel to areas endemic for some of the aforementioned infectious diseases. A complete general physical examination should be undertaken. A thorough ophthalmic examination should be conducted with special attention to intraocular pressure, pupillary light reflexes and menace responses, aqueous flare, and lens changes, and indirect and direct ophthalmoscopy of the retina should be performed. A systematic approach enables the clinician to diagnose chorioretinitis, RD, and possibly panuveitis if anterior uveitis is present (see Chapter 242). When a large RD is present, the pupil is mydriatic and the pupillary light reflex is absent or reduced in the affected eye (see Web Chapter 80). With retinal elevation the retinal blood vessels are in focus at a different plane than the optic nerve. If the retina is markedly elevated, a “membrane” (which may be the detached retina) with blood vessels may be visible through the pupil during anterior segment examination. With serous subretinal fluid, the underlying retinal pigment epithelium—or, in subalbinotic animals, the choroidal vasculature—is not clearly visualized in the nontapetal region, and a similar dulling of the tapetal region occurs. With severe exudation, a turbid subretinal fluid obscures the view of the normal tapetum and nontapetum (Web Figure 76-2). With rhegmatogenous RD a retinal tear or break may be visible (Web Figure 76-3). If opacification of the cornea, aqueous, lens, or vitreous caused by anterior uveitis or cataract prevents visualization of the retina, ocular ultrasonography can be used to diagnose RD, intraocular hemorrhage, and intraocular masses. If systemic disease is suspected, a complete blood count, serum biochemistry panel, and urinalysis are important initial tests. The results of these tests may point toward a cause and direct additional testing. For example, if an animal with RD has marked hyperglobulinemia, then protein electrophoresis should be performed, radiographs of the limbs and spine taken, and Bence Jones proteinuria documented. If these abnormalities are found, it would be diagnostic for multiple myeloma. Serologic testing, enzyme-linked immunosorbent assay, or polymerase chain reaction–based tests for infective agents may be useful in some cases. Blood pressure should be measured in cases of serous RDs with or without hemorrhage, especially if renal disease or hyperthyroidism is evident. Repeated blood pressure measurements should be taken if initial blood pressure is normal but hypertension still is suspected, especially in cases of bilateral disease. Additional testing that might be pursued includes determination of coagulation profile and cultures and cytologic analyses of ocular or body fluids. Dogs with panuveitis and mucocutaneous lesions (especially if

Web Figure 76-2  Exudative retinal detachment in a dog. This

type of subretinal fluid is seen more commonly in infectious or neoplastic diseases. The exudative fluid obscures the view of the normal tapetal and nontapetal colors. This type of subretinal fluid is more detrimental to retinal health than is serous fluid. Even if the cause is identified and treated, the retina often degenerates quickly so that visual recovery is unlikely even if reattachment occurs.

Web Figure 76-3  Rhegmatogenous retinal detachment in a

dog that had previously undergone cataract surgery. The edge of the torn retina can be visualized through the pupil in this case. This type of retinal detachment should be treated surgically.

depigmentation is prevalent) should undergo biopsy of the skin lesions, especially in susceptible breeds (Akita, chow-chow, Samoyed). Cytologic analysis or biopsy of cutaneous lesions also may aid in the diagnosis of fungal diseases. An antinuclear antibody test may be performed if systemic lupus erythematosus is suspected.

WEB CHAPTER  76  Canine Retinal Detachment Thoracic radiography is a useful screening test to search for lymphadenopathy, metastatic disease, or infiltrates consistent with infectious agents. Abdominal ultrasonography also can add information that may help with the diagnosis if it reveals abnormalities in the organs or peritoneal space such as adrenal masses or lymphadenopathy. Abdominal radiographs may be useful, but abdominal ultrasonography is superior for evaluation of the kidneys, adrenal glands, and other organs. Analysis of cerebrospinal fluid is indicated if signs of central nervous system disease or optic neuritis are present. Vitreocentesis or subretinal fluid aspiration can be performed if other diagnostic tests have failed to yield a cause and an infectious agent or neoplastic disease is suspected. However, vitreocentesis can aggravate intraocular inflammation or induce vitreous hemorrhage, which decreases the chance of retinal reattachment and restoration of vision. Thus the pros and cons of this procedure should be discussed with the owner. If an eye is irreversibly blind and painful, enucleation with subsequent histopathologic examination may yield a diagnosis.

Treatment Exudative Retinal Detachment Exudative RD is treated medically by identifying and treating the underlying cause. This may include antimicrobial therapy for bacterial disease or antifungal therapy for fungal infections. If systemic hypertension is the cause of an RD, appropriate antihypertensive therapy should be initiated. Amlodipine generally is the most effective drug for treatment of severe hypertension in dogs (see Chapter 169). If neoplastic disease is amenable to chemotherapy, it should be treated appropriately. Resolution of the underlying cause of RD sometimes leads to spontaneous retinal reattachment, especially if the fluid is relatively serous. However, if an inflammatory cause is diagnosed or there is severe chorioretinal inflammation (with a cellular subretinal fluid), systemic corticosteroid treatment may be necessary in conjunction with treatment of the primary disease. The longer a retina is detached and the more turbid the subretinal fluid, the faster the retina degenerates, with consequences of irreversible blindness or vision loss. Systemic steroid use can hasten reattachment; however, it is extremely important to eliminate or concurrently treat diseases such as a systemic mycosis because infections may be exacerbated by systemic administration of steroids at immunosuppressive dosages. If the patient appears to be irreversibly blind, and especially if secondary glaucoma is present, enucleation or evisceration with insertion of an intraocular prosthesis may be the best course to minimize systemic steroid use, aid in diagnosis, and eliminate pain. Systemic corticosteroids are the treatment of choice for idiopathic or immune-mediated exudative RD such as that caused by uveodermatologic syndrome. The author prescribes prednisone (1.1 mg/kg q12h PO for 3 to 10 days) and then, if the retina is beginning to reattach, begins tapering the dosage slowly while monitoring to see if retinal reattachment occurs and watching for

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signs of recurrent inflammation or detachment as the prednisone dosage is lowered. Prednisone may be dosed as high as 2 mg/kg PO q12h but the author usually starts with the 1.1 mg/kg dosage q12h. If corticosteroid treatment does not rapidly improve the RD, adjunctive immunosuppressive agents such as azathioprine or cyclosporine may be added to the treatment regimen. The patient should be monitored closely for adverse effects such as bone marrow suppression, hepatopathy, and renal toxicity when these drugs are used. In cases of hypertensive retinopathy the author rarely uses systemic corticosteroids unless there is a severe uveitis or vitritis secondary to intraocular hemorrhage. RD cases (with or without uveitis and secondary glaucoma) can be difficult to manage. Referral to an ophthalmologist should be strongly considered for diagnosis and treatment of any vision-threatening ophthalmic diseases.

Rhegmatogenous (Nonexudative) Retinal Detachment In contrast to exudative RD, rhegmatogenous RD and traction RD represent surgical conditions, and these patients should be referred promptly to an ophthalmologist for diagnosis and treatment. This type of detachment is treated by identifying and then sealing all retinal tears or holes. Small detachments may be stabilized by performing barrier laser retinopexy around the border of the detachment and at the periphery of the retina. Large or complete detachments with giant retinal tears, several holes, or vitreous problems must be repaired surgically. Surgery involves a pars plana vitrectomy, retinal reattachment, laser retinopexy, and typically tamponade with silicone oil to replace the vitreous. Unfortunately, not all patients are good candidates for this surgery. Surgical repair requires protracted general anesthesia and extensive postoperative monitoring and is very costly. Depending on the individual eye, the anatomic success rate may be as high as 90%; however, this does not always correlate with a functional success of vision recovery.

Prognosis The prognosis for an RD relates directly to the cause and timing of the diagnosis and treatment. If there is a lifethreatening systemic disease, the prognosis for life often is poor. If there is no life-threatening disease, an animal may become blind or visually impaired or might lose a painful eye but subsequently may live a well-adjusted life. In patients with RD and visual impairment at presentation, prognosis is guarded. Recovery of vision depends on the promptness of diagnosis and treatment. If the underlying condition can be identified rapidly and treated, the retina may reattach, and some vision may return. However, up to 80% of the retinal nutrition and oxygen supply is derived from the choroidal vasculature. Therefore, as soon as the retina separates from the choroid and retinal pigment epithelium, retinal degeneration begins. The nature of the subretinal fluid, duration of detachment, and height of detachment influence the degree and rapidity of retinal degeneration. Blood or dense exudative subretinal fluid (as in systemic mycoses), prolonged RD,

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and very elevated (bullous) detachment all hasten retinal degeneration and negatively affect visual recovery. In animals with a small or partial RD or smaller or multifocal areas of chorioretinitis, the prognosis is fair to good for maintaining some vision if the cause is identified quickly and treated appropriately.

References and Suggested Reading Hakansan N, Forrester SD: Uveitis in the dog and cat, Vet Clin North Am Small Anim Pract 20(3):715, 1990. Hendrix DV et al: Clinical signs, concurrent disease, and risk factors associated with retinal detachments in dogs, Prog Vet Comp Ophthalmol 3:87, 1993.

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Martin CL: Ocular manifestations of systemic disease: the dog. In Gelatt KN, editor: Veterinary ophthalmology, ed 3, Philadelphia, 1999, Lippincott Williams & Wilkins, p 1401. Narfstrom K, Ekesten B: Diseases of the canine ocular fundus. In Gelatt KN, editor: Veterinary ophthalmology, ed 3, Philadelphia, 1999, Lippincott Williams & Wilkins, p 869. Smith PJ: Vitreous and retina. In Slatter D, editor: Textbook of small animal surgery, ed 3, Philadelphia, 2003, Saunders, p 1418. Vainisi SJ, Wolfer JC: Canine retinal surgery, Vet Ophthalmol 5:291, 2004. Wilkie DA: Control of ocular inflammation, Vet Clin North Am Small Anim Pract 20(3):693, 1990.

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Epiphora CHARLOTTE B. KELLER, New Westminster, Canada

E

piphora is defined as an overflow of tears from the conjunctival sac, as may occur with dysfunction of the lacrimal drainage system or with excessive lacrimation that results from ocular pain or irritation (Web Box 77-1). Chronic epiphora leads to staining of the facial hair and moist facial dermatitis, which results in a noncosmetic appearance and an unpleasant odor. Determination of the cause of epiphora is essential before treatment can be instituted and requires a mechanistic approach at first. Conditions that lead to excessive lacrimation should be ruled out before congenital or acquired dysfunction of the lacrimal drainage system is diagnosed. Other causes of epiphora include the irritating or painful conditions of entropion, corneal ulceration, anterior uveitis, and glaucoma (these disorders are addressed in other chapters in this section of Current Veterinary Therapy). Management of epiphora involves identifying and treating the underlying cause. When surgical treatment of the eye or adnexa is recommended to correct a cause of epiphora, referral to a veterinary ophthalmologist is recommended.

General Principles The nasolacrimal apparatus in dogs and cats comprises an upper and a lower punctum, which open into the upper and lower canaliculus, respectively. The canaliculi meet at the nasolacrimal sac and continue as a single nasolacrimal duct into the nose or nasopharynx. Several tests can evaluate nasolacrimal drainage system patency. These include applying topical fluorescein and observing it

when it exits at the nares, flushing the duct with a nasolacrimal cannula or intravenous catheter, and imaging using dacryocystorhinography and computed tomography. The results of these tests must be interpreted carefully. In some animals, the nasolacrimal duct opens into the pharynx, so that dye is not seen at the nares despite normal patency. These animals may be noted to swallow after the duct has been flushed, and the swallowing is used as an indicator of patency. Furthermore, during the flushing, the lids are everted so that the patient’s normal anatomy and physiology of the nasolacrimal drainage apparatus are altered. Therefore a positive result indicates a patent duct, but this finding does not prove that tears can drain under normal physiologic conditions. Additional diagnostic tests may help to establish an accurate diagnosis in patients with epiphora. These include Schirmer tear test, cytologic examination and microbial culture of nasolacrimal system discharge, retrograde flushing of the nasolacrimal system, orbital ultrasonography, and magnetic resonance imaging.

Congenital Disorders Epiphora in Small Breeds Shallow orbits, as seen in brachycephalic dogs and cats, cause prominent globe positions and as a result very tight-fitting lids with small lacrimal lakes. Because of this, tears are more likely to spill over onto the face than to

WEB CHAPTER  77  Epiphora

WEB BOX 77-1  Causes of Epiphora • Shallow orbits and prominent globes with tight-fitting lids and small lacrimal lakes • Aberrant hair at medial canthus and caruncle acting as a wick • Medial lower lid entropion or medial canthal entropion with punctum closure • Imperforate or obstructed punctum or canaliculus • Dacryocystitis • Obstruction of nasolacrimal duct • Irritation or pain due to distichiasis, trichiasis, ectopic cilia, entropion, conjunctival or corneal disease, uveitis, glaucoma

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enhancing tear access to the nasolacrimal puncta (Gelatt, 2007). Cryoepilation of the caruncular hair also can be helpful if surgery is not an option. Seldom is there complete resolution of the epiphora because the shallow orbit persists. Treatment with oral tetracycline (50 mg per dog daily) or metronidazole (100 to 200 mg per dog daily) meets with variable success in dogs to reduce staining of the facial hair and thereby make the epiphora less noticeable. Pet owners may obtain tylosin tartrate (sold under the trade name Angel Eyes), which promises stain-free eyes. All these drugs may alter tear composition and reduce bacterial growth but do not affect tear production. Keeping the facial hair short and clean is beneficial and preferable in most cases, especially if the problem is minor. Removal of the third eyelid gland is a poor choice of therapy because of the risk of keratoconjunctivitis sicca in predisposed animals.

Imperforate Punctum

Web Figure 77-1  Bilateral epiphora in a 4-month-old Shih Tzu

with distichiasis, trichiasis, and ectopic cilia. Chronic epiphora leads to tear staining of the facial hair.

remain in the lake and drain through the nasolacrimal puncta and duct. These animals also have hairs that originate from the medial caruncle and canthal area and act as a wick, which facilitates drainage of tears onto the face (Web Figure 77-1). In many animals, the punctum, although normally developed and in the correct location, is occluded due to entropion of the medial lower lid or the entire medial canthal region. When the lid rolls inward, the punctum is compressed, which prevents normal tear drainage and irritates the cornea due to the resultant trichiasis. Thus careful examination of the medial canthal region and the nasolacrimal system is necessary for determination of all the factors that lead to epiphora. Treatment consists of surgical correction of the abnormal lid position. A Hotz-Celsus procedure can be used to correct lower medial entropion but tends to make an already large palpebral fissure even larger and may reduce the ability to blink. For this reason, a medial canthoplasty with removal of the caruncle and usually about one fourth of the upper and lower eyelid margins is performed. This corrects the macropalpebral fissure, caruncular trichiasis, and lower medial entropion while

Imperforate puncta may occur as a congenital anomaly or may be acquired as a result of scarring after trauma or severe conjunctivitis. Atresia of the punctum most often occurs alone but may be associated with atresia of the canaliculus or the nasolacrimal duct. Epiphora is the predominant sign if the lower punctum is abnormally developed. Minimal clinical signs are associated with atresia of the upper punctum. Imperforate puncta commonly are seen in cocker spaniels and poodles but can occur in any breed. A slight indentation in the conjunctiva often is seen in the area of the missing punctum. Flushing saline through the other (usually upper) punctum with a lacrimal cannula or an intravenous catheter results in ballooning of the mucous membrane over the canaliculus. Addition of fluorescein dye to the saline can enhance visibility of the solution through the mucous membrane. Treatment consists of surgical removal of the mucous membrane over the canaliculus. The ballooning mucous membrane is held with fine forceps and is excised with scissors. The opening is enlarged along the canaliculus. In case of atresia of both puncta an incision is made in the location where the canaliculus is expected to be and the aforementioned procedure is performed. A topical antibiotic-corticosteroid solution is used after surgery every 8 hours for 7 to 10 days to prevent infection and reduce scarring and the possibility of occlusion. Sometimes the punctum is present but is abnormally small (micropunctum). In this case the goal is to enlarge the punctum by using a punctal dilator, surgically increasing the size of the opening by removing a triangular piece of the mucosa, or combining the two procedures.

Imperforate Canaliculus Imperforate canaliculus is a relatively uncommon anomaly but occurs sometimes with atresia of the punctum. The diagnosis of atresia of the canaliculus is made if, in the absence of one punctum (usually the lower), flushing of the other punctum does not lead to the ballooning of the mucosa. Dacryocystorhinography may confirm the diagnosis. Treatment ideally consists of

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creation of a new drainage pathway; however, this may be difficult to achieve. If one punctum and one canaliculus exist, it may be possible to create the other canaliculus and punctum surgically. A metal cannula is placed within the existing canaliculus to define its location, and a new punctum and canaliculus are created in the appropriate position using an 18-gauge needle. A size 0 monofilament suture or small-diameter polyethylene (PE 50 or PE 90) tubing is placed in the duct and is left for 2 to 3 weeks. Topical antibiotic-corticosteroid solution is applied every 6 hours while the tube is in place. In the absence of both canaliculi, treatment options include conjunctivorhinostomy, conjunctivobuccostomy (conjunctivoralostomy), and conjunctival-maxillary sinostomy to create a new drainage pathway into the nose, mouth, or maxillary sinus, respectively (Gelatt and Gelatt, 2001).

Acquired Disorders Obstructed Punctum and Canaliculus The nasolacrimal punctum and canaliculus can become obstructed by inflammatory cells, debris, plant material, or other foreign bodies. In rare cases, a cyst (canaliculops) can compress the canaliculus. Usually the lower punctum and canaliculus are affected, which causes epiphora, possibly mucopurulent discharge, and conjunctivitis with possible swelling of the medial canthal area. Flushing the obstructed punctum and canaliculus often is unsuccessful, but flushing through the patent (usually upper) punctum can dislodge debris or foreign material. This procedure may have to be performed with the patient under sedation or general anesthesia, especially in cats. Foreign bodies may be grasped with forceps if they are protruding through the punctum, or the punctum and canaliculus may have to be enlarged surgically. After the obstructing material has been removed, topical treatment with an antibiotic-corticosteroid solution every 8 hours for 10 days is initiated. Surgical removal of a canaliculops is performed after a dacryocystorhinography study. A large suture or smalldiameter polyethylene tubing may be placed in the nasolacrimal duct after surgery for 2 to 3 weeks to prevent scarring. Topical antibiotic-corticosteroid therapy is continued until the stent is removed.

Dacryocystitis Inflammation of the lacrimal sac is relatively uncommon. Clinical signs may include epiphora, mucopurulent discharge, conjunctivitis, and swelling of the medial canthal region just below the lower eyelid. Palpation may cause apparent pain and force discharge out of the punctum into the conjunctival sac. Abscessation can occur with fistulation ventromedial to the lower eyelid. Cellular debris, foreign material, and swelling of the mucosa lead to obstruction of the nasolacrimal drainage system. Dacryocystorhinography or computed tomographic scan may be helpful in making a diagnosis. Vigorous flushing under sedation or general anesthesia may dislodge obstructing material through the punctum, the fistula, or

the nose. Material flushed in this manner should be collected for bacterial culture and sensitivity testing before or after flushing. A nasolacrimal catheter is placed after the flushing and is left in place for 2 to 3 weeks. Topical and systemic antibiotic therapy as dictated by culture and sensitivity results is indicated throughout this period. Nonsteroidal antiinflammatory drugs are used only if severe swelling or discomfort is present. Fistulas usually heal when infection is controlled and duct patency is restored. If clinical signs persist, flushing is repeated. If the material cannot be dislodged or if the condition becomes chronic, surgical exploration of the nasolacrimal sac (dacryocystotomy) is performed. The sac is flushed through an opening made in the lacrimal bone (Gelatt and Gelatt, 2001) or through an incision in the conjunctiva over the lacrimal sac (Allgoewer and Nöller, 2009).

Obstruction of the Nasolacrimal System Congenital cyst formation (dacryops), foreign material, inflammation, trauma, or neoplasia can cause obstruction of the nasolacrimal duct. Epiphora, mucopurulent discharge from the eye and sometimes the nose, and mild conjunctivitis may be seen. Dacryocystorhinography is necessary for diagnosis and localization of the obstruction. Nasal endoscopy also may be helpful. Dacryops are removed surgically, drained, or perforated to relieve the obstruction. Foreign material such as inflammatory debris and foreign bodies may be dislodged through vigorous flushing so that patency of the duct is restored. Topical antibiotic-corticosteroid solution is applied every 6 hours for 10 days. Repeated flushing may be necessary. Facial trauma with bony fractures can lead to laceration and scarring of the nasolacrimal duct with secondary epiphora. Creation of a new drainage pathway into the nose (conjunctivorhinostomy), into the mouth (conjunctivobuccostomy), or into the maxillary sinus (conjunctivalmaxillary sinostomy) is necessary to improve clinical signs in these patients; however, these procedures seldom are performed. Nasal and paranasal tumors, as well as osteomyelitis of the orbital and nasal bones or severe rhinitis, may lead to deviation, occlusion, or invasion of the duct.

Laceration of the Canaliculus Medial canthal trauma is uncommon; however, it often results in laceration of a canaliculus. Hemorrhage and edema make recognition of the tissues difficult. Cannulation of the duct through the punctum will allow identification of the proximal portion of the canaliculus. Finding the distal part is more challenging but may be achieved by flushing or cannulating the opposite punctum. A size 0 monofilament synthetic suture or small-diameter polyethylene tubing is placed in the nasolacrimal duct. The canaliculus may be sutured with 8-0 absorbable suture material. After the lid laceration is closed in two or more layers, the ends of the suture or tubing are sutured to the skin outside the nares and near the medial canthus. This catheter is left in place for at least 3 weeks. Treatment consists of systemic and topical antibiotics (every 6 hours) until the stent is removed.

WEB CHAPTER  78  Ocular Emergencies

Lacrimation Caused by Disorders of the Cilia Facial hairs (trichiasis) or cilia originating from the meibomian glands (distichiasis/districhiasis) cause ocular irritation if they rub against the cornea. Clinical signs include epiphora and slight blepharospasm (see Web Figure 77-1). Very fine distichia or those that do not touch the cornea, as may be seen in the cocker spaniel, do not result in clinically significant irritation. Treatment of trichiasis includes shortening of the facial hair or surgical removal of the facial fold or the skin containing the hair. Treatment of distichiasis consists of destruction of the hair follicle using electrocoagulation, thermocoagulation, or cryotherapy followed by epilation. If only a few hairs are present they may be epilated manually every 4 to 5 weeks; however, these tend to grow back in a short and bristly form and cause even more irritation. Manual epilation alone is not recommended for long-term management of distichiasis. Postoperative treatment consists of a topical antibiotic solution or ointment applied every 8 hours for 7 to 10 days. Postoperative application of cold compresses may prevent some of the swelling seen after cryoepilation. Ectopic cilia originate from the meibomian glands but exit through the palpebral conjunctiva and therefore

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cause severe irritation often resulting in a linear or oval corneal ulceration and keratitis. The underside of the lids, usually the upper lid, needs to be examined carefully with magnification for the tiny cilium to be visualized. Often the conjunctiva around the hair is slightly elevated or pigmented. After application of fluorescein, a small positively staining dot can be seen in the location of the ectopic cilia. Treatment of ectopic cilia consists of surgical removal of a piece of palpebral conjunctiva and meibomian gland containing the ectopic cilia and its follicle using appropriate surgical techniques to minimize complications or disfigurement. Postoperative treatment consists of a topical antibiotic solution or ointment applied every 8 hours for 7 to 10 days.

References and Suggested Reading Allgoewer I, Nöller C: A surgical technique for dacryocystotomy in dogs with foreign body induced dacryocystitis, Annual Meeting of the European College of Veterinary Ophthalmologists/European Society of Veterinary Ophthalmologists, Copenhagen, Denmark, June 3-7, 2009, Vet Ophthalmol 12(6):384, 2009 (abstract). Gelatt KN: Veterinary ophthalmology, ed 4, Ames, IA, 2007, Blackwell Publishing, p 599. Gelatt KN, Gelatt JP: Small animal ophthalmic surgery: practical techniques for the veterinarian, ed 1, Woburn, MA, 2001, Butterworth-Heinemann, p 131-133.

78 

Ocular Emergencies K. TOMO WIGGANS, Davis, California JULIET R. GIONFRIDDO, Fort Collins, Colorado

O

cular emergencies are common in veterinary practice. To preserve vision and minimize patient discomfort, it is important to diagnose and treat ocular disease rapidly. The most common ocular emergencies are discussed in this chapter.

Proptosis Proptosis is the anterior displacement of the globe with entrapment of the eyelids posterior to the globe. This condition frequently is caused by blunt trauma. Brachycephalic animals may experience proptosis with application of less force than animals of other skull shapes. Because of their shallow orbits, less severe ocular damage may occur in brachycephalic animals with proptosis. In contrast, dolichocephalic dogs and cats require much greater force to produce proptosis because of the

deep-seated position of the globe in the orbit in dogs and greater coverage of the globe by the orbital rim in cats. Dolichocephalic animals frequently experience concurrent facial bone fractures and optic nerve trauma. The prognosis for vision following proptosis is guarded; however, nonvisual eyes may be salvaged for cosmesis. Evaluation of the globe for rupture (based on overall shape and turgor), intraocular hemorrhage, and extraocular muscle rupture is an important component of the initial assessment and the decision making regarding when a proptosed globe should be replaced. Rupture of the posterior sclera is difficult to detect visually; ocular ultrasonography can be useful for assessing the integrity of the globe when rupture is suspected. Pupil size does not reflect prognosis, but intact direct or indirect pupillary light reflexes may indicate a better prognosis for vision. If any extraocular muscle is ruptured, the

SECTION  XII  Ophthalmologic Diseases

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A

C

B

D

E

Web Figure 78-1  A, Cross-sectional and lateral view of a prolapsed eye. B, First suture place-

ment in the eyelid. C, Replacement of a proptosed globe showing simultaneous tension on the sutures and downward pressure on the globe using a scalpel handle. D, Replacement of the globe and tightening of the sutures. E, Final appearance of the replaced globe and temporary tarsorrhaphy. (Modified from Severin GA: Severin’s veterinary ophthalmology notes, ed 3, Fort Collins, CO, 1995, Severin, with permission.)

prognosis for vision decreases because this indicates that severe trauma has occurred and optic nerve damage is likely. When the globe has been ruptured, two or more extraocular muscles have been avulsed, or significant intraocular hemorrhage (i.e., filling more than 50% of the anterior chamber) is present, the prognosis for vision is grave, and the globe should be enucleated. Otherwise, replacement of the globe should be attempted. A complete physical examination and assessment of the patient’s fitness for general anesthesia should be performed before replacement of a proptosed globe. Globe replacement should be performed under general anesthesia after the patient’s condition has been stabilized (Web Figure 78-1). First, the eyelids are gently clipped and cleaned. A lubricating gel or ointment should be applied to protect the corneal surface. Using 4-0 nonabsorbable monofilament suture, two to three horizontal mattress sutures are then pre-placed through the eyelids starting 5 to 8 mm distal to the margins. Care should be taken to ensure that the sutures are not full thickness because penetration of the lids through the palpebral conjunctiva leads to corneal ulceration. A lateral canthotomy may aid in replacing the globe. While the sutures are pulled upward to evert the eyelids, gentle pressure is placed on the globe using a scalpel handle or other flat, smooth instrument. Stents may be required to relieve tension on

the skin sutures. The medial canthus may be left open to facilitate administration of topical medications. Postoperative systemic therapy should consist of broad-spectrum antibiotics and antiinflammatory dosages of prednisolone (0.5 to 1 mg/kg/day PO) for 7 to 14 days. Topical therapy should consist of broad-spectrum antibiotic drops (one drop every 6 to 12 hours) and atropine (one drop every 24 to 48 hours). Sutures may need to remain in place for at least 4 to 6 weeks and should be replaced after 2 weeks if they have loosened. All animals should wear an Elizabethan collar for as long as the sutures are in place. Complications following proptosis include blindness, keratoconjunctivitis sicca, keratitis, strabismus, anterior uveitis, glaucoma, phthisis bulbi, and optic neuritis.

Eyelid Laceration Full-thickness eyelid lacerations require immediate surgical closure to prevent drying of the ocular surface and trauma to the globe. Partial-thickness and older wounds should be closed promptly because second-intention healing can lead to eyelid margin irregularities and subsequent keratitis. For all lacerations, débridement of the eyelid should be minimal, and only the truly devitalized tissue should be removed. If more than one third of the

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A

e379

B

Web Figure 78-2  A, Figure-eight suture pattern for eyelid margin apposition. B, Final appearance of tied figure-eight suture. (Modified from Severin GA: Severin’s veterinary ophthalmology notes, ed 3, Fort Collins, CO, 1995, Severin, with permission.)

eyelid is missing or requires removal, then reconstructive blepharoplasty is required. Repair should be performed under general anesthesia. Gentle clipping and surgical preparation should be performed. A two-layer closure is required for full-thickness wounds. Apposition of the eyelid margins should be performed first, using 5-0 or 6-0 absorbable suture (Web Figure 78-2). Meticulous care should be used to realign the eyelid margin properly and tie the knot away from the margin. The remainder of the subcutaneous tissue may be closed with a simple interrupted pattern, but placement of full-thickness sutures that penetrate the palpebral conjunctiva should be avoided. The skin then should be apposed with 5-0 nylon or silk. Home care consists of use of an Elizabethan collar to prevent self-trauma and broad-spectrum topical and systemic antibiotic therapy.

Corneal Ulceration Corneal ulcers are considered emergencies because of their painful nature and the potential for infection, which may lead to loss of the globe. Clinical signs of ulceration of any depth include blepharospasm, serous or mucoid discharge, miosis, and conjunctival or scleral hyperemia. Diagnosis is made by observation of fluorescein stain retention by the stroma. If an ulcer is present, taking a complete history and performing ophthalmic examination with Schirmer’s tear test are essential to determine the underlying cause (e.g., foreign body, eyelid mass, eyelid or eyelash disorder, keratoconjunctivitis sicca, lagophthalmos, or neurologic deficits). Ulcerations of the cornea are classified as uncomplicated or complicated. Uncomplicated ulcers involve loss of only the corneal epithelium and should heal completely within 1 week. Treatment of uncomplicated corneal ulcers includes application of topical broadspectrum antibiotic drops or ointments (every 6 to 8 hours) to prevent infection and topical atropine (typically one dose is sufficient) to reduce pain from ciliary body muscle spasm. The use of topical steroids alone or in combination with antibiotics is contraindicated because they impair the normal healing process and promote

stromal melting. Prognosis for complete healing of uncomplicated ulceration is excellent. Complicated corneal ulcers may be superficial, progressive, or deep. They are characterized by one or more of the following: • Failure to heal within 7 to 10 days • Increasing depth despite the use of standard treatment for an uncomplicated corneal ulcer • Change in stromal character (e.g., a melting appearance) • Presence of corneal neovascularization • Presence of stromal infiltrate (i.e., white blood cells) If an uncomplicated ulcer does not heal in 7 to 10 days, the reason must be determined. A nonhealing superficial ulcer that has no apparent inciting cause most likely can be identified as a spontaneous chronic corneal epithelial defect, also known as an indolent ulcer. Initial treatment options for indolent ulcers include cottontipped applicator débridement, diamond burr débridement, and grid keratotomy under topical anesthesia. Deep ulcers that were not produced by deep trauma likely are infected. These have a melting appearance to the stroma due to the actions of collagenases produced by microorganisms and inflammatory cells. A descemetocele is a very deep ulcer that has reached Descemet’s membrane. A characteristic of descemetoceles is that the base of the ulcerated region does not absorb fluorescein stain. Referral of patients with complicated ulcers to a veterinary ophthalmologist is recommended. Unless the ulcer appears rapidly melting, an infected ulcer with stromal loss of less than 50% of the corneal thickness may be managed with aggressive topical treatment. Broadspectrum topical antibiotics should be applied every 1 to 2 hours for at least the first 24 to 48 hours. Because of the possibility of corneal rupture through a deep ulcer, ointments should be avoided. Fungal keratitis in dogs and cats is rare, but topical antifungal agents should be used if fungal hyphae are observed on cytologic examination. Unless corneal neovascularization has reached the ulcer bed, systemic antimicrobial therapy is of little benefit. In addition to antimicrobial therapy, treatment should be instituted to stop stromal melting and alleviate pain.

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SECTION  XII  Ophthalmologic Diseases

Autologous serum contains endogenous anticollagenases and initially should be applied topically every 1 to 2 hours to help prevent further melting. Topical acetylcysteine also may be used, but the growth factors present in serum are lacking. Analgesia should be provided by topical atropine applied every 6 to 8 hours initially to prevent ciliary body spasm. Frequency then may be decreased to every 12 to 24 hours. Systemic antiinflammatory medications, either corticosteroids at antiinflammatory dosages or nonsteroidal antiinflammatory drugs (NSAIDs), can be used to control inflammation. The use of topical steroids is contraindicated. Ulcers deeper than 50% of the corneal thickness should be treated initially as described previously, and the patient should be referred immediately to a veterinary ophthalmologist for surgical placement of a conjunctival or amnion graft. If corneal melting can be halted and the eye does not rupture, the prognosis for deep ulceration is fair to good. Scarring of the cornea may result, and the degree of corneal involvement will determine how much vision is compromised. Third eyelid flaps are not recommended in the treatment of complicated corneal ulcers because they can interfere with topical drug delivery, do not deliver vasculature to the ulcer, and impede evaluation of the healing process. Temporary partial tarsorrhaphy can provide protection and allow for medication and visualization but does not provide vascular or structural support of the ulcer. Please see Chapter 246 for more information about corneal ulcers.

Corneal Laceration, Perforation, or Foreign Body Corneal lacerations often are caused by sharp penetrating foreign objects such as plant material or cat claws. Separation of the cornea from the sclera at the limbus typically is due to blunt trauma. Partial-thickness wounds may present with a visible corneal defect and edema in the surrounding stroma. It is common to find foreign material embedded within the cornea following traumatic penetration. Negative prognostic indicators include fullthickness lacerations, lacerations that cross the limbus, and significant intraocular damage. Full-thickness perforations caused by trauma or progression of severe corneal ulceration usually are sealed by prolapsed iris tissue or a fibrin plug, each of which appears as abnormal tissue protruding above the corneal surface. With iris prolapse or dyscoria, the pupil is minimally responsive or unresponsive. A Seidel test should be performed in all cases of corneal trauma. To perform the test, a concentrated drop of fluorescein dye is applied to the cornea. A positive test result is indicated by dilution of the concentrated dye due to leakage of aqueous humor from the perforation site. Full-thickness penetration and blunt trauma can result in intraocular damage, including hyphema, anterior uveitis, and lens capsule rupture. If the capsule of the lens is compromised, severe phacoclastic uveitis can result. Phacoclastic uveitis is extremely difficult to control and frequently leads to secondary glaucoma despite aggressive

medical therapy. Prompt referral to a veterinary ophthalmologist is recommended in cases of suspected or confirmed lens capsule rupture.

Treatment of Lacerations Partial-thickness lacerations may be treated in the same way as uncomplicated corneal ulcers. Full-thickness lacerations, however, should be repaired using very small suture material (7-0 or smaller) with meticulous suture placement accomplished with the aid of an operating microscope and with the patient under general anesthesia. Referral to a veterinary ophthalmologist is recommended. Postoperative treatment consists of broadspectrum oral and topical antibiotics to prevent secondary infection and topical atropine for pain relief. Oral corticosteroids or NSAIDs should be given to treat the secondary uveitis. In the absence of intraocular damage, the prognosis for saving the eye and vision is good.

Treatment of Foreign Bodies After application of a topical anesthetic, superficial foreign bodies may be removed using a moistened cotton-tipped applicator, small forceps, or sterile eyewash or saline under slight pressure. If the foreign material is more firmly embedded, the animal should be sedated, and the tip of a 25-gauge needle can be used to help dislodge the material. The eye then should be treated medically in a fashion similar to that for a corneal ulcer. Corneal penetration by plant material carries an increased risk of development of keratomycosis, which may manifest as persistent keratitis, corneal melting, or corneal abscessation despite antibiotic therapy. Foreign bodies that are more deeply embedded in the cornea should be excised surgically by a veterinary ophthalmologist.

Glaucoma Acute glaucoma is a painful and vision-threatening emergency. Clinical signs of acute glaucoma are secondary to elevations in intraocular pressure (IOP). Behavioral signs of acute glaucoma presumably are the result of severe pain and include blepharospasm, lethargy, decreased appetite or water intake, inability to rest comfortably, and subtle changes in behavior. Clinical signs of glaucoma include mydriasis with decreased or absent pupillary light reflex, epiphora, engorged episcleral vessels, diffuse corneal edema, abnormal anterior chamber depth (deep or shallow), and decreased or absent vision. The diagnosis is made by measuring IOP via tonometry. When IOP is measured, care should be taken to avoid compression of the jugular vein or manipulation of the eyelids that may elevate pressures. IOP values above 25 mm Hg are considered abnormal in the adult dog and cat. A case of acute glaucoma should be classified as primary or secondary to determine the optimal treatment. Primary glaucoma is a hereditary, breed-related abnormality of the drainage angle in both dogs and cats. Diagnosis of primary glaucoma is based on signalment and history, elevated IOP, and absence of underlying ophthalmic disease. Anterior uveitis, lens luxation or

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Ophthalmic examination

Is the eye buphthalmic? Yes

No

Consensual PLR? No

Measure IOP Yes

Refer to an ophthalmologist

Decreased

Increased

Uveitis (treat accordingly)

Duration? 24 hours

Perform salvage procedure (e.g., enucleation, evisceration, chemical ciliary body ablation)

No

Consensual PLR?

 24 hours

Yes

Institute emergency medical management • Topical prostaglandin analogs • Intravenous mannitol (0.5-1.5 g/kg) • Topical carbonic anhydrase inhibitors • Topical β-blockers • Oral carbonic anhydrase inhibitors

Refer to an ophthalmologist (for additional surgical treatment of affected eye, evaluation of contralateral eye)

Web Figure 78-3  Algorithm for the treatment of canine or feline glaucoma. (Modified and reprinted with permission of Jeannette da Silva Curiel, DVM, DACVO.)

subluxation, intraocular neoplasia, and cataracts can lead to secondary glaucoma in dogs and cats. Normal IOP in an eye with severe uveitis is consistent with secondary glaucoma because uveitis usually is associated with decreases in IOP. Regardless of the cause, prognosis for long-term IOP control and retention of vision is guarded to poor. Early and aggressive treatment should be instituted to decrease pain and preserve any remaining vision (Web Figure 78-3). All efforts should be directed at lowering the IOP rapidly. The following medications are recommended for glaucoma treatment in the emergency setting: • Topical prostaglandin analogs (PGAs) such as latanoprost or travoprost: These rapidly lower IOP in dogs by promoting aqueous drainage but are less effective in cats. One drop should be applied and IOP rechecked in 30 to 60 minutes. This can be effective as a sole agent to decrease IOP. • Intravenous mannitol: 0.5 to 1.5 g/kg is given slowly over 30 minutes to dehydrate the vitreous. A second dose can be given no sooner than 4 hours later, and no more than two doses should be given in a 24-hour period. Water should be withheld for several hours following administration to prevent rehydration of the vitreous. Mannitol should be used if topical PGAs are unavailable or ineffective. Contraindications to mannitol administration

include dehydration, renal insufficiency, and congestive heart disease. • Oral carbonic anhydrase inhibitors (CAIs) such as methazolamide (2 to 5 mg/kg every 8 to 12 hours PO): CAIs decrease the production of aqueous humor and can be given if topical PGAs are unavailable or ineffective. The adverse effects of these drugs are gastrointestinal upset, metabolic acidosis, and hypokalemia. Contraindications to administration of oral CAIs include preexisting acid-base and electrolyte disorders. • Topical CAIs such as dorzolamide or brinzolamide (one drop every 8 to 12 hours). These are less effective than topical PGAs at reducing IOP. • Topical β-blockers such as timolol or betaxolol (one drop every 8 to 12 hours). Systemic effects include bradycardia and bronchoconstriction, so their use is not recommended in patients with lower airway disease and cardiac disease. Once the pressure has normalized, maintenance treatment with (1) oral and topical CAIs, (2) a combination of a topical CAI and a β-blocker, or (3) a combination of other systemic and topical therapies should be instituted. Because of their potency, topical PGAs should be reserved as rescue therapy for refractory cases. When the eye retains some degree of vision, the patient may be referred to an ophthalmologist for endoscopic or

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SECTION  XII  Ophthalmologic Diseases

transscleral laser surgery or gonioimplantation. This also is recommended in cases in which an underlying cause (such as anterior lens luxation) may be addressed surgically to preserve vision. In acute cases in which the eye is blind and refractory to medical management and chronic cases in which damage is irreversible (e.g., buphthalmos), enucleation or evisceration with intrascleral prosthesis implantation is preferred. Chemical ciliary body ablation with intravitreal injection of gentamicin should be reserved for use in patients in which surgery under prolonged general anesthesia is contraindicated. Please see Chapters 251 and 252 for more information about glaucoma.

Anterior Uveitis Local or systemic insults to the blood-aqueous barrier in the anterior uvea lead to the release of inflammatory mediators, fibrin, and inflammatory cells into the anterior chamber. These substances can damage the corneal endothelium, block the iridocorneal angle, decrease production of aqueous humor, or cause cataracts or lens instability. Since uveitis is painful and may be vision threatening, it should be treated as an emergency. Clinical signs of anterior uveitis include decreased vision or blindness, blepharospasm, epiphora, enophthalmos, and third eyelid protrusion. Ophthalmic findings include episcleral injection, aqueous flare, miosis, hypopyon, hyphema, keratic precipitates, rubeosis iridis, decreased IOPs (typically 25). These PK : PD targets are met when antimicrobials are administered at label dosages for the pathogens indicated on the label. For extralabel pathogens with high MIC values, such as Pseu­ domonas aeruginosa, achieving the optimum PK : PD ratios systemically may be impossible with label or even higher

than label dosages. In such cases, underdosing is ineffective and merely contributes to antimicrobial resistance.

Time-Dependent Antimicrobials For antimicrobials whose efficacy is time dependent, the time during which the antimicrobial concentration exceeds the MIC of the pathogen (T > MIC) determines clinical efficacy (Figure 260-2). How much above the MIC and for what percentage of the dosing interval concentrations should be above the MIC still is being debated and likely is specific for individual bacteria-drug combinations. Typically, exceeding the MIC by one to five multiples for between 40% and 100% of the dosing interval is appropriate for time-dependent antimicrobial agents. The time that the concentration exceeds MIC should be closer to 100% for bacteriostatic antimicrobials and for patients that are immunosuppressed. Therefore these drugs typically require frequent dosing or constant-rate infusions for appropriate therapy. An exception is cefovecin; this third-generation cephalosporin maintains concentrations above the target MIC for 7 days because of its high degree of protein binding. In sequestered infections, penetration of the antimicrobial to the site of infection may require high plasma concentrations to achieve a sufficient concentration gradient. In such cases, the AUC0-24 hr : MIC or Cmax : MIC, or both, also may be important in determining the efficacy of an otherwise time-dependent antimicrobial. The penicillins, cephalosporins, most macrolides and lincosamides, tetracyclines, chloramphenicol, and potentiated sulfonamides are considered time-dependent antimicrobials.

Urinary Tract Infections Bacterial urinary tract infection (UTI) results when normal skin and gastrointestinal tract flora ascend the urinary tract and overcome the normal urinary tract defenses that prevent colonization. Large retrospective studies have documented the most common species of uropathogens in dogs and cats, with Escherichia coli being the single most common isolate in both acute and recurrent UTIs (Ball et al, 2008). Gram staining and determination of  pH of a urine sample help direct empiric antimicrobial therapy. If the urine is persistently alkaline, a ureaseproducing pathogen such as Staphylococcus spp. should be suspected if Gram-positive cocci are seen, and Proteus if Gram-negative rods are seen. If the urine is acidic, 1219

SECTION  XIII  Infectious Diseases

1220

14

Suggested Empiric Antimicrobial Therapy by Site of Infection Based on the Likely Pathogens and Their Antimicrobial Susceptibility Site of Infection

First-Choice Antimicrobials

Urinary tract

Amoxicillin Cephalexin or cefadroxil Nitrofurantoin Tetracycline or doxycycline

Pyoderma

Upper respiratory tract Amoxicillin/clavulanic acid Cephalexin or cefadroxil Azithromycin Doxycycline Lower respiratory tract

Amoxicillin/clavulanic acid ± fluoroquinolone* or aminoglycoside† Cephalosporin ± fluoroquinolone* or aminoglycoside† Clindamycin ± fluoroquinolone* Chloramphenicol Tetracycline or doxycycline Azithromycin

Musculoskeletal: surgical prophylaxis

Potassium penicillin G Cefazolin

Musculoskeletal: septic arthritis, tenosynovitis, osteomyelitis

Cephalosporins Clindamycin Amoxicillin/clavulanic acid Fluoroquinolones* Aminoglycosides†

Septicemia/bacteremia Cefazolin Cefazolin or penicillin + enrofloxacin Cefazolin or penicillin + aminoglycoside† Cefoxitin *Fluoroquinolones include enrofloxacin, orbifloxacin, marbofloxacin, and pradofloxacin, but only enrofloxacin is available in an injectable formulation. †Aminoglycosides include amikacin and gentamicin. In orthopedic infections, these drugs can be used in local therapy to avoid toxicity.

Concentration (g/ml)

25 Cmax: MIC > 10

15 AUC0-24 hr:MIC > 125

10

MIC  2

5 0

0

1

2

3

4

5 6 7 Time (hr)

8

9

10

11 12

Figure 260-1  For concentration-dependent antimicrobials, the ratio of maximum plasma concentration (Cmax) to minimum inhibitory concentration (MIC) and the ratio of area under the curve to MIC are the major determinants of clinical efficacy.

7 Hr

12 10

T>MIC  50%

8 6 4

MIC  2

2 0

Cephalexin or cefadroxil Amoxicillin/clavulanic acid Cloxacillin, dicloxacillin, or oxacillin Clindamycin, lincomycin, or erythromycin

20

Concentration (g/ml)

TABLE 260-1 

0

1

2

3

4

5 6 7 Time (hr)

8

9

10

11

12

Figure 260-2  For time-dependent antimicrobials, the time

during which the antimicrobial concentration exceeds the minimum inhibitory concentration for the pathogen determines clinical efficacy.

the most likely pathogens are E. coli if Gram-negative rods are seen, and Enterococcus spp. or Streptococcus canis if Gram-positive cocci are seen. Initial treatment of uncomplicated UTIs is straightforward because most antimicrobials undergo renal elimination to a great extent, so urine concentrations may be up to 100 times peak plasma concentrations. All of the first-choice treatments are time-dependent antimicrobials, so frequent dosing is important for efficacy. Amoxicillin has excellent activity against staphylococci, streptococci, enterococci, and Proteus and can achieve high enough urinary concentrations to be effective against E. coli and Klebsiella if dosed frequently. Therefore amoxicillin every 8 hours is the most rational empiric therapy for bacterial UTI while culture and susceptibility results are pending. Amoxicillin/ clavulanic acid has excellent bactericidal activity against βlactamase–producing staphylococci, E. coli, and Klebsi­ ella. However, clavulanic acid undergoes some hepatic metabolism and excretion, so the efficacy of amoxicillin/ clavulanic acid may be due primarily to the high concentrations of amoxicillin achieved in urine; therefore it is not preferred over amoxicillin for first-line therapy. First-generation cephalosporins, such as cephalexin or cefadroxil, have greater stability to β-lactamases than penicillins and therefore have greater activity against staphylococci and Gram-negative bacteria. They have excellent activity against staphylococci, streptococci, E. coli, Proteus, and Klebsiella. Pseudomonas, enterococci, and Enterobacter are resistant, and the use of cephalosporins predisposes patients to nosocomial enterococcal infections. Thus cephalexin and cefadroxil are suitable empiric alternatives to amoxicillin, as long as enterococcal infection has been ruled out by the Gram stain results and urine pH. Nitrofurantoin is an old antimicrobial approved only for treatment of UTIs in people because therapeutic concentrations are not attained in plasma or tissues. It is also a good first-line treatment for UTIs caused by E. coli, enterococci, staphylococci, Klebsiella, and Enterobacter. Bacterial resistance to nitrofurantoin usually does not convey resistance to other antimicrobial classes, so this old antimicrobial is increasingly recommended as a firstline treatment in women. Similarly, recommendations for its use in veterinary medicine are increasing, but good

CHAPTER  260  Rational Empiric Antimicrobial Therapy PK : PD studies have not been carried out in dogs and cats, and its adverse effects profile in dogs and cats is not well documented. Tetracyclines are broad-spectrum antimicrobials that can be used empirically for the treatment of UTIs, but because of plasmid-mediated resistance, staphylococci, enterococci, Enterobacter, E. coli, Klebsiella, and Proteus have variable susceptibility. However, the tetracyclines are excreted unchanged in the urine, so high urinary concentrations may result in therapeutic efficacy despite susceptibility test results that indicate resistance. Doxycycline is a very lipid-soluble tetracycline that is better tolerated in cats and achieves therapeutic concentrations in the prostatic and renal tissues. Because of biliary elimination, it was thought initially not to be useful for treatment of uncomplicated UTIs, but effective concentrations for treatment of the most common pathogens are achieved in the urine of dogs and cats. Combinations of trimethoprim or ormetoprim with a sulfonamide are synergistic and bactericidal against staphylococci, streptococci, E. coli, and Proteus. Activity against Klebsiella is variable, and Enterococcus spp. and Pseudomonas are resistant. Although their spectrum of activity makes the potentiated sulfonamides rational first-line treatment choices, they are  associated with a number of adverse effects that discourage more frequent selection. Enrofloxacin, orbifloxacin, and marbofloxacin are all fluoroquinolones approved for treatment of UTIs in dogs and some are approved for cats, but all are used in cats. All fluoroquinolones have excellent activity against staphylococci and Gram-negative bacteria but have variable activity against streptococci and enterococci. The therapeutic advantage of these drugs is their Gram-negative antimicrobial activity and excellent penetration into the prostate gland and activity in infected tissues. Their concentration-dependent killing allows for client-convenient once-daily dosing. However, it is inappropriate to use these important antimicrobials for empiric treatment of uncomplicated UTIs. Their use should be reserved for complicated UTIs, such as cases of pyelonephritis that involve Gram-negative bacteria, and for UTIs in intact male dogs in which prostatic involvement is likely.

Pyoderma Pyoderma is a common primary bacterial skin disease of dogs caused by Staphylococcus pseudintermedius, whereas pyoderma occurs in cats only secondary to a primary pathologic problem (e.g., flea allergy). S. pseudintermedius is part of normal skin flora and colonizes the upper respiratory tract, the oral cavity, the anal region, and the external ear canal of dogs. Most canine staphylococci produce slime that allows the bacteria to adhere to cells, and contain protein A, which activates the complement cascade and incites inflammation. E. coli, Proteus spp., and Pseudomonas spp. can colonize the skin transiently and occasionally may become involved in pyoderma secondary to the staphylococcal infection. Treatment of the primary staphylococcal infection usually is sufficient to resolve these secondary infections. Effective treatment of pyoderma requires systemically administered antimicrobials and topically applied

1221

antibacterial agents, along with specific treatment of any  underlying causes (e.g., atopy). Appropriate empiric antimicrobials must be resistant to β-lactamase produced by staphylococci. Historically, S. pseudintermedius isolates did not demonstrate significant antimicrobial resistance because they did not readily retain antimicrobial resistance plasmids. However, methicillin-resistant S. pseudin­ termedius (MRSP) infections in dogs and cats have become increasingly common since 2006 and present a significant therapeutic challenge. MRSP can contain a wide range of different antimicrobial resistance genes, which makes these organisms resistant not only to all β-lactam antibiotics but also to other classes of antimicrobial drugs, including the fluoroquinolones. Two major clonal MRSP lineages have disseminated in Europe and North America. Isolates originating in North America often are susceptible to chloramphenicol, whereas isolates in Europe often are resistant. There are reports of MRSP isolates resistant to all approved veterinary antimicrobials, which has resulted in pressure to use “last-resort” antimicrobials approved for human use, such as linezolid. Amoxicillin/clavulanic acid and first-generation cephalosporins, such as cephalexin or cefadroxil, are the usual empiric treatment choices for staphylococcal pyoderma, and dosing every 12 hours achieves a concentration above the MIC for 40% to 50% of the dosing interval. Cefpodoxime proxetil and cefovecin, thirdgeneration cephalosporins, are attractive for use because of their client-convenient dosing schedules but should be reserved for more serious skin infections than superficial pyoderma. The antistaphylococcal penicillins (cloxacillin, dicloxacillin, and oxacillin) are excellent first choices for treatment of pyoderma, but because of a limited spectrum of activity these human-approved drugs usually are not on stock in a veterinary clinic, although they can be prescribed easily from a pharmacy. Because of poor oral bioavailability and rapid renal elimination, they must be dosed every 6 hours, which makes client compliance difficult. The macrolides and lincosamides are reasonable empiric choices for treatment of pyoderma, but recurrent infections are likely to be resistant. Erythromycin is associated with a high incidence of gastrointestinal upset in dogs. This can be avoided by using enteric-coated tablets, administering with food, prescribing antiemetics for the first 2 or 3 days of therapy, and initiating therapy with a lower dose. This treatment regimen is too complicated and inconvenient for most clients, and most clinicians prefer to use antimicrobials that do not routinely induce vomiting. Lincomycin has the same activity as erythromycin and does not cause gastrointestinal upset. Clindamycin typically is very active against Staphylococcus spp. and anaerobic bacteria. Trimethoprim or ormetoprim combined with a sulfonamide is effective in most cases of superficial pyoderma, but the risks of adverse effects such as keratoconjunctivitis sicca and multisystemic drug reactions limit their use. Enrofloxacin, marbofloxacin, and orbifloxacin are first choices only for antimicrobial treatment of deep pyoderma. Pradofloxacin is specifically approved for skin infections in cats. Fluoroquinolones have ideal pharmacokinetic properties; they accumulate in leukocytes and retain activity in necrotic and purulent debris. Since they are concentration-dependent

1222

SECTION  XIII  Infectious Diseases

killers, high-dose once-daily administration is ideal and increases client compliance with the treatment regimen. The fluoroquinolones initially have excellent activity against S. pseudintermedius, Pseudomonas, and Proteus, but MRSP frequently also is resistant to fluoroquinolones and Pseudomonas readily becomes resistant if the underlying pathologic condition is not addressed.

Respiratory Tract Infections Upper Respiratory Tract Primary bacterial disease of the upper respiratory tract is uncommon, but almost all dogs and cats with a mucopurulent or purulent nasal discharge have some bacterial component to their disease. Bordetella bronchiseptica can cause primary upper respiratory tract (URT) infections in dogs, whereas B. bronchiseptica, Mycoplasma, and Chla­ mydophila felis cause primary URT infections in cats. Most cases of rhinitis are secondary to other diseases, and because of the variety of normal flora found in the nasal passages, culture and susceptibility test results are difficult to interpret. Treating the bacterial infection without correcting the underlying cause is very unrewarding and encourages emergence of antimicrobial-resistant pathogens such as P. aeruginosa. Empiric therapy for URT infections in dogs and cats includes amoxicillin, amoxicillin/ clavulanic acid, cephalexin or cefadroxil, or drugs with efficacy against Mycoplasma and C. felis, such as doxycycline or azithromycin. Doxycycline is considered the most effective therapy, but clinical signs of chlamydiosis improve with any of these drugs; yet cats frequently continue to have positive results on polymerase chain reaction or immunofluorescent antibody testing. In children, doxycycline is the least likely of the tetracyclines to cause dental damage, and there are no published reports of dental abnormalities from the use of doxycycline in puppies and kittens. However, oral administration of doxycycline to cats has been associated with esophagitis in some cats that can lead to stricture, so administration of tablets or capsules should be followed with consumption of food or water to ensure passage into the stomach. Fluoroquinolones should be reserved for resistant infections, preferably on the basis of culture and susceptibility testing. Enrofloxacin and orbifloxacin should be used carefully in cats because of the potential for retinal damage; marbofloxacin and pradofloxacin are not associated with such retinal toxicity. Tetracycline, chloramphenicol, or erythromycin ophthalmic ointments can be used to treat concurrent conjunctivitis. For chronic URT infection in dogs or cats, drugs that penetrate bone and target anaerobic bacteria, such as clindamycin, amoxicillin/ clavulanic acid, or cephalexin or cefadroxil, should be chosen.

Lower Respiratory Tract Bacterial pneumonia in dogs and cats usually is secondary to some pathologic process that disrupts normal pulmonary defense mechanisms. Treatment depends on the specific cause and the clinical status of the patient. In dogs with community-acquired bacterial infections,

the likely causative pathogens are B. bronchiseptica, Myco­ plasma spp., Streptococcus zooepidemicus, Pasteurella spp., and E. coli. In cats, the pathogens are similar with the addition of C. felis. In previously ill animals or animals with hospital-acquired illness, E. coli, Klebsiella, Pasteu­ rella, streptococci, staphylococci, anaerobes, B. bronchi­ septica, Pseudomonas, and Mycoplasma frequently are involved, and more than one bacterial pathogen commonly is isolated. The unpredictable antimicrobial susceptibility of E. coli and other Gram-negative bacteria makes it difficult to choose antimicrobial therapy without susceptibility testing. In the critically ill patient a  broad-spectrum parenteral antimicrobial regimen should be started as soon as possible until definitive culture results are obtained. Gram-negative rods frequently are susceptible to potentiated sulfonamides, gentamicin, chloramphenicol, third-generation cephalosporins (e.g., cefpodoxime proxetil), and the fluoroquinolones (enrofloxacin, orbifloxacin, marbofloxacin, pradofloxacin). B. bronchiseptica typically is susceptible to amoxicillin/ clavulanic acid, tetracyclines, or azithromycin, but some isolates are resistant to the fluoroquinolones. Grampositive cocci frequently are susceptible to amoxicillin/ clavulanic acid, chloramphenicol, cephalosporins, or azithromycin. Aminoglycosides or enrofloxacin can be administered concurrently with parenteral formulations of penicillins or cephalosporins for broad-spectrum treatment of seriously ill patients. Clindamycin or metronidazole provides activity against β-lactamase–producing Bacteroides fragilis.

Musculoskeletal Infections Prophylactic Antimicrobials Veterinary surgeons routinely administer prophylactic antimicrobials to surgical patients undergoing orthopedic procedures, but there is little evidence from clinical trials to demonstrate the efficacy of this practice. In human patients undergoing clean bone surgery, antimicrobials are administered intravenously from 30 minutes before skin incision to no longer than 24 hours after the operation. Cefazolin typically is the prophylactic antimicrobial of choice in small animal practice. However, in the only published veterinary trial of prophylactic antimicrobial therapy in dogs undergoing elective orthopedic surgery, prophylaxis decreased the postoperative infection rate, but potassium penicillin G was as effective as cefazolin (Whittem et al, 1999). Prophylactic antimicrobial therapy should be followed by close observation and treatment with appropriate antibiotics and surgery if postoperative infection is diagnosed.

Septic Arthritis, Tenosynovitis, Osteomyelitis Because of the variety of pathogens involved in musculoskeletal infections, appropriate samples must be submitted for culture and susceptibility testing. Aggressive empiric antimicrobial therapy must be initiated as soon as there is sufficient evidence of infection because of the devastating consequences of bone, joint, or tendon sheath infections. While culture results are awaited,

CHAPTER  260  Rational Empiric Antimicrobial Therapy initial antimicrobial selection can be based on the clinical case characteristics. In adult dogs and cats, septic arthritis and tenosynovitis commonly result from wounds or iatrogenic contamination with bacteria. In wounds, a variety of Gram-positive and Gram-negative bacteria typically are present, whereas Staphylococcus aureus and S. pseudinter­ medius are the usual isolates from iatrogenic infections, with methicillin-resistant S. aureus (MRSA) and MRSP increasingly reported in veterinary cases. Osteomyelitis in dogs and cats most commonly is caused by S. pseudinter­ medius. Polymicrobial infections are common in small animals, and organisms may include mixtures of streptococci, enterococci, Enterobacteriaceae (E. coli, Klebsiella, Pseudomonas), and anaerobic bacteria. Cat fight abscesses typically are caused by Pasteurella multocida and anaerobes. Pseudomonas often colonizes devitalized tissues, such as those occurring with big dog–little dog degloving injuries. For most bone and joint infections caused  by β-lactamase–producing staphylococci, cephalosporins (cefazolin, cephalexin, cefpodoxime proxetil), clindamycin, and amoxicillin/clavulanic acid are effective. In treating MRSA or MRSP infections in dogs and cats, clindamycin may be selected for empiric therapy because of its antimicrobial activity and good tissue distribution. However, an inducible form of clindamycin resistance may be present in canine MRSA isolates. These staphylococcal strains appear susceptible on routine antimicrobial susceptibility testing, but resistance is induced during clindamycin treatment, resulting in treatment failure. On a Kirby-Bauer plate, strains with this inducible resistance are difficult to detect because they appear erythromycin resistant and clindamycin sensitive in vitro. However, if the clindamycin disk is placed next to the erythromycin disk, inducible resistance is detected by the presence of a D-shaped zone of inhibition around the clindamycin disk. Therefore it is recommended that the D-test be performed for all erythromycin-resistant isolates that initially test as susceptible to clindamycin. Clindamycin  and metronidazole are effective for musculoskeletal infections caused by anaerobic bacteria. The aminoglycosides (amikacin, gentamicin) and fluoroquinolones (enrofloxacin, orbifloxacin, marbofloxacin, pradofloxacin) typically have good activity against staphylococci and excellent activity against Gram-negative pathogens. The excellent broad-spectrum antimicrobial activity and good safety profiles of the fluoroquinolones and the availability of injectable (enrofloxacin) and oral formulations make them popular choices for treatment of musculoskeletal infections. Although amikacin usually has good activity against Pseudomonas, it has poor activity against streptococci compared with gentamicin. Because nephrotoxicity and ototoxicity are related to duration of treatment, the

1223

aminoglycosides often are reserved for treatment of musculoskeletal infections by local delivery techniques. The newer human macrolide antimicrobials (azithromycin, clarithromycin) also may be effective for musculoskeletal infections and have good safety profiles in dogs and cats.

Septicemia/Bacteremia Septicemia is common in critically ill canine and feline patients, and the majority that are septicemic have blood cultures positive for bacteria. In dogs, Gram-negative bacteria (especially E. coli) are most common, followed by Gram-positive cocci and anaerobes. Polymicrobial infections also are common and usually involve Gram-negative enterics and anaerobes. Bacteria cultured from cats are primarily Gram-negative enterics or anaerobes. Therefore it is common to use intravenous cephalosporins or β-lactam/aminoglycoside or β-lactam/enrofloxacin combinations for initial treatment of septic dogs and cats. The concentration-dependent drugs are administered once daily, but the time-dependent β-lactam drugs either must be administered by constant-rate infusion or must be given at least every 6 hours. Cefoxitin is a secondgeneration cephalosporin with good activity against anaerobes and Gram-negative enterics that can be used to treat septic dogs and cats. Imipenem, meropenem, and vancomycin occasionally are used to treat resistant infections in severely ill dogs and cats, but because of their importance in human medicine their use should not be routine in veterinary patients.

References and Suggested Reading Ball KR et al: Antimicrobial resistance and prevalence of canine uropathogens at the Western College of Veterinary Medicine Veterinary Teaching Hospital, 2002-2007, Can Vet J 49:985, 2008. Faires MC et al: Inducible clindamycin-resistance in methicillinresistant Staphylococcus aureus and methicillin-resistant Staphy­ lococcus pseudintermedius isolates from dogs and cats, Vet Microbiol 139:419, 2009. Giguere S et al: Antimicrobial therapy in veterinary medicine, ed 4, Ames, IA, 2006, Iowa State University Press. McKellar QA, Sanchez Bruni SF, Jones DG: Pharmacokinetic/ pharmacodynamic relationships of antimicrobial drugs used in veterinary medicine, J Vet Pharmacol Ther 27:503, 2004. Weese JS et al: Antimicrobial use guidelines for treatment of urinary tract disease in dogs and cats: Antimicrobial Guidelines Working Group of the International Society for Companion Animal Infectious Diseases, Vet Med Int 2011:263768, 2011. Whittem TL et al: Effect of perioperative prophylactic antimicrobial treatment in dogs undergoing elective orthopedic surgery, J Am Vet Med Assoc 215:212, 1999.

CHAPTER 

261 

Infectious Causes of Polyarthritis in Dogs RICHARD E. GOLDSTEIN, New York, New York MICHAEL R. LAPPIN, Fort Collins, Colorado

D

ogs with lameness and pain usually have disease of the muscles, joints, bone, or meninges, or have referred pain from parenchymal organs such as the prostate. The site of pain or lameness usually can be determined on careful physical examination. Some, but not all, dogs with polyarthritis have swollen, hot, painful joints. Since many causes of polyarthritis involve immune complex deposition (see discussion later), the small joints often are affected. Discomfort frequently is most evident in the carpi. Dogs with polyarthritis usually are reluctant to move, and when they ambulate the gait often is described as “walking on eggshells” because they do not want to flex the small joints. There are three primary clinical groupings of polyarthritis based on joint fluid cytologic analysis: mononuclear polyarthritis (primary osteoarthritis and rarely primary immune disease); septic, suppurative polyarthritis (the organism causing disease is present in the joint); and nonseptic, suppurative polyarthritis (organisms are not demonstrated). Dogs with nonseptic, suppurative polyarthritis usually have either a primary immune disease (idiopathic polyarthritis or systemic lupus erythematosus [SLE]), an infectious disease, or a secondary immune reaction to noninfectious antigens. Polyarthritis also can be classified by whether the syndrome is erosive or nonerosive. Hypersensitivity reactions are an amplification of  the host’s normal defense mechanisms. These reactions are most common with infectious disease agents that  cause chronic infection and persist within the body. Primary immune-mediated diseases like SLE and neoplasia also can induce hypersensitivity reactions. Immunologic hypersensitivity reactions often contribute greatly to the overall extent of pathogenic changes, particularly when the organisms involved are of relatively low virulence such as the systemic fungal agents and Bartonella spp. Type III (immune complex) hypersensitivity reactions are thought to be involved in a number of primary immune or infectious causes of polyarthritis. These reactions develop as immune complexes (antibody and specific antigen) form and are deposited in or on tissues, which leads to secondary inflammation. Alternatively, free antigen can bind to membranes and subsequently react with circulating antibody. After the immune complex is deposited, complement is fixed, which leads to an inflammatory reaction. Neutrophils and platelets are attracted to the area and release lysosomal enzymes and vasoactive substances, respectively, that lead to increased 1224

vascular permeability. Synovial membranes commonly are affected in type III hypersensitivity reactions.

Differential Diagnosis Dogs with septic joints generally are systemically ill and have swollen, hot, red, and painful joints. Synovial fluid cytologic examination reveals increased numbers of nondegenerative neutrophils, degenerative neutrophils, and macrophages; bacteria, fungi, or protozoans may or may not be observed. In dogs, bacterial arthritis generally involves only one joint, and often there is a portal of entry such as a laceration or bite wound. In most dogs with nonseptic, suppurative polyarthritis the clinical signs include intermittent fever, general malaise, anorexia, joint pain, and stiffness. However, some affected dogs can have normal findings on joint palpation. It is important to remember that the infectious causes of nonerosive, nonseptic, suppurative polyarthritis often are clinically indistinguishable from primary immune causes. A number of vector-borne or non–vector-borne infectious agents causing polyarthritis are relatively common in the United States and include Anaplasma phagocytophilum (dogs or cats), Bartonella spp. (dogs), Borrelia burgdorferi (dogs), Ehrlichia canis (dogs or cats), Mycoplasma spp. (dogs or cats), and Rickettsia rickettsii (dogs). Since these organisms generally are not seen in the joints, the joint fluid usually is classified cytologically as nonseptic. Secondary immune-mediated, suppurative, nonerosive polyarthritis commonly occurs due to infectious diseases that do not directly involve the joints but cause inflammation from type III hypersensitivity. Examples are brucellosis, ehrlichiosis, bacterial endocarditis, chronic otitis externa, pyometra, actinomycosis, coccidioidomycosis, and leishmaniasis. Nonerosive, nonseptic, suppurative, polyarthritis also is believed to occur as a manifestation of vaccine reactions, although this is not well documented in dogs. It occurs most frequently with modified live calicivirus vaccination of kittens. There may be other historical data and clinical signs associated with infectious causes of nonerosive, nonseptic, suppurative polyarthritis that vary with the infectious agent. For example, R. rickettsii replicates in endothelial cells, which leads to severe inflammation in multiple tissues, and so most clinically affected dogs are extremely ill. R. rickettsii infection (Rocky Mountain spotted fever) has only an acute stage; this finding, combined with the

CHAPTER  261  Infectious Causes of Polyarthritis in Dogs fact that tick vectors are not active in the winter, make this a seasonal syndrome (spring through fall). Most cases of R. rickettsii infection are reported in the midwestern and southeastern United States. In contrast, Ehrlichia ewingii is not seasonal, clinical signs other than polyarthritis are minimal, and infection occurs mostly in dogs living in states harboring the Lone Star tick, Amblyomma americanum. Another classic finding is that polyarthritis associated with A. phagocytophilum or B. burgdorferi infection occurs almost exclusively in dogs that have visited areas endemic for the deer tick, Ixodes spp. Finally, A. phagocytophilum, E. ewingii, and R. rickettsia primarily are associated only with acute disease, which leaves Bartonella spp., B. burgdorferi, E. canis, and Mycoplasma spp. as the most likely infectious agent differentials if polyarthritis has been present long term.

Diagnostic Plan When polyarthritis is suspected, the initial diagnostic plan generally includes radiography of the affected joints to determine whether osteoarthritis or erosive changes are present and a complete blood cell count, serum biochemical testing, and urinalysis to evaluate for possible causes or sites of inflammation. Arthrocentesis usually is performed to determine whether the joint fluid is septic or nonseptic and whether the predominant cells are mononuclear cells, degenerative neutrophils, or nondegenerative neutrophils. If bacteria are seen, synovial fluid should be cultured for aerobes, anaerobes, and Mycoplasma spp. In all dogs in which the predominant cells are neutrophils, urine also should be cultured regardless of whether the neutrophils are degenerative or nondegenerative, even if bacteria are not seen. Transport media and specific culture media are required for successful culture of Mycoplasma spp. Thoracic and abdominal radiography or ultrasonography should be considered for dogs with nonerosive, nonseptic, suppurative polyarthritis to evaluate for occult infectious or neoplastic antigen sources. Urine and blood cultures should be considered. Protein : creatinine ratio should be determined if proteinuria without hemorrhage or inflammation is detected on initial urinalysis. Echocardiography can be performed to evaluate heart valves for changes associated with bacterial endocarditis. In some dogs with valvular endocarditis murmurs may not be auscultated. The decision to perform tests for primary immune diseases depends on the individual case. It has been shown that positive results on tests for antinuclear antibodies and rheumatoid factors do not correlate with the presence of primary immune-mediated diseases (Smith et al, 2004). However, because most dogs with SLE are antinuclear antibody positive, a negative test result may rule out this syndrome as a cause of the polyarthritis. The signalment, risk of vector exposure, vector disease control history, travel history, and clinical findings should be used to rank the differential list. The clinician then can select tests for individual infectious disease agents to complete the diagnostic workup. Several laboratories now offer panels of infectious agent serologic tests or polymerase chain reaction (PCR) assays that amplify the DNA

1225

of infectious disease agents. However, the results of these assays can be positive in healthy dogs as well as in dogs with polyarthritis, so positive test results do not always correlate with illness. See the later sections on each individual agent for a discussion of currently available diagnostic tests.

Treatment Animals with septic polyarthritis should be treated with antibiotics that kill aerobes, anaerobes, and gram-positive and gram-negative organisms until culture results return. The combination of a quinolone with a penicillin or a cephalosporin is a logical first choice. Quinolones often are effective against gram-negative bacteria as well as Bartonella spp., L-form bacteria, Mycoplasma, and R. rickettsii. Penicillin derivatives are effective against gram-positive bacteria, anaerobic bacteria, and B. burgdorferi. Animals with nonseptic, suppurative polyarthritis often are administered doxycycline (5 to 10 mg/kg q12-24h PO) while the workup is completed. Doxycycline generally is effective for management of infections with A. phagocytophilum, B. burgdorferi, Ehrlichia spp., Mycoplasma spp., and R. rickettsii. However, Bartonella spp. infections of dogs rarely respond to doxycycline alone, and so this agent should stay on the differential list for dogs with polyarthritis in which a doxycycline trial fails (see the section on Bartonella). An additional benefit of doxycycline is that it has antiinflammatory properties and may lessen discomfort in some affected dogs nonspecifically. If doxycycline is unavailable or not tolerated, alternative options do exist such as minocycline (at the same dose as doxycycline), penicillins, or cephalosporins for B. burgdorferi; minocycline or imidocarb for E. canis; and so forth. Because the inflammation usually is neutrophilic, low-dose prednisone administered at 1 mg/kg q12-24h PO initially may give dramatic improvement in clinical signs of disease. However, excessive doses can activate some infectious agents such as B. burgdorferi. If the syndrome turns out to be a primary immune-mediated disorder, increased doses of prednisone with or without other immunosuppressive drugs may be required.

Specific Infectious Agents Anaplasma phagocytophilum Anaplasma phagocytophilum, a gram-negative, obligate, intracellular bacterium in the order Rickettsiales, is the cause of canine granulocytotropic anaplasmosis. This organism was previously thought to be an Ehrlichia sp. and was described in different reports as Ehrlichia equi, Ehrlichia phagocytophila, and the agent causing human granulocytic ehrlichiosis. Like B. burgdorferi, A. phagocytophilum is vectored by Ixodes spp. Thus areas around the world that are considered endemic for Lyme disease in dogs or people also are endemic for A. phagocytophilum. Cats also can develop acute clinical signs of disease after exposure to infected ticks. Definitive hosts are thought to be small rodents and the white-tailed deer. The transmission from the tick occurs during the blood meal. The transition into the tick

1226

SECTION  XIII  Infectious Diseases

salivary glands and eventual infection of the dog is thought to require at least 24 hours of feeding. Coinfection of dogs with A. phagocytophilum together with other organisms like B. burgdorferi is thought to play a role in the pathogenic potential. It also is known that some A. phagocytophilum strains are more pathogenic than others, which partially explains the high prevalence of seropositive healthy dogs. Dogs experimentally exposed to A. phagocytophilum– infected ticks either develop subclinical infections or demonstrate vague clinical signs of illness including fever, lethargy, malaise, anorexia, and general muscle pain resulting in reluctance to move. Some dogs exhibit joint pain and lameness resulting from inflammatory polyarthritis. These signs are remarkably similar to those of acute Lyme disease, and because of the very high prevalence of coinfection it often is impossible to determine which agent is causing the disease. Although the organism is known to persist in the blood and synovial fluid of experimentally inoculated dogs, associations with chronic polyarthritis or other inflammatory diseases are unclear. Other clinical findings are gastrointestinal signs such as vomiting, diarrhea, or both, or respiratory signs such as coughing and labored breathing. Central nervous system disease (meningitis) also can occur, resulting in seizure activity, ataxia, or neurologic deficits. Dogs infected with A. phagocytophilum are more likely than those infected with B. burgdorferi to have laboratory abnormalities, with mild to moderate thrombocytopenia being noted most commonly. Morulae may be seen within the cytoplasm of circulating neutrophils or those in synovial fluid. It has been shown that some acutely infected dogs have positive results on PCR analysis of blood samples before detectable levels of serum antibodies appear, so seronegative dogs should be evaluated by PCR testing of blood or both tests should be run simultaneously. One experimental study found that diagnostic sensitivity was not increased by performing PCR analysis of synovial fluid in addition to testing the blood. Although dose optimization studies have not been performed, administration of doxycycline at 5 to 10  mg/ kg q12-24h PO generally leads to rapid resolution of clinical signs of disease (Neer et  al, 2002). Experimentally infected dogs treated with doxycycline at 10  mg/kg q24h PO for 28 days tested negative for A. phagocytophilum DNA in blood during and after treatment (Moroff et  al, 2011). However, immunosuppressive therapy was not given in an attempt to reactivate infection. Although penicillins and some cephalosporins are effective for the treatment of clinical borreliosis, they are not effective for anaplasmosis. Thus doxycycline always should be considered the drug of choice for dogs with nonseptic polyarthritis, especially in areas with Ixodes ticks. The prognosis for acute disease appears to be good. However, tick control should be maintained because reinfection can occur and A. phagocytophilum is a significant zoonotic agent.

Bartonella Species Bartonella vinsonii subsp. berkhoffii initially was isolated from a dog with endocarditis in North Carolina

(Breitschwerdt et al, 1995). Since that time, additional Bartonella species have been isolated from dogs or have had DNA amplified from blood or tissues, including B. henselae, B. clarridgeiae, B. koehlerae, B. washoensis, B. quintana, B. rochalimae, and B. elizabethae (see Chapter 270). Although each of these organisms potentially can induce illness in dogs, most have been infected with B. vinsonii subsp. berkhoffii, B. henselae, or B. clarridgeiae. Each of these agents is associated with fleas, and so Bartonella spp. should be high on the differential list for dogs with nonerosive, nonseptic polyarthritis that also have current or previous flea infestations. Coinfection with other agents, such as Anaplasma spp. or Ehrlichia spp., may play a role in the pathogenesis of clinical canine bartonellosis. For example, in one study of valvular endocarditis, all dogs with Bartonella spp.–associated disease also were seropositive for A. phagocytophilum (MacDonald et al, 2004). Clinical findings or syndromes most frequently attributed to Bartonella spp. infections in dogs are endocarditis, fever, arrhythmias, hepatitis, granulomatous lymphadenitis, cutaneous vasculitis, rhinitis, polyarthritis, meningoencephalitis, thrombocytopenia, eosinophilia, monocytosis, immune-mediated hemolytic anemia, epistaxis, idiopathic cavitary effusions, and uveitis. B. henselae and B. vinsonii subsp. berkhoffii seem to be the most likely species to be associated with clinical disease, and both should be on the differential list for dogs with polyarthritis. Serum antibodies can be detected in both healthy  and clinically ill dogs, so the presence of antibodies does not always correlate with illness. In addition, approximately 50% of dogs with clinical bartonellosis are seronegative, and so serum antibody testing never should  be used as the sole diagnostic method in suspect cases. Bartonella spp. can be difficult to grow or amplify from dogs because the agents frequently are present in low numbers. Thus the combination of serologic testing with culture and PCR assay of blood often is needed to confirm infection (Duncan et al, 2007; Galaxy Diagnostics, 2013). For some dogs, samples must be tested repeatedly to prove the presence of the organism. It also is unclear whether there is benefit in performing PCR testing and culture of synovial fluid in addition to blood. If test results are positive in a clinically ill dog and no  other explanation for the illness is obvious, treatment is indicated. Doxycycline treatment alone has failed in dogs with suspected bartonellosis; thus failure to respond to this drug should not exclude the diagnosis. Dual therapy is thought by some veterinarians to be more effective than monotherapy, but more information is needed. Doxycycline at 5 mg/kg q12h PO combined with a veterinary fluoroquinolone such as enrofloxacin at 5 to 10 mg/kg q24h PO is recommended. Rifampin in combination with another antibiotic may be required in resistant cases. Amikacin administered at 20 mg/kg q24h IV commonly is recommended for the treatment of endocarditis but requires monitoring for potential renal toxicity. No matter which drug is used, a minimum of 4 to 6 weeks of treatment usually is recommended. Flea and tick control also should be maintained to avoid reinfection and to lessen the risk of zoonotic transfer of disease.

CHAPTER  261  Infectious Causes of Polyarthritis in Dogs

Borrelia burgdorferi Lyme disease (Lyme borreliosis), caused by Borrelia burgdorferi and transmitted by Ixodes spp. ticks, is reviewed in Chapter 271. Ixodes spp. are found mainly in the Northeast, the Upper Midwest, and some parts of northern California in the United States. Lyme disease should be included in the differential list for dogs with acute or chronic polyarthritis that live or have visited those  areas, particularly if strict tick control has not been maintained. Evidence suggests that about 5% to 10% of dogs that are exposed to B. burgdorferi will develop clinical disease within 2 to 5 months of infection. Why some dogs but not others develop polyarthritis is not completely understood. Experimental studies have shown that the number of infected ticks that feed is critical, and the age and immune status of the animal also seem to be important. Humans with certain haplotypes of the major histocompatibility complex are prone to more severe clinical manifestations of the disease, and there may be a genetic link in dogs as well. In experimentally infected dogs, overt clinical illness begins 2 to 5 months after tick exposure and consists of fever, inappetence, lethargy, lymphadenopathy, and episodic shifting limb lameness related to polyarthritis. Arthritis starts first in the joint that is closest to the tick bite. It has been shown that the release of proinflammatory cytokines and especially interleukin-8 plays an important role in the pathogenesis of acute and possibly more chronic progressive arthritis in dogs. Synovial fluid analysis findings are typical for a suppurative polyarthritis, with leukocyte counts ranging from 2000 to 100,000 nucleated cells/µl; however, the organism generally is not seen cytologically. PCR assay to detect B. burgdorferi DNA in blood is not indicated because the organism migrates in connective tissue. However, if clinical signs of disease are present, PCR testing can be used to detect B. burgdorferi DNA in joint fluid and samples of synovium. PCR assays cannot distinguish between live and dead organisms, but B. burgdorferi DNA was cleared within 3 weeks of injection in experimental animals. Research has shown that small DNA fragments of B. burgdorferi can persist in synovial membranes after treatment, and these fragments can be amplified by PCR. Although the sensitivity of PCR is high, the sample must contain B. burgdorferi DNA to yield positive results. A negative PCR result therefore never excludes the presence of the organism elsewhere in the body. As discussed in Chapter 271, multiple serologic assays are available, but positive results alone do not correlate with Lyme polyarthritis because of the high exposure rates in endemic areas. The antibiotics that are most effective for treating B. burgdorferi infection are the tetracyclines, ampicillin or amoxicillin, some third-generation intravenous cephalosporins, and erythromycin and its derivatives; current protocols are reviewed in Chapter 271. Improvement in polyarthritis often occurs within 24 to 48 hours of initiation of antimicrobial therapy in acute cases. The greatest success is achieved in the initial phases of clinical illness. Research suggests that the organism is difficult to eliminate from animals with established infection and that

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relapses occur despite seemingly adequate treatment regimens. Most treatment is instituted for a minimum of  30 days. However, on the basis of research studies, clearance of the organism after 30 days of treatment is  questionable. Relapse can occur and PCR results can become positive after discontinuation of antimicrobials. Also, inflammatory changes that occur in various tissues, such as the joints, may become self-perpetuating. Intraarticular persistence of B. burgdorferi may stimulate chronic immune and inflammatory processes. Dogs with more chronic borreliosis are less likely to show improvement or to have relapses, even if treatment is continued for weeks to months. Nonsteroidal antiinflammatory drugs may be helpful for pain relief during episodes of recurrent B. burgdorferi–associated arthritis. Immunosuppressive doses of glucocorticoids definitely should be avoided because immunosuppression may potentiate infection exacerbation. Tick-exposed dogs that had recovered  from clinical signs of Lyme disease and were treated with oral prednisolone for a 2-week period 16 months after  the original exposure again demonstrated lameness and polyarthritis. Administration of B. burgdorferi vaccines before exposure can lessen the likelihood of development of polyarthritis. Whether vaccination potentiates polyarthritis in previously exposed dogs is unclear. Tick control should be maintained in endemic areas to help prevent infection or reinfection.

Ehrlichia canis Canine monocytotropic ehrlichiosis caused by Ehrlichia canis is reviewed in Chapter 276. Because this agent is vectored by the brown dog tick (Rhipicephalus sanguineus), it has a worldwide distribution and should be on the  differential list for all dogs with clinical manifestations  of polyarthritis. In addition, R. sanguineus lives within homes and kennels and feeds year round, so ehrlichiosis should be considered a year-round differential. Anaplasma platys, Babesia spp., Hepatozoon canis, and R. rickettsii are other agents transmitted by this tick, and the presence of coinfections may potentiate E. canis–associated disease. Although most exposed dogs never develop clinical illness, polyarthritis can occur in either the acute or chronic phases of disease. In the acute phase, polyarthritis may relate to vasculitis, and in the chronic phase it may relate to immune complex disease. Polyarthritis rarely is the only manifestation of disease in dogs with monocytotropic ehrlichiosis. As discussed in Chapter 276, dogs in the acute phase can be seronegative by immunofluorescence assay or point-of-care diagnostic assays (Neer et al, 2002). Thus PCR testing of blood should be considered in these cases; very little has been published concerning synovial fluid cytologic findings or PCR assay results in dogs with monocytotropic ehrlichiosis. Dogs with chronic ehrlichiosis usually are seropositive, but the presence of serum antibodies does not always correlate with disease. Unlike in canine granulocytotropic ehrlichiosis (caused by E. ewingii), morulae rarely are detected in blood or synovial fluid. Doxycycline generally is the drug of first choice for treatment, and current protocols are reviewed in Chapter 276. There currently is no licensed vaccine, so

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strict tick control should be maintained to lessen the likelihood of infection or reinfection.

Ehrlichia ewingii Canine granulocytotropic ehrlichiosis caused by Ehrlichia ewingii is documented most commonly in dogs and human beings that reside in the central region as well as the southern and southeastern United States. For example, in a recent study by Beall et al (2012) seroreactivity to E. ewingii was highest in the central region (14.6%) followed by  the southeast region (5.9%). The geographic distribution relates to that of the vector, A. americanum (Lone Star tick). The incubation period after tick exposure is approximately 13 days, so some clinically affected dogs are seronegative when initially screened. To date, only acute clinical signs of disease have been detected, and these generally are less severe than those caused by E. canis infection. Concurrent disease or infections may play a significant role in the pathogenesis of E. ewingii infection. Nonspecific signs of E. ewingii infection include fever, lethargy, anorexia, depression, and signs consistent with polyarthritis, such as stiffness. Other clinical signs are vomiting, diarrhea, and peripheral edema and neurologic signs such as ataxia, paresis, and vestibular disease. As in infection with A. phagocytophilum and R. rickettsii, acute disease seems to be most common; thus E. ewingii infection should be highest on the list of differential diagnoses from spring through autumn when A. americanum is most active. Suppurative polyarthritis is common with E. ewingii infection, and morulae of E. ewingii can be detected inconsistently in neutrophils and eosinophils from peripheral blood and in neutrophils from synovial fluid. Other clinicopathologic findings include mild to moderate thrombocytopenia as described for acute E. canis or A. phagocytophilum infections. Antibodies can be detected by several methods, but since they can be detected in healthy as well as diseased dogs, the presence of E. ewingii–specific antibodies cannot be used alone to diagnose clinical granulocytotropic ehrlichiosis. Some dogs with acute disease have negative test results on presentation, so antibody testing during convalescence is required. PCR assays for amplification of E. ewingii DNA in blood currently are available, and test results are likely to be positive before seroconversion. Whether there is clinical utility in performing PCR testing of synovial fluid in addition to blood is unknown. Supportive care should be provided as indicated. The treatment protocols discussed for A. phagocytophilum and E. canis infections generally are effective. Reinfection probably can occur and the agent also infects humans, so strict tick control should be maintained.

References and Suggested Reading Battersby IA et al: Retrospective study of fever in dogs: laboratory testing, diagnoses and influence of prior treatment, J Small Anim Pract 47:370, 2006.

Beall MJ et al: Seroprevalence of Ehrlichia canis, Ehrlichia chaffeensis and Ehrlichia ewingii in dogs in North America, Parasit Vectors 8(5):29, 2012. Berg RI et al: Effect of repeated arthrocentesis on cytologic  analysis of synovial fluid in dogs, J Vet Intern Med 23:814, 2009. Breitschwerdt EB et al: Endocarditis in a dog due to infection with a novel Bartonella subspecies, J Clin Microbiol 33:154, 1995. Clements DN et al: Type I immune-mediated polyarthritis  in dogs: 39 cases (1997-2002), J Am Vet Med Assoc 224:1323, 2004. Colopy SA, Baker TA, Muir P: Efficacy of leflunomide for treatment of immune-mediated polyarthritis in dogs: 14 cases (2006-2008), J Am Vet Med Assoc 236:312, 2010. Duncan AW et al: A combined approach for the enhanced  detection and isolation of Bartonella species in dog blood samples: pre-enrichment liquid culture followed by PCR  and subculture onto agar plates, J Microbiol Methods 69:273, 2007. Foley J et al: Association between polyarthritis and thrombocytopenia and increased prevalence of vector borne pathogens in Californian dogs, Vet Rec 160:159, 2007. Galaxy Diagnostics: The most effective test for active Bartonella infection, 2013. Available at www.galaxydx.com. Accessed June 29, 2013. Goodman RA et al: Molecular identification of Ehrlichia ewingii infection in dogs: 15 cases (1997-2001), J Am Vet Med Assoc 222:1102, 2003. Goodman RA, Breitschwerdt EB: Clinicopathologic findings in dogs seroreactive to Bartonella henselae antigens, Am J Vet Res 66:2060, 2005. Hegemann N et al: Cytokine profile in canine immune-mediated polyarthritis and osteoarthritis, Vet Comp Orthop Traumatol 18:67, 2005. Johnson KC, Mackin A: Canine immune-mediated polyarthritis. Part 1: Pathophysiology, J Am Anim Hosp Assoc 48:12, 2012a. Johnson KC, Mackin A: Canine immune-mediated polyarthritis. Part 2: Diagnosis and treatment, J Am Anim Hosp Assoc 48:71, 2012b. Littman MP et al: ACVIM small animal consensus statement on lyme disease in dogs: diagnosis, treatment, and prevention,  J Vet Intern Med 20:422, 2006. MacDonald KA et al: A prospective study of canine infective endocarditis in northern California (1999-2001): emergence of Bartonella as a prevalent etiologic agent, J Vet Intern Med 18:56, 2004. Moroff S et al: Detection of antibodies against Anaplasma phagocytophilum in experimentally infected dogs using an automated fluorescence based system (Accuplex4™ BioCD). In Proceedings of the 29th Annual ACVIM Forum, June 2011. Neer TM et al: Consensus statement of ehrlichial disease of small animals from the infectious disease study group of the ACVIM, J Vet Intern Med 16:309, 2002. Rondeau MP et al: Suppurative, nonseptic polyarthropathy in dogs, J Vet Intern Med 19:654, 2005. Smith BE et al: Antinuclear antibodies can be detected in dog sera reactive to Bartonella vinsonii subsp. berkhoffii, Ehrlichia canis, or Leishmania infantum antigens, J Vet Intern Med 18:47, 2004. Stull JW et al: Canine immune-mediated polyarthritis: clinical and laboratory findings in 83 cases in western Canada (19912001), Can Vet J 49:1195, 2008.

CHAPTER 

262 

Immunotherapy for Infectious Diseases STEVEN DOW, Fort Collins, Colorado JESSICA M. QUIMBY, Fort Collins, Colorado

Role of Immune-Stimulatory and Immunosuppressive Therapy

Key Role of Type I Interferons in Antiviral Immunity

Some infections in dogs and cats cannot be treated effectively with antimicrobial drugs alone. Often these are chronic infections, typically in sites that may not be fully accessible so that effective antimicrobial drug concentrations can be reached. These difficult-to-treat infections include chronic viral infections in cats (e.g., feline herpesvirus 1, feline calicivirus, feline coronavirus, feline immunodeficiency virus infections) as well as chronic infections in dogs caused by certain intracellular pathogens (e.g., Toxoplasma gondii, Mycobacterium spp, Ehrlichia canis, Coccidioides immitis, canine papilloma virus). For these infections, active immunotherapy can be an effective alternative or adjunct to conventional antimicrobial therapy. At the other extreme, there are some infections in which the immune response to infection elicits such a marked inflammatory response that inflammation actually causes more injury to the host than the pathogen itself. Examples of these infections include acute rickettsial infections (e.g., E. canis and Rickettsia rickettsii infection), hemoplasma infections (e.g., Mycoplasma haemofelis, Candidatus Mycoplasma haemominutum), and some bacterial pneumonias and meningitides. For these infections, brief immunosuppression with glucocorticoids can reduce host inflammatory responses and thereby ameliorate the damage caused by unchecked inflammation, while at the same time not interfering with the overall effectiveness of treatment with conventional antimicrobial drugs (see Chapter 278).

Type I IFNs, which actually consist of a family of closely related isoforms of IFN-α plus a single isoform of IFN-β, play a key role in early immune responses to viral infections and infections with certain bacterial pathogens. IFN-α is produced by all nucleated cells in the body in response to viral entry and replication and represents one of the primary immune defenses against viral pathogens (Seo and Hahm, 2010). For example, IFN-α suppresses viral replication in the host cell and augments cellular immunity, especially natural killer (NK) cell activity and CD8 T-cell responses. After chronic infection has become established, type I IFNs remain important, but IFN-γ responses become much more important as mediators of effector T-cell antiviral activity, including both CD4 T-cell and CD8 T-cell activity.

Principles of Immune-Stimulatory Therapy The primary goal of active immunotherapy for treatment of most infections is to induce repeated production of large amounts of both type I interferons, or IFNs (IFN-α, IFN-β) and type II IFNs (IFN-γ). Depending on the site and distribution of infection, the immune-stimulatory drug is administered either locally (e.g., intranasally) or systemically. Strong IFN responses, particularly those that include type I IFNs, can suppress replication and increase intracellular killing of most pathogens, including viral, bacterial, and fungal pathogens. In addition, repeated activation of innate immune responses can lead to the generation of pathogen-specific T-cell responses.

Major Role of Interferon-γ in Antibacterial and Antifungal Immunity IFN-γ plays a key role in regulating both early and late immunity to bacterial and fungal pathogens, and the importance of IFN-γ has been established clearly in a number of different animal models (Seder et al, 1999). Unlike the production of type I IFNs, the production of IFN-γ is restricted to only a few cell types in the body, primarily NK cells and T lymphocytes. Early after infection, IFN-γ is produced primarily by NK cells, whereas later in the course of infection, IFN-γ production is restricted to antigen-specific CD4+ and CD8+ T cells. Production of IFN-γ by T lymphocytes is largely responsible for maintaining sustained immune control of bacteria, fungal, and viral infections. IFN-γ has numerous immune effects, including direct suppression of intracellular replication as well as induction of effective intracellular killing mechanisms by macrophages and neutrophils.

Effective Immune Therapeutics and Balanced Interferon Production Both type I and type II IFNs are important for controlling persistent infections by viruses, fungi, and bacteria. Therefore the most effective immunotherapeutics are those that produce balanced induction of both type I and type II IFN responses. For example, Zylexis, a veterinary 1229

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immune stimulant produced from inactivated parapoxviral particles, has been shown potently to induce IFN  production (Fachinger et al, 2000). Type I IFN and type II IFNs exert critical and nonredundant activities against intracellular pathogens. However, although most currently licensed veterinary immune therapeutics can elicit some IFN-γ production, few are strong inducers of IFN-α production, with the possible exception of Zylexis. Thus there is still a need for veterinary immune therapeutics capable of potently activating both IFN-α and IFN-γ production in vivo.

Importance of Sustained Interferon Production Effective immunotherapeutics should induce sustained immune activation and IFN production, which may require the administration of relatively long-acting immune stimulants (e.g., live bacille Calmette-Guérin) or repeated administration of shorter-acting immune activators (e.g., Toll-like receptor 3 [TLR-3] or TLR-9 agonists; see Table 262-1). For example, effective intracellular killing of persistent intracellular pathogens often requires prolonged exposure to activating concentrations of IFNs because effective pathogen elimination typically takes time to develop. This principle is one of the primary drawbacks to the use of recombinant cytokines, such as human recombinant IFN-α (Roferon-A, others), for treatment of persistent viral infections in cats. Frequent  and repeated dosing also means that there is a higher likelihood of development of neutralizing antibodies against human recombinant cytokines such as IFN-α (Zeidner et al, 1990). The use of recombinant feline  IFN omega (currently available only in Europe) avoids the issue of neutralizing antibodies, but long-term, frequent

treatment still is required, and optimal daily dosing regimens have not been established for most pathogens.

Cytokine Induction Profiles of Currently Available Immune Therapeutics Currently little published information is available allowing direct comparison of the ability of commercially available immune stimulants to induce production of cytokines (and especially IFN-γ). However, several general trends can be discerned from experimental studies of different classes of immune therapeutics. Immune therapeutics based on nucleic acids (or inactivated viral particles) appear to be the most effective inducers of both type I and type II IFN responses. For example, Zylexis was shown to induce IFN-γ production by porcine peripheral blood mononuclear cells, most likely by activation of the TLR-3 pathway (Fachinger et al, 2000). Likewise, an immune stimulant comprised of cationic liposomes and noncoding plasmid DNA (a TLR-9 agonist) has been shown by us and others to induce high levels of IFN-α and IFN-γ production in mice, cats, and dogs (Kamstock et al, 2006; Veir et al, 2006). In contrast, immune stimulants based on purified or enriched bacterial or fungal extracts tend to induce high levels of tumor necrosis factor-α (TNF-α) production, but lower amounts of IFN-γ and little or no IFN-α production. For example, killed Propionibacterium acnes (ImmunoRegulin) has been reported to induce TNF-α production by bovine leukocytes. Likewise, Staphylococcus phage lysate (SPL) has been reported to activate innate immunity. Cell wall extracts of Aloe vera (Acemannan Immunostimulant), which are rich in polysaccharides, are reported to induce TNF-α production by macrophages in vitro (Zhang and Tizard, 1996).

TABLE 262-1  Immunotherapeutics for Use in Infectious Diseases Drug

Mechanism of Action

Indications

Dosage

Adverse Effects

Killed Propionibacterium (ImmunoRegulin)

Activation of innate immunity

Chronic staphylococcal pyoderma

0.03-0.06 ml/kg IV   as needed

Fever, injection site reactions

Staphylococcus phage lysate (SPL)

Activation of innate immunity

Chronic staphylococcal pyoderma, bacterial infection

0.5-1.5 ml twice to once weekly SC

Local or systemic vaccine reactions

Cationic liposomes with Toll-like receptor ligands

Activation of innate immunity

Chronic viral or fungal infections

1-2 ml SC or IP   as needed

Lethargy and fever

Human recombinant interferon alfa (Roferon-A, others)

Activation of innate and adaptive immunity

Feline viral infections

1 million units/kg IV or SC injection daily for 5 consecutive days

Anemia, hepatotoxicity

Feline interferon omega (Virbagen Omega)

Direct antiviral activity

Feline viral infections

1 million units/kg   every other day to weekly SC

Anemia, lethargy, fever

Inactivated parapoxvirus (Zylexis)

Activation of innate immunity

Viral or fungal infections

Not published for dogs or cats

Fever, cutaneous reactions

IL, Intralesionally; IV, intravenously; IP, intraperitoneally; SC, subcutaneously.

CHAPTER  262  Immunotherapy for Infectious Diseases

Potential Adverse Effects of Immune Stimulants Strong activation of the immune system has the potential to cause harmful adverse effects, in addition to enhancing pathogen immunity. The primary adverse effect is overstimulation of innate immunity with excessive production of proinflammatory cytokines such as TNF-α, interleukin-6 (IL-6), and IL-1β, which can cause fever and hypotension. Overstimulation of innate immunity is more likely to occur when immune stimulants are administered systemically than following subcutaneous or mucosal administration. In the case of recombinant cytokines, overdosing is a more substantial risk, particularly with potent cytokines such as IFN-α or IL-2. However, to date, significant adverse effects from overdosing of recombinant cytokines have not been reported in veterinary medicine, although adverse effects from intravenous administration of human recombinant IL-2 have been noted in dogs with cancer. Administering xenogeneic recombinant cytokines (e.g., human recombinant IFN-α) to animals also introduces the risk of development of broadly cross-reactive neutralizing antibodies. Thus in theory treatment of a cat or dog with human recombinant IFN-α can induce antibodies that not only neutralize the foreign human IFN but  may also neutralize the animal’s own endogenous IFN-α, although this adverse effect has not been specifically documented in companion animals.

Immunotherapy for Persistent Infections in Dogs There are several chronic infections in dogs that may benefit from active immunotherapy, although in most

A

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cases clinical trials have not been completed. For example, animals with persistent infections with rickettsial agents or fungal organisms in the bone marrow or lymphoid tissues may benefit from activation of innate immunity with nonspecific immunotherapy. Chronic bacterial infections are relatively rare in dogs, although persistent infections with atypical mycobacteria (e.g., Mycobacterium avium spp.) have been reported. More commonly, dogs with acquired deficiencies in adaptive immunity (e.g., animals being treated with glucocorticoids or cyclosporine), or those with immunoglobulin deficiency, may develop persistent or recurrent infections with common bacterial agents such as Staphylococcus or Streptococcus and may benefit from immunotherapy. Although chronic viral infections are uncommon in dogs, papillomatosis due to chronic infection with canine papillomavirus is an exception and appears to be increasing in prevalence. In part, the increase in canine papillomatosis may be iatrogenic, driven by the increasing use of potent T-cell immunosuppressants such as cyclosporine, which is believed to result in reactivation of viral replication at mucous membrane surfaces (Lange and Favrot, 2011). Although still relatively rare, papillomatosis can be a devastating disease in older animals because of interference with eating and swallowing (Figure 262-1). A number of strategies have been evaluated in the past for treatment of papillomatosis in dogs, although few have been consistently effective. We recently have observed a high response rate in dogs with persistent papillomatosis treated with a liposome-based immunotherapeutic (cationic liposome-DNA complexes, or CLDCs) (see Figure 262-1). The CLDC immune therapeutic has been widely evaluated in rodent models as well as in dogs with cancer and cats with chronic upper respiratory virus infection and is noteworthy because of its strong induction of both

B Figure 262-1  Oral papillomatosis lesions and response to nonspecific immunotherapy. A, A 9-month-old Rhodesian ridgeback dog with chronic, unresponsive oral papillomatosis of 5 months’ duration. The dog was treated with weekly injections of cationic liposome-DNA complex (CLDC) immunotherapy. B, The oral lesions following 4 weeks of treatment.

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A

B Figure 262-2  Response to immunotherapy in a dog with primary immune deficiency and dis-

seminated toxoplasmosis. A 3-year-old Border collie developed progressive, disseminated toxoplasmosis that was unresponsive to clindamycin, azithromycin, and trimethoprim/sulfonamide therapy. A, Thoracic radiographs revealing marked pulmonary infiltrates associated with disseminated Toxoplasma gondii infection. Immunotherapy with weekly injections of cationic liposome-DNA complex (CLDC) was instituted, followed by injections every other week for 3 months. B, Thoracic radiographs taken after 2 months of CLDC treatment in conjunction with clindamycin treatment revealing complete resolution of the pulmonary parenchymal changes.

type I and II IFNs. Immunotherapy with CLDC also has shown activity in cats and dogs with chronic Cryptococcus neoformans infections and in animals with disseminated toxoplasmosis (Figure 262-2).

Immunotherapy for Persistent Viral Infections in Cats Cats suffer disproportionately from persistent viral infections, especially chronic upper respiratory tract and oral mucosal infections with feline herpesvirus 1 and feline calicivirus (Veir et al, 2008). For these patients, recurrent infections are common and treatment is frustrating and often requires combinations of antibiotic therapy, appetite stimulants, and antiviral agents such as lysine or famciclovir. Cats persistently infected with pathogenic feline coronaviruses that induce feline infectious peritonitis also currently lack effective treatment options. However, the key role played by cellular immunity in controlling coronavirus replication suggests that an active immune-stimulatory therapeutic that could augment cellular immunity (i.e., T-cell immunity) should be effective in suppressing viral replication and reducing immune sequelae. It was reported in one study that treatment with feline IFN omega reduced clinical signs and improved survival in cats with feline immunodeficiency virus and feline leukemia virus infections (de Mari et al, 2004). Treatment with feline IFN omega and glucocorticoids also resulted in disease remission and prolonged survival in one third of treated cats with feline infectious peritonitis in a small study (Ishida et al, 2004).

Immunotherapy to Augment Antimicrobial and Antifungal Therapy Immunotherapy also may be used to amplify the effectiveness of conventional antimicrobial therapy. For example, we reported recently that IFN-γ immunotherapy markedly enhanced the effectiveness of antibiotic therapy

against the intracellular bacterial pathogen Burkholderia (Propst et al, 2010). It also has been noted that the effectiveness of antibiotic therapy against Mycobacterium tuberculosis was enhanced in vitro by combining IFN-γ therapy with antimycobacterial drugs. In addition, the effectiveness of vancomycin therapy against infection with Enterococcus sp. was enhanced by IFN-γ treatment in vitro. IFN-γ immunotherapy also has been reported to increase the effectiveness of antifungal therapy against Cryptococcus neoformans in a mouse model of infection (Lutz et al, 2000). The use of immunoantimicrobial therapy for treatment of chronic fungal infections may have clinical utility. For example, we observed that cats and dogs with chronic Cryptococcus infection that failed to respond to sustained treatment with fluconazole responded rapidly when the immune therapeutic CLDC was added to fluconazole treatment. There is preclinical data from rodent models to support the use of combined immunoantimicrobial therapy for treatment of selected chronic fungal infections.

Immunosuppressive Therapy in the Management of Infectious Diseases? There are also examples of infections in which brief immunosuppression and reduction of inflammation can generate important benefits. In veterinary medicine few studies have addressed either the effectiveness or the safety of combined immunosuppressive and antimicrobial therapy. However, there has been renewed interest in the role of short-term glucocorticoid therapy in the management of certain infectious diseases in humans. In an interesting metaanalysis (McGee and Hirschmann, 2008) it was determined that, with few exceptions, administration of glucocorticoids to humans with infections either was clearly beneficial or had no effect on patient outcomes. In only two situations did glucocorticoid administration worsen clinical disease: prolonged glucocorticoid

CHAPTER  262  Immunotherapy for Infectious Diseases administration for chronic viral hepatitis and for cerebral malaria. Based on these findings, it was concluded that a brief course of modest doses of glucocorticoids could be beneficial for many infectious diseases, while not interfering with resolution of infection. What are the lessons for veterinary medicine? For years, it has been dogma that glucocorticoids never should be administered to patients with infections. However, it may be time now to reexamine the use  of glucocorticoids for the management of certain infections. Although there are few published data to guide recommendations for veterinary patients, the following examples describe situations in which brief, low-dose glucocorticoid therapy may benefit patients and improve overall treatment outcomes, as suggested in a recent review (see also Chapter 278). Glucocorticoid therapy is nearly always likely to be beneficial in the management of bacterial meningitis in dogs or cats, where even short-term inflammation can cause significant collateral damage to the central nervous system. Glucocorticoids also have been recommended to suppress the inflammation that develops following initiation of antifungal therapy in dogs with disseminated  Blastomyces or Histoplasma infection. In one study, brief glucocorticoid therapy reduced coughing while not worsening the underlying infection in animals with fungal infection. Although not yet examined in a properly controlled clinical trial, it also has been recommended that a brief antiinflammatory course of glucocorticoids (e.g., 0.5 mg/kg q24h PO for 3 to 5 days) in dogs with acute tracheobronchitis can reduce the severity of clinical signs, while not altering the disease course. Similarly, the brief use of glucocorticoids has been recommended for dogs with acute infections with E. canis or R. rickettsii, primarily to reduce the immunologic sequelae of red blood cell and platelet destruction. For cats with infections with hemoplasmas, glucocorticoid therapy may be especially beneficial in reducing the immune-mediated destruction of red blood cells. Although currently not supported by well-designed clinical trials, the use of glucocorticoids to ameliorate pulmonary inflammation in animals with acute bacterial pneumonia (e.g., following inhalational pneumonia) also has been proposed. Clearly, additional, carefully controlled clinical studies are warranted before these recommendations can be more widely adopted.

Summary and Recommendations Immune therapy is an attractive and currently underutilized treatment option for primary management of

1233

persistent infections in dogs and cats. Recent studies suggest that immunotherapy also may be a way to increase the effectiveness of conventional antimicrobial therapy for certain chronic infections, especially fungal and bacterial infections. It is also important to understand that in some infections short-term suppression of host immunity actually may be more beneficial than stimulation of immunity.

References and Suggested Reading de Mari K et al: Therapeutic effects of recombinant feline interferon-omega on feline leukemia virus (FeLV)-infected and FeLV/feline immunodeficiency virus (FIV)-coinfected symptomatic cats, J Vet Intern Med 18:477, 2004. Fachinger V et al: Poxvirus-induced immunostimulating effects on porcine leukocytes, J Virol 74:7943, 2000. Ishida T et al: Use of recombinant feline interferon and glucocorticoid in the treatment of feline infectious peritonitis,  J Feline Med Surg 6:107, 2004. Kamstock D et al: Liposome-DNA complexes infused intravenously inhibit tumor angiogenesis and elicit antitumor activity in dogs with soft tissue sarcoma, Cancer Gene Ther 13:306, 2006. Lange CE, Favrot C: Canine papillomaviruses, Vet Clin North Am Small Anim Pract 41:1183, 2011. Lutz JE, Clemons KV, Stevens DA: Enhancement of antifungal chemotherapy by interferon-gamma in experimental systemic cryptococcosis, J Antimicrob Chemother 46:437, 2000. McGee S, Hirschmann J: Use of corticosteroids in treating infectious diseases, Arch Intern Med 168:1034, 2008. Propst KL et al: Immunotherapy markedly increases the effectiveness of antimicrobial therapy for treatment of Burkholderia pseudomallei infection, Antimicrob Agents Chemother 54:1785, 2010. Seder RA, Gazzinelli RT: Cytokines are critical in linking the innate and adaptive immune responses to bacterial, fungal, and parasitic infection, Adv Intern Med 44:353, 1999. Seo YJ, Hahm B: Type I interferon modulates the battle of host immune system against viruses, Adv Appl Microbiol 73:83, 2010. Veir JK et al: Prevalence of selected infectious organisms and comparison of two anatomic sampling sites in shelter cats with upper respiratory tract disease, J Feline Med Surg 10:551, 2008. Veir JK, Lappin MR, Dow SW: Evaluation of a novel immunotherapy for treatment of chronic rhinitis in cats, J Feline Med Surg 8:400, 2006. Zeidner NS et al: Alpha interferon (2b) in combination with zidovudine for the treatment of presymptomatic feline leukemia virus-induced immunodeficiency syndrome, Antimicrob Agents Chemother 34:1749, 1990. Zhang L, Tizard IR: Activation of a mouse macrophage cell line by acemannan: the major carbohydrate fraction from Aloe vera gel, Immunopharmacology 35:119, 1996.

CHAPTER 

263 

Systemic Antifungal Therapy JANE E. SYKES, Davis, California AMY M. GROOTERS, Baton Rouge, Louisiana JOSEPH TABOADA, Baton Rouge, Louisiana

O

ver the past three decades, immunocompromise associated with human immunodeficiency virus infection and transplantation medicine has resulted in the emergence of opportunistic fungi as increasingly important causes of morbidity and mortality in human patients. The subsequent demand for safer and more effective antifungal therapies has led to the development of new pharmacologic agents that selectively target components unique to fungi (such as the cell wall), as well as the reformulation of drugs with good efficacy but a narrow therapeutic window (such as amphotericin B) in ways that make them less toxic. In addition, new drugs with a broader spectrum of activity have been developed in classes of drugs (such as the azoles) that traditionally have been valuable for the treatment of fungal infections in veterinary patients. Consequently, veterinarians recently have gained access to a number of new antifungal drugs with high efficacy and low toxicity that, despite being limited in use in some patients because of high cost, hold significant promise for the treatment of mycotic infections in small animal patients. The purpose of this chapter is to provide indications, initial drug protocol recommendations, and information concerning potential toxicities for the antifungal drugs most frequently prescribed to dogs and cats (Table 263-1). For amphotericin products, the drug generally is dosed repeatedly to a cumulative drug target as described. For the other antifungal drugs, duration of therapy varies with the fungal species and clinical manifestations in the individual case. However, the duration of therapy is generally weeks to months.

Amphotericin B Amphotericin B, a polyene antibiotic, traditionally has been the treatment of choice for invasive fungal infections in human and veterinary patients because it is highly active against a wide range of fungal organisms. Because it is absorbed poorly from the gastrointestinal tract, amphotericin B must be given parenterally. Following intravenous administration, amphotericin B is highly protein bound and then is redistributed quickly to tissues. It acts by binding to ergosterol in the fungal cell membrane; this compromises membrane stability and alters permeability, which leads quickly to leakage of cell contents and cell death. Although amphotericin B has greater affinity for fungal ergosterol than for mammalian cholesterol, its clinical usefulness has been hampered by 1234

dose-limiting nephrotoxicity, which may be mediated by direct renal epithelial cytotoxicity as well as renal vasoconstriction. As a result, when the original formulation of amphotericin B (amphotericin B deoxycholate [Fungizone]) is used for the treatment of systemic mycoses in dogs and cats, nephrotoxicity may occur before an effective cumulative dose can be administered. However, the development of novel delivery systems for amphotericin B in the early 1990s resulted in three newer (albeit more expensive) formulations with reduced nephrotoxicity and improved organ-specific drug delivery: amphotericin B lipid complex (Abelcet), amphotericin B colloidal  dispersion (Amphotec), and liposomal amphotericin B (AmBisome). Amphotericin B is used for the initial treatment of rapidly progressive or severe systemic mycoses (for which oral azoles are not likely to act quickly enough) or treatment of systemic mycoses that fail to respond to azole therapy, and provides a less expensive alternative to parenteral azole therapy in the treatment of fungal disease of the gastrointestinal tract when frequent vomiting precludes the use of oral medications. Amphotericin B has been used successfully in both human and veterinary patients for the treatment of blastomycosis, histoplasmosis, cryptococcosis, coccidioidomycosis, aspergillosis, hyalohyphomycosis, phaeohyphomycosis, sporotrichosis, zygomycosis, disseminated candidiasis, and rarely pythiosis.

Amphotericin B Deoxycholate Amphotericin B deoxycholate typically is administered as a series of intravenous infusions. Dogs receive 0.5 to 1 mg/kg IV three times weekly to a cumulative dose of 4 to 8 mg/kg or until azotemia develops; cats receive 0.25 mg/kg IV three times weekly to a cumulative dose of 4 to 6 mg/kg. Each dose should be diluted in 5% dextrose and administered to a well-hydrated patient over 10 minutes to 5 hours. Sodium loading and longer infusion times may reduce nephrotoxicity and diminish infusionrelated adverse effects, such as trembling, pyrexia, and nausea. Infusion-related adverse effects also may be lessened by pretreatment with diphenhydramine (0.5 mg/kg IV or PO), aspirin (10 mg/kg PO) or other nonsteroidal antiinflammatory drugs, or a physiologic dose of a glucocorticoid. Not all animals experience infusion-related adverse effects, so nonsteroidal antiinflammatory drugs and glucocorticoids should be only administered if such adverse effects are likely based on previous observations. Additionally, tolerance to infusion-related adverse effects

CHAPTER  263  Systemic Antifungal Therapy

1235

TABLE 263-1  Drugs Used for Systemic Antifungal Therapy in Dogs and Cats Drug*

Dosage

Formulations

Amphotericin B deoxycholate

0.5-1 mg/kg IV infusion three times weekly to a cumulative dose of 4-8 mg/kg (dogs) 0.25 mg/kg IV infusion three times weekly to a cumulative dose of 4-6 mg/kg (cats)

50-mg vial (reconstitute with 10 ml sterile water, then dilute to 0.1 mg/ml with 5% dextrose for IV infusion)

Amphotericin B lipid complex

1-3 mg/kg IV infusion three times weekly to a cumulative dose of 12-36 mg/kg (dogs) 1 mg/kg IV infusion three times weekly to a cumulative dose of 12 mg/kg (cats)

100-mg vial (dilute to 1 mg/ml in 5% dextrose for IV infusion); although each 100-mg vial is labeled for single use only, the doses for each treatment can be aliquoted into sterile vials and used for up to 1 wk after the 100-mg vial is opened

Itraconazole

5-10 mg/kg/day PO (dogs) 5 mg/kg q12h PO (25 or 50 mg per cat)

100-mg capsule 10-mg/ml oral solution

Fluconazole

5-10 mg/kg/day PO or IV (dogs) 50-100 mg per cat per day PO (cats)

50-mg, 100-mg, 150-mg, 200-mg oral tablets; 150-mg oral capsule 10-mg/ml, 40-mg/ml powder for oral suspension 100 ml or 200 ml of 2-mg/ml solution for IV infusion

Voriconazole

4 mg/kg q12h PO or IV (dogs) Do not use in cats

50-mg, 200-mg oral tablets 40-mg/ml powder for oral suspension 200-mg vial (reconstitute with sterile water to 10 mg/ml for IV infusion)

Posaconazole

5 mg/kg q24h PO (dogs and cats)

40-mg/ml powder for oral suspension

Ketoconazole

10-15 mg/kg q12h PO (dogs) 5-10 mg/kg q24h PO (cats)

200-mg oral tablet

Caspofungin

1 mg/kg IV infusion q24h (dogs)

50-mg, 70-mg vials (dilute in 0.9% saline for IV infusion)

Flucytosine

50 mg/kg q6-8h PO (cats) Do not use in dogs

250-mg, 500-mg oral capsules

Terbinafine

10-30 mg/kg q24h PO (dogs and cats)

250-mg oral tablets

*For amphotericin products, the drug generally is dosed repeatedly to a cumulative drug target as described. For the other antifungal drugs, duration of therapy will vary by the fungal agent and clinical manifestations in the individual case. However, the duration of therapy generally is weeks to months.

often occurs over time, which reduces the need for pretreatment with antiinflammatory drugs. Saline diuresis before administration of amphotericin B may decrease its effect on renal blood flow and should be considered in patients with preexisting renal disease or those at high risk of nephrotoxicity. Other adverse effects reported in humans treated with amphotericin B include hypokalemia, distal renal tubular acidosis, hypomagnesemia, anemia, and nephrogenic diabetes insipidus. Serum levels of blood urea nitrogen (BUN) and creatinine should be measured before each infusion. If azotemia develops, infusions should be discontinued until it has resolved. Amphotericin B–induced azotemia usually is reversible, but it may take weeks to months for BUN and creatinine levels to return to baseline. Permanent renal damage is more likely to occur in patients with underlying renal disease and in those that are receiving other nephrotoxic drugs concurrently. A protocol for subcutaneous administration of amphotericin B was developed with the intent of decreasing nephrotoxicity and avoiding the need for prolonged vascular access, and its use for the treatment of cryptococcosis was described by Malik and colleagues (1996) in three dogs and three cats. Amphotericin B deoxycholate (0.5 to 0.8 mg/kg) was diluted in 400 ml (for cats) or 500 ml (for dogs) of 0.45% NaCl/2.5% dextrose and administered subcutaneously two to three times per week

to a cumulative dose of 8 to 26 mg/kg. Although this protocol was successful in the six patients described, sterile abscesses caused by local tissue irritation occurred at concentrations higher than 20 mg/L, which is unavoidable in very large dogs. In addition, sterile abscesses often are seen even in smaller dogs for which more dilute concentrations are attainable. Despite this significant adverse affect, this protocol provides an alternative for antifungal therapy when financial limitations preclude the use of triazoles or amphotericin B lipid complex.

Amphotericin B Lipid Complex Of the three newer formulations of amphotericin B designed to be less nephrotoxic, amphotericin B lipid complex (ABLC) has been the most extensively used and evaluated in veterinary patients. In dog studies, it is 8 to 10 times less nephrotoxic than amphotericin B deoxycholate, due in part to the fact that binding of amphotericin B to phospholipids decreases its ability to interact with cholesterol in the mammalian cell membrane and facilitates its selective transfer to ergosterol in fungal membranes. The efficacy of ABLC is increased by uptake of the lipid-complex drug by cells of the reticuloendothelial system, followed by liberation of amphotericin B from its lipid complex by lipases released from inflammatory cells at the site of infection.

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SECTION  XIII  Infectious Diseases

For administration, ABLC is diluted in 5% dextrose to a concentration of 1 mg/ml and infused over a 1- to 4-hour period. Dogs receive 1 to 3 mg/kg IV three times weekly to a cumulative dose of 12 to 36 mg/kg; cats receive 1 mg/kg IV three times weekly to a cumulative dose of 12 mg/kg. The authors typically start with a dose at the lower end of the range and then increase the dose in subsequent infusions to the higher end of the range if the dose is well tolerated; this allows a reasonable cumulative dose to be administered within a 3-week period. Saline diuresis does not appear to be necessary before administration of ABLC but may be beneficial in animals with preexisting renal disease. As with amphotericin B deoxycholate, BUN and creatinine levels should be closely monitored, and infusion-related adverse effects may be diminished by pretreatment with antihistamines, aspirin, or glucocorticoids. Other adverse effects of amphotericin B such as hypokalemia, distal renal tubular acidosis, and nephrogenic diabetes insipidus rarely occur with these less nephrotoxic formulations.

Azoles The azoles are an essential class of antifungal agents that block ergosterol biosynthesis by inhibiting lanosterol 14α-demethylase, a cytochrome P-450 enzyme that allows conversion of lanosterol to ergosterol. This disrupts  fungal cell membrane function by causing depletion of ergosterol and accumulation of lanosterol and other 14-methylated sterols. Azoles are classified based on  the number of nitrogen atoms contained in the azole ring: imidazoles (ketoconazole, clotrimazole, miconazole) contain two nitrogen atoms, whereas triazoles (itraconazole, fluconazole, voriconazole, posaconazole) contain three. Because of their more potent inhibitory effects on mammalian cytochrome P-450 enzymes, imidazoles such as ketoconazole tend to cause more adverse effects than triazoles. In addition, several azoles interfere with the activity of hepatic microsomal enzymes, which can lead to increased blood concentrations of concurrently administered drugs, such as cyclosporine and digoxin. In general, the triazoles play a major role in the treatment of systemic mycoses in human and veterinary patients because they provide an alternative to intravenous amphotericin B, which allows endemic mycoses such as blastomycosis and histoplasmosis to be treated with oral medication on an outpatient basis. Imidazoles such as ketoconazole have been largely replaced by the triazoles for treatment of systemic fungal infection because the triazoles have fewer adverse effects and better efficacy. Nevertheless, several imidazoles still are used in topical preparations.

Itraconazole Itraconazole (Sporanox) is a triazole released in the  early 1990s that has become the initial treatment of choice in dogs and cats for most systemic mycoses that are not immediately life threatening. Itraconazole is a weak base that requires an acid environment for maximal gastrointestinal absorption. Therefore its oral bioavailability is increased when it is given with food or cola

beverages and decreased when it is given with antacids. Itraconazole is highly protein bound, but because of its lipophilicity, it distributes well to most tissues. However, it does not cross the blood-brain, blood-prostate, or blood-ocular barriers well, and its concentration in cerebrospinal fluid (CSF) and urine is low. Despite this fact, itraconazole often is used successfully for the treatment of fungal infections of the central nervous system (CNS) and eye, perhaps because inflammation-mediated compromise of these barriers allows more of the drug to move across them into infected tissues. In dogs and cats, itraconazole typically is used to treat systemic fungal infections at a dosage of 5 to 10 mg/kg/ day PO (either once daily or 10 mg/kg divided twice daily). It is available as both an oral capsule (100 mg) and an oral solution (10 mg/ml), the latter of which has improved gastrointestinal absorption. Itraconazole is notorious for its erratic oral bioavailability, especially when generic preparations are used. For this reason,  substitution with generic itraconazole is not recommended because it may not result in therapeutic plasma concentrations, especially when the generic powder is compounded. If therapeutic drug monitoring can be performed, the recommended trough concentration target is between 0.25 and 0.5 µg/ml. Adverse effects associated with itraconazole often are dose dependent and include gastrointestinal signs, hepatotoxicity, and cutaneous vasculitis. When gastrointestinal adverse effects occur, dividing the daily dose into two treatments, administered 12 hours apart, may be beneficial. Liver enzyme levels should be monitored every 4 weeks during itraconazole therapy, or sooner if inappetence or vomiting occurs. Increased transaminase activity is common but is not an indication to discontinue therapy unless it is accompanied by anorexia, vomiting, abdominal pain, or hyperbilirubinemia. Cutaneous vasculitis manifested as an ulcerative dermatitis most often is observed at dosages higher than 10 mg/kg/day. Therefore the development of ulcerative skin lesions in an animal receiving high-dose itraconazole should prompt biopsy of the lesion rather than an assumption that the lesion is caused by the underlying fungal infection. Lesions typically resolve when the dose of itraconazole is reduced.

Fluconazole Fluconazole (Diflucan) is a triazole that traditionally has been used for the treatment of cryptococcosis and candidiasis. Because it crosses the blood-brain, blood-prostate, and blood-ocular barriers well, it often is chosen for the treatment of fungal infections of the eye or brain. Fluconazole is highly water soluble and minimally protein bound, achieving high concentrations in urine. It is not affected by gastric pH, and its oral bioavailability generally is consistent and is not affected by food or antacids. In general, fluconazole is more active against yeasts than molds. Therefore fluconazole is most often indicated in dogs and cats for the treatment of cryptococcosis and candidiasis or for ocular and CNS infections, whereas itraconazole or other triazoles are more likely to be  effective for systemic mold infections such as aspergillosis and hyalohyphomycosis. The recent availability of

CHAPTER  263  Systemic Antifungal Therapy fluconazole in an inexpensive generic formulation has expanded its use to include diseases such as blastomycosis and histoplasmosis that traditionally have been treated successfully with itraconazole. Results of a recent investigation failed to show that fluconazole was noninferior to itraconazole for the treatment of blastomycosis and did show that dogs treated with fluconazole were treated longer than dogs receiving itraconazole (Mazepa et al, 2011). A higher mortality in the fluconazole-treated dogs appeared to be limited to the first 2 weeks of therapy, which may indicate that there is a difference in early efficacy. However, clinicians who commonly treat blastomycosis have not observed a clinically significant difference between itraconazole and fluconazole, and often choose fluconazole as initial therapy for the treatment of this disease because of its much lower cost, even when longer treatment times are required. Fluconazole is available as tablets of various strengths, an oral suspension, and an injectable formulation. Cats typically receive 50 mg per cat per day, which can be increased to 100 mg per cat divided twice daily if needed. Dogs typically receive 5 to 10 mg/kg q24h PO. Fluconazole generally is well tolerated, occasionally causing moderate subclinical increases in transaminase activity.

Voriconazole Voriconazole (Vfend) is a fluconazole derivative with greater potency and a broader spectrum of activity than fluconazole. In human patients, it is currently the drug of choice for treatment of invasive aspergillosis. It also is used to treat other invasive and refractory mycoses such as those caused by Scedosporium spp. (Pseudallescheria spp.) and Paecilomyces spp. It is at least as active as itraconazole against veterinary isolates of Cryptococcus spp., Candida spp., and Aspergillus fumigatus. It is not active against Sporothrix schenckii and zygomycetes. Voriconazole is available as a tablet, oral suspension, and an intravenous solution. Like fluconazole, it has excellent oral bioavailability, but its absorption is reduced in the presence of fatty food. Voriconazole is poorly water soluble and moderately protein bound. It is metabolized extensively by hepatic cytochrome P-450 enzymes and eliminated into bile. Of all the triazoles, it also is the most potent inhibitor of P-450 enzymes, and it can even induce its own metabolism over time. It has good penetration of the CNS, and although it is expensive, it has been used with some success to treat systemic aspergillosis in dogs and CNS coccidioidomycosis. If therapeutic drug monitoring can be performed, the recommended targets are a trough concentration of between 2 and 5.5 mg/L and a peak concentration of less than 5.5 mg/L to minimize toxicity. Adverse effects have not yet been well documented in dogs, but the authors have observed decreased appetite, increased serum liver enzyme activities, and in uncommon cases CNS signs, including ataxia and staring or “star gazing”. Tachypnea and marked pyrexia after intravenous infusion was observed in one dog. Cats are highly sensitive to the adverse effects of voriconazole and develop inappetence; CNS signs such as ataxia, pelvic limb paresis, mydriasis, apparent blindness, decreased pupillary light

1237

responses, and a decreased menace response; cardiac arrhythmias; and hypokalemia. As a result, the use of voriconazole in cats currently is not recommended. Among the adverse effects of voriconazole in humans  are reversible visual effects including photophobia and blurred vision, hallucinations, peripheral neuropathies, and photosensitization, as well as the same toxicities seen with other triazoles.

Posaconazole Posaconazole (Noxafil) is an itraconazole analog that has demonstrated good activity in the treatment of several refractory deep mold infections in dogs and cats, including infections with Aspergillus spp. and Mucor spp. in cats and systemic infections with Aspergillus spp. in dogs. Its spectrum of activity is similar to that of voriconazole, with the addition of zygomycetes. Posaconazole is available as an oral suspension. Because of variable absorption in different individuals, therapeutic drug monitoring is recommended in human patients, with target peak concentrations of more than 1.48 mg/L. As with itraconazole, in humans its absorption is promoted by the concurrent presence of fatty food and gastric acidity. Absorption also is improved when the total daily dose is divided into two to four doses. Posaconazole is highly protein bound (>95%) and undergoes hepatic metabolism, with some inhibition of P-450 enzymes. Most administered posaconazole is eliminated in the feces. Data on CSF concentrations of posaconazole are not yet available. Adverse effects appear to be less common in cats than with voriconazole.

Ketoconazole Ketoconazole largely has been replaced by itraconazole for treatment of many mycoses because of the greater toxicity and lower efficacy of ketoconazole compared with triazole antifungal drugs. Because of its low cost, it continues to be used in veterinary medicine when the cost of other antifungal drugs is prohibitive for the client, and it remains effective for the treatment of Malassezia spp. dermatitis, feline nasal and cutaneous cryptococcosis, and long-term treatment of coccidioidomycosis.  The dosage is 10 to 15 mg/kg PO q12h for dogs and 5 to 10 mg/kg PO q12h for cats. The absorption of ketoconazole is improved when the drug is administered with food and inhibited by concurrent use of antacids. Ketoconazole is highly protein bound and is metabolized extensively by the liver, with inactive products being excreted in bile and, to a lesser extent, in urine. It has poor penetration of the CNS and generally is ineffective for treatment of CNS mycoses. Vomiting, anorexia, lethargy, and diarrhea are relatively common adverse effects of treatment with ketoconazole. Administration of ketoconazole with food may help to reduce gastrointestinal adverse effects. Liver enzyme activities should be monitored monthly during treatment and earlier if gastrointestinal signs occur. It  is common to see mild increases in the activity of  serum transaminases during treatment, which do not warrant discontinuation of the drug. Less commonly,

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SECTION  XIII  Infectious Diseases

ketoconazole causes a hepatopathy, which may be  accompanied by anorexia, vomiting, lethargy, increased activities of serum alanine transaminase and alkaline phosphatase, and hyperbilirubinemia. The drug should be discontinued if this occurs. Pruritus and cutaneous erythema have been reported in fewer than 1% of dogs treated with ketoconazole. Lightening of the hair coat color and cataract formation also rarely have been associated with ketoconazole administration in dogs. Ketoconazole is a potent inhibitor of mammalian cytochrome P-450 enzymes and efflux transporter proteins such as P-glycoprotein. It inhibits testosterone and cortisol synthesis in mammals. Ketoconazole also can interfere with P-glycoprotein transport of ivermectin, which predisposes dogs to ivermectin toxicity. Inhibition of adrenal steroid synthesis can cause transient infertility during treatment of intact male animals and in rare cases clinical signs of hypoadrenocorticism.

Echinocandins Echinocandins represent a new class of lipopeptide antifungal agents that target the cell wall rather than the cell membrane. Specifically, they inhibit the formation of (1,3)-β-d-glucans in the fungal cell wall. The prototype drug is caspofungin acetate (Cancidas). Other drugs in this class are micafungin and anidulafungin. Their use in dogs and cats has been limited by their high cost and need for once-daily intravenous infusion. Caspofungin was used successfully to induce remission in a dog with disseminated aspergillosis (1 mg/kg diluted in 250 ml 0.9% NaCl administered IV over 1 hour q24h). Synergism has been reported when echinocandins are used in  combination with other antifungal drugs. The echinocandins are not active against Cryptococcus spp., which possess little glucan synthase. In human patients, caspofungin is approved for treatment of refractory invasive aspergillosis. In human patients, caspofungin is extensively protein bound and is metabolized slowly by the liver, with some renal excretion. It has limited ability to penetrate the CNS and eye. Adverse effects noted in humans include fever, phlebitis, and elevated alanine transaminase levels (10 mcg/ kg/min seizures are more likely.

Nizatidine

Axid

150- and 300-mg capsules

Dog: 5 mg/kg PO q24h

o,p’-DDD

See Mitotane (Lysodren) Continued

1326

APPENDIX  I  Table of Common Drugs: Approximate Dosages

Drug Name

Other Names

Formulations Available

Dosage

Olsalazine

Dipentum

500-mg tablet

Dose not established (usual human dose is 500 mg or 5-10 mg/kg PO twice daily)

Omeprazole

Prilosec (formerly Losec), Gastrogard (equine paste)

20-mg capsule

Dog: 20 mg/dog PO once daily (or 0.7 mg/kg q24h) Cat: 0.5-0.7 mg/kg q24h PO

Ondansetron

Zofran

4- and 8-mg tablets; 2-mg/ml injection

0.5-1.0 mg/kg IV, PO 30 minutes before administration of cancer drugs

Orbifloxacin

Orbax

5.7-, 22.7-, and 68-mg tablets, and 30 mg/mL oral suspension

Dogs and cats (tablets): 2.5-7.5 mg/kg PO once daily; cats: 7.5 mg/kg once daily (oral suspension)

Ormetoprim

See Primor (ormetoprimsulfadimethoxine)

Oxacillin

Prostaphlin and generic

250- and 500-mg capsules; 50-mg/ml oral solution

22-40 mg/kg PO q8h

Oxazepam

Serax

15-mg tablet

Cat: Appetite stimulant: 2.5 mg/cat PO

Oxtriphylline

Choledyl-SA

400- and 600-mg tablet (oral solutions and syrup available in Canada but not U.S.)

Dog: 47 mg/kg (equivalent to 30 mg/kg theophylline) PO q12h

Oxybutynin chloride

Ditropan

5-mg tablet

Dog: 5 mg/dog PO q6-8h

Oxymetholone

Anadrol

50-mg tablet

1-5 mg/kg/day PO

Oxymorphone

Numorphan

1.5- and 1-mg/ml injection

Dog: Analgesia: 0.1-0.2 mg/kg IV, SC, IM (as needed), redose with 0.05-0.1 mg/kg q1-2h Cat: 0.03 mg/kg bolus, followed by 0.02 mg/kg q2h Preanesthetic: 0.025-0.05 mg/kg IM, SC

Oxytetracycline

Terramycin

250-mg tablets; 100- and 200-mg/ ml injection

7.5-10 mg/kg IV q12h; 20 mg/kg PO q12h

Oxytocin

Pitocin and Syntocinon (nasal solution) and generic

10- and 20-U/ml injection; 40-U/ml nasal solution

Dog: 5-20 U/dog SC, IM (repeat every 30 min for primary inertia) Cat: 2.5-3 U/cat SC, IM (repeat every 30 min)

2-PAM

See Pralidoxime chloride

Pamidronate

Aredia

30-, 60-, 90-mg vials for injection

Dog: 2 mg/kg IV, SC For treatment of cholecalciferol toxicosis: 1.3-2 mg/kg for two treatments

Pancreatic enzyme

See Pancrelipase

Pancrelipase

Viokase

16,800 U of lipase, 70,000 U of protease, and 70,000 U of amylase per 0.7 gm; also capsules and tablets

Mix 2 tsp powder with food per 20 kg body weight or 1-3 tsp/0.45 kg of food 20 min before feeding

Pancuronium bromide

Pavulon

1- and 2-mg/ml injection

0.1 mg/kg IV or start with 0.01 mg/kg and additional 0.01-mg/kg doses every 30 min

Pantoprazole

Protonix

40-mg tablets, 0.4-mg/ml vials for injection

Dog, cat: 0.5 mg/kg q24h IV or 0.5-1 mg/ kg IV infusion over 24 hr

Paregoric

Corrective mixture

2 mg morphine per 5 ml of paregoric

0.05-0.06 mg/kg PO q12h

Paroxetine

Paxil

10-, 20-, 30-, and 40-mg tablets

Cat:

D-Penicillamine

Cuprimine, Depen

125- and 250-mg capsules and 250-mg tablets

10-15 mg/kg PO q12h

Penicillin G benzathine

Benza-pen and other names

150,000 U/ml, combined with 150,000 U/ml of procaine penicillin G

24,000 U/kg IM q48h

Penicillin G potassium; penicillin G sodium

Many brands

5- to 20-million unit vials

20,000-40,000 U/kg IV, IM q6-8h

Penicillin G procaine

Generic

300,000 U/ml suspension

20,000-40,000 U/kg IM q12-24h

Penicillin V

Pen-Vee

250- and 500-mg tablets

10 mg/kg PO q8h

1 8

to

1 4

of a 10-mg tablet daily PO

APPENDIX  I  Table of Common Drugs: Approximate Dosages

1327

Drug Name

Other Names

Formulations Available

Dosage

Pentobarbital

Nembutal and generic

50 mg/ml

25-30 mg/kg IV to effect; or 2-15 mg/kg IV to effect, followed by 0.2-1.0 mg/kg/hr IV

Pentoxifylline

Trental

400-mg tablet

Dog: For use in canine dermatology and for vasculitis, 10 mg/kg PO q12h and up to 15 mg/kg q8h Cat: 14 of 400-mg tab PO q8-12h

Pepto Bismol

See Bismuth subsalicylate

Phenobarbital

Luminal and generic

15-, 30-, 60-, and 100-mg tablets; 30-, 60-, 65-, and 130-mg/ml injection; 4-mg/ml oral elixir solution

Dog: 2-8 mg/kg PO q12h Cat: 2-4 mg/kg PO q12h Dog and cat: Adjust dose by monitoring plasma concentration Status epilepticus: Administer in increments of 10-20 mg/kg IV (to effect)

Phenoxybenzamine

Dibenzyline

10-mg capsule

Dog: 0.25 mg/kg PO q8-12h or 0.5 mg/kg q24h Cat: 2.5 mg/cat q8-12h or 0.5 mg/cat PO q12h (in cats, doses as high as 0.5 mg/ kg IV have been used to relax urethral smooth muscle)

Phentolamine

Regitine (Rogitine in Canada)

5-mg vial for injection

0.02-0.1 mg/kg IV

Phenylbutazone

Butazolidin and generic

100-, 200-, 400-mg and 1-gm tablets; 200-mg/ml injection

Dog: 15-22 mg/kg PO, IV q8-12h (44 mg/ kg/day) (800 mg/dog maximum) Cat: 6-8 mg/kg IV, PO q12h

Phenylephrine

Neo-Synephrine

10-mg/ml injection; 1% nasal solution

0.01 mg/kg IV q15min 0.1 mg/kg IM, SC q15min

Phenylpropanolamine

PPA, Propalin, Proin PPA

25-, 50-, and 75-mg tablets and 25-mg/ml liquid

Dog: 1 mg/kg q12h PO and increase to 1.5-2.0 mg/kg as needed q8h PO

Phenytoin

Dilantin

30- and 125-mg/ml oral suspension; 30- and 100-mg capsules; 50-mg/ml injection

Antiepileptic dog: 20-35 mg/kg q8h Antiarrhythmic: 30 mg/kg PO q8h or 10 mg/kg IV over 5 min

Physostigmine

Antilirium

1-mg/ml injection

0.02 mg/kg IV q12h

Phytomenadione

See Vitamin K1

Phytonadione

See Vitamin K1

Pimobendan

Vetmedin

2.5- and 5-mg capsules (Europe and Canada); 1.25-, 2.5-, 5-mg chewable tablets (US)

Dog: 0.05 mg/kg/day in divided treatments q12h Cat: 0.25 mg/kg q12h, PO; 1.25 mg per cat q12h also has been used

Piperacillin

Pipracil

2-, 3-, 4-, and 40-gm vials for injection

40 mg/kg IV or IM q6h

Piperazine

Many

860-mg powder; 140-mg capsule, 170-, 340-, and 800-mg/ml oral solution

44-66 mg/kg PO administered once

Piroxicam

Feldene and generic

10-mg capsule

Dog: 0.3 mg/kg PO q48h Cat: 0.3 mg/kg q24h PO

Pitressin (ADH)

See Vasopressin, Desmopressin acetate

Plicamycin (old name is mithramycin)

Mithracin

2.5-mg injection

Dog: Antineoplastic: 25-30 µg/kg day IV (slow infusion) for 8-10 days Antihypercalcemic: 25 µg/kg/day IV (slow infusion) over 4 hr Cat: Not recommended

Polyethylene glycol electrolyte solution

GoLYTELY

Oral solution

25 ml/kg PO repeat in 2-4 hr PO Continued

1328

APPENDIX  I  Table of Common Drugs: Approximate Dosages

Drug Name

Other Names

Formulations Available

Dosage

Polysulfated glycosaminoglycan (PSGAG)

Adequan Canine

100-mg/ml injection in 5-ml vial (for horses vials are 250 mg/ml)

4.4 mg/kg IM twice weekly for up to 4 wk

Potassium bromide (KBr)

No commercial formulation

Usually prepared as oral solution Must be compounded

Dog and cat: 30-40 mg/kg PO q24h If administered without phenobarbital, higher doses of up to 40-50 mg/kg may be needed. Adjust doses by monitoring plasma concentrations. Loading doses of 600-800 mg/kg divided over 3-4 days have been administered.

Potassium chloride (KCI)

Generic

Various concentrations for injection (usually 2 mEq/ml); oral suspension and oral solution

0.5 mEq potassium/kg/day; or supplement 10-40 mEq/500 ml of fluids, depending on serum potassium

Potassium citrate

Generic, Urocit-K

5-mEq tablet; some forms are in combination with potassium chloride

0.5 mEq/kg/day PO

Potassium gluconate

Kaon, Tumil-K, generic

2-mEq tablet; 500-mg tablet; Kaon elixir is 20-mg/15-ml elixir

Dog: 0.5 mEq/kg PO q12-24h Cat: 2-8 mEq/day PO divided twice daily

Potassium iodide

Cat: 30-100 mg/cat daily (in single or divided doses) for 10-14 days

Pralidoxime chloride (2-PAM)

2-PAM, Protopam Chloride

50-mg/ml injection

20 mg/kg q8-12h (initial dose) IV slow or IM

Praziquantel

Droncit

23- and 34-mg tablets; 56.8-mg/ml injection

Dog (PO): 6.8 kg, 5 mg/kg, once (IM, SC): 5 kg, 5 mg/kg, once Cat (PO): 1.8 kg, 5 mg/kg, once (for Paragonimus use 25 mg/kg q8h for 2-3 days) (IM, SC): 5 mg/kg

Prazosin

Minipress

1-, 2-, and 5-mg capsules

0.5- and 2-mg/dog or cat (1 mg/15 kg) PO q8-12h

Prednisolone

Delta-Cortef and many others

5- and 20-mg tablets

Dog (cat often requires two times dog dose) Antiinflammatory: 0.5-1 mg/kg IV, IM, PO q12-24h initially, then taper to q48h Immunosuppressive: 2.2-4.4 mg/kg/day IV, IM, PO initially, then taper to 2-4 mg/kg q48h Replacement therapy: 0.2-0.3 mg/kg/day PO

Prednisolone sodium succinate

Solu-Delta-Cortef

100- and 200-mg vials for injection (10 and 50 mg/ml)

Shock: 15-30 mg/kg IV (repeat in 4-6 hr) Central nervous system trauma: 15-30 mg/ kg IV, taper to 1-2 mg/kg q12h

Prednisone

Deltasone and generic; Meticorten for injection

1-, 2.5-, 5-, 10-, 20-, 25-, and 50-mg tablets; 1-mg/ml syrup (Liquid Pred in 5% alcohol) and 1-mg/ml oral solution (in 5% alcohol); 10- and 40-mg/ml prednisone suspension for injection

Same as prednisolone, except that prednisone is not recommended for cats

Primidone

Mylepsin, Neurosyn (Mysoline in Canada)

50- and 250-mg tablets

8-10 mg/kg PO q8-12h as initial dose, then is adjusted via monitoring to 10-15 mg/ kg q8h

Primor (ormetoprim + sulfadimethoxine)

Primor

Combination tablet (ormetoprim + sulfadimethoxine)

27 mg/kg on first day, followed by 13.5 mg/kg PO q24h

Procainamide

Pronestyl, generic

250-, 375-, 500-mg tablets or capsules; 100- and 500-mg/ml injection

Dog: 10-30 mg/kg PO q6h (to a maximum dose of 40 mg/kg), 8-20 mg/kg IV IM; 25-50 µg/kg/min IV infusion Cat: 3-8 mg/kg IM, PO q6-8h

APPENDIX  I  Table of Common Drugs: Approximate Dosages

1329

Drug Name

Other Names

Formulations Available

Dosage

Prochlorperazine

Compazine

5-, 10-, and 25-mg tablets (prochlorperazine maleate); 5-mg/ml injection (prochlorperazine edisylate)

0.1-0.5 mg/kg IM, SC q6-8h

Progesterone, repositol

See Medroxyprogesterone acetate

Promethazine

Phenergan

6.25- and 25-mg/5-ml syrup; 12.5-, 25-, 50-mg tablets; 25- and 50-mg/ml injection

0.2-0.4 mg/kg IV, IM PO q6-8h (up to a maximum dose of 1 mg/kg)

Propantheline bromide

Pro-Banthine

7.5- and 15-mg tablet

0.25-0.5 mg/kg PO q8-12h

Propiomazine

Tranvet

5-, 10-mg/ml injection or 20-mg tablet

1.1-4.4 mg/kg q12-24h PO or 0.1-1.1 mg/ kg IM, IV (range of dose depends on degree of sedation needed)

Propofol

Rapinovet and PropoFlo (veterinary); Diprivan (human)

1% (10 mg/ml) injection in 20-ml ampules

6.6 mg/kg IV slowly over 60 seconds; constant-rate IV infusions have been used at 5 mg/kg slowly IV, followed by 100-400 µg/kg/min IV

Propranolol

Inderal

10-, 20-, 40-, 60-, 80-, and 90-mg tablets; 1-mg/ml injection; 4and 8-mg/ml oral solution

Dog: 20-60 µg/kg over 5-10 min IV; 0.2-1 mg/kg PO q8h (titrate dose to effect) Cat: 0.4-1.2 mg/kg (2.5-5 mg/cat) PO q8h

Propylthiouracil (PTU)

Generic, Propyl-Thyracil

50- and 100-mg tablets

11 mg/kg PO q12h

Prostaglandin F2 alpha (dinoprost)

Lutalyse

5-mg/ml solution for injection

Pyometra: Dog: 0.1-0.2 mg/kg SC once daily for 5 days Cat: 0.1-0.25 mg/kg SC once daily for 5 days Abortion: Dog: 0.025-0.05 mg (25-50 µg)/ kg IM q12h Cat: 0.5-1 mg/kg IM for two injections

Pseudoephedrine

Sudafed and many others (some formulations have been discontinued)

30- and 60-mg tablets; 120-mg capsule; 6-mg/ml syrup

0.2-0.4 mg/kg (or 15-60 mg/dog) PO q8-12h

Psyllium

Metamucil and others

Available as powder

1 tsp/5-10 kg (added to each meal)

Pyrantel pamoate

Nemex, Strongid

180-mg/ml paste and 50-mg/ml suspension

Dog: 5 mg/kg PO once and repeat in 7-10 days Cat: 20 mg/kg PO once

Pyridostigmine bromide

Mestinon, Regonol

12-mg/ml oral syrup; 60-mg tablet; 5-mg/ml injection

Dog: Antimyasthenic: 0.02-0.04 mg/kg IV q2h or 0.5-3 mg/kg PO q8-12h, or CRI of 0.01-0.03 mg/kg/hr Antidote (nondepolarizing muscle relaxant): 0.15-0.3 mg/kg IM, IV Cat: 0.1-0.25 mg/kg q24h, PO

Pyrimethamine

Daraprim, ReBalance (Equine)

25-mg tablet Equine formulation (ReBalance) contains 250 mg sulfadiazine and 12.5 mg pyrimethamine per ml

Dog: 1 mg/kg PO q24h for 14-21 days (5 days for Neospora caninum) Cat: 0.5-1 mg/kg PO q24h for 14-28 days

Quinidine gluconate

Quinaglute, Duraquin

324-mg tablets; 80-mg/ml injection

Dog: 6-20 mg/kg IM q6h; 6-20 mg/kg PO q6-8h (of base)

Quinidine sulfate

Cin-Quin, Quinora

100-, 200-, and 300-mg tablets; 200- and 300-mg capsules; 20-mg/ml injection

Dog: 6-20 mg/kg PO q6-8h (of base); 5-10 mg/kg IV

Quinidine polygalacturonate

Cardioquin

275-mg tablet

Dog: 6-20 mg/kg PO q6h (of base) (275 mg quinidine polygalacturonate = 167 mg quinidine base)

Racemethionine (DL-methionine)

Uroeze, MethioForm, and generic. Human forms include Pedameth, Uracid, and generic

500-mg tablets and powders added to animal’s food; 75-mg/5 ml pediatric oral solution; 200-mg capsule

Dog: 150-300 mg/kg/day PO Cat: 1-1.5 gm/cat PO (added to food each day) Continued

1330

APPENDIX  I  Table of Common Drugs: Approximate Dosages

Drug Name

Other Names

Formulations Available

Dosage

Ranitidine

Zantac

75-, 150-, and 300-mg tablets; 150- and 300-mg capsules; 25-mg/ml injection

Dog: 2 mg/kg IV, PO q8h Cat: 2.5 mg/kg IV q12h, 3.5 mg/kg PO q12h

Retinoids

See Isotretinoin (Accutane), Retinol (Aquasol-A), or Etretinate (Tegison)

Retinol

See Vitamin A (Aquasol-A)

Riboflavin (vitamin B2)

See Vitamin B2

Rifampin

Rifadin

150- and 300-mg capsules

Dog: 5 mg/kg q12h, PO

Ringer’s solution

Generic

250-, 500-, and 1000-ml bags for infusion

55-65 ml/kg/day IV, SC, or IP; 50 ml/kg/hr IV for severe dehydration

Ronidazole

No formulation available; must be compounded

There are no commercial formulations. However, compounding pharmacies have prepared formulations for cats.

Dog: Dose not established Cat: 30 mg/kg/day PO for 2 wk. Dose of 30 mg/kg per day may be divided into twice daily treatments

Salicylate

See Aspirin, acetylsalicylic acid

Selegiline (deprenyl)

Anipryl (also known as deprenyl, and l-deprenyl); human dose form is Eldepryl

2-, 5-, 10-, 15-, and 30-mg tablets

Dog: Begin with 1 mg/kg PO q24h; if there is no response within 2 months, increase dose to maximum of 2 mg/kg PO q24h Cat: 0.25-0.5 mg/kg q12-24h PO

Senna

Senokot

Granules in concentrate, or syrup

Dog: Syrup; 5-10 ml/dog q24h; granules: 1 to 1 tsp/dog q24h PO with food 2 Cat: Syrup: 5 ml/cat q24h; granules: 12 teaspoon/cat q24h (with food)

Septra (sulfamethoxazole + trimethoprim)

See Trimethoprim/ sulfonamides

Sildenafil

Viagra

25-, 50-, 100-mg tablets

Dog: 0.5-1 mg/kg q12h PO; higher dose of 2-3 mg/kg q8h may be needed in some cases Cat: 1 mg/kg q8h, PO

Silymarin

Silybin, Marin, “milk thistle”

Silymarin tablets are widely available OTC. Commercial veterinary formulations (Marin) also contain zinc and vitamin E in a phosphatidylcholine complex in tablets for dogs and cats.

30 mg/kg/day PO

Sodium bicarbonate (NaHCO3)

Generic, Baking Soda, Soda Mint

325-, 520-, and 650-mg tablets; injection of various strengths (4.2% to 8.4%), and 1 mEq/ml

Acidosis: 0.5-1 mEq/kg IV Renal failure: 10 mg/kg PO q8-12h Alkalization of urine: 50 mg/kg PO q8-12h (1 tsp is approximately 2 gm)

Sodium bromide

No commercial form

Must be compounded

Same as potassium bromide, except dose is 15% lower (30 mg/kg potassium bromide is equivalent to 25 mg/kg sodium bromide)

Sodium chloride 0.9%

Generic

500- and 1,000-ml infusion

15-30 ml/kg/hr IV

Sodium chloride 7.5%

Generic

Infusion

2-8 ml/kg IV

Sodium thiomalate

See Gold sodium thiomalate

Somatrem, Somatropin See Growth hormone Sotalol

Betapace

80-, 160-, 240-mg tablets

Dog: 1-2 mg/kg PO q12h (one can start with 40 mg/dog q12h, then increase to 80 mg if no response) Cat: 1-2 mg/kg PO q12h

Spironolactone

Aldactone

25-, 50-, and 100-mg tablets

Dog: 2-4 mg/kg/day (or 1-2 mg/kg PO q12h) Cat: Questionable efficacy, may produce skin lesions

APPENDIX  I  Table of Common Drugs: Approximate Dosages

1331

Drug Name

Other Names

Formulations Available

Dosage

Stanozolol

Winstrol-V

50-mg/ml injection; 2-mg tablet

Dog: 2 mg/dog (or range of 1-4 mg/dog) PO q12h; 25-50 mg/dog/wk IM Cat: 1 mg/cat PO q12h; 25 mg/cat/wk IM

Succimer

Chemet

100-mg capsule

Dog: 10 mg/kg PO q8h for 5 days, then 10 mg/kg PO q12h for 2 more wk Cat: 10 mg/kg q8h for 2 wk

Sucralfate

Carafate (Sulcrate in Canada)

1-gm tablet; 200-mg/ml oral suspension

Dog: 0.5-1 gm/dog PO q8-12h Cat: 0.25 gm/cat PO q8-12h

Sufentanil citrate

Sufenta

50-µg/ml injection

2 µg/kg IV, up to a maximum dose of 5 µg/kg

Sulfadiazine

Generic, combined with trimethoprim in Tribrissen

500-mg tablet; trimethoprimsulfadiazine 30-, 120-, 240-, 480-, and 960-mg tablets

100 mg/kg IV, PO (loading dose), followed by 50 mg/kg IV, PO q12h (see also Trimethoprim)

Sulfadimethoxine

Albon, Bactrovet, and generic

125-, 250-, and 500-mg tablets; 400-mg/ml injection; 50-mg/ml suspension

55 mg/kg PO (loading dose), followed by 27.5 mg/kg PO q12h (see also Primor)

Sulfamethoxazole

Gantanol

50-mg tablet

100 mg/kg PO (loading dose), followed by 50 mg/kg PO q12h (see also Bactrim, Septra)

Sulfasalazine (sulfapyridine + mesalamine)

Azulfidine (Salazopyrin in Canada)

500-mg tablet

Dog: 10-30 mg/kg PO q8-12h (see also Mesalamine, Olsalazine) Cat: 20 mg/kg q12hr PO

Sulfisoxazole

Gantrisin

500-mg tablet; 500-mg/5 ml syrup

50 mg/kg PO q8h (urinary tract infections)

Tamoxifen

Nolvadex

10- and 20-mg tablets (tamoxifen citrate)

Veterinary dose not established; 10 mg PO q12h is human dose

Taurine

Generic

Available in powder

Dog: 500 mg PO q12hr Cat: 250 mg/cat PO q12hr

Telazol

See Tiletamine-Zolazepam

Terbinafine

Lamisil

125-, 250-mg tablets

Dog: Malassezia dermatitis: 30 mg/kg/day PO Cat: Dermatophytosis: 30-40 mg/kg PO q24h

Terbutaline

Brethine, Bricanyl

2.5- and 5-mg tablets; 1-mg/ml injection

Dog: 1.25-5 mg/dog PO q8h Cat: 0.1-0.2 mg/kg PO q12h (or 0.625 mg/ cat, 14 of 2.5-mg tablet) For acute treatment in cats: 5-10 µg/kg q4h SC or IM

Testosterone cypionate ester

Andro-Cyp, Andronate, Depo-Testosterone and other forms

100- and 200-mg/ml injection

1-2 mg/kg IM q2-4wk (see also Methyltestosterone)

Testosterone propionate ester

Testex (Malogen in Canada)

100-mg/ml injection

0.5-1 mg/kg 2-3 times/wk IM

Tetracycline

Panmycin

250- and 500-mg capsules; 100-mg/ml suspension

15-20 mg/kg PO q8h; or 4.4-11 mg/kg IV, IM q8h

Thenium closylate

Canopar

500-mg tablet

Dog: >4.5 kg: 500 mg PO once, repeat in 2-3 wk 2.5-4.5 kg: 250 mg q12h for 1 day, repeat in 2-3 wk

Theophylline

Many brands and generic

100-, 125-, 200-, 250-, and 300-mg tablets; 27-mg/5 ml oral solution or elixir; injection in 5% dextrose

Dog: 9 mg/kg PO q6-8h Cat: 4 mg/kg PO q8-12h

Continued

1332

APPENDIX  I  Table of Common Drugs: Approximate Dosages

Drug Name

Other Names

Formulations Available

Dosage

Theophylline extended-release

Inwood labs extended release

100-, 200-, 300-, and 400-mg tablets or 125-, 200-, 300-mg capsules

Dog: 10 mg/kg q12h PO of extendedrelease tablet or capsule Cat: 20 mg/kg q24-48h PO extendedrelease tablet or 25 mg/kg q24-48h PO extended-release capsule

Thiamine (vitamin B1)

Bewon and others

250-µg/5 ml elixir; tablets of various size from 5 mg to 500 mg; 100- and 500-mg/ml injection

Dog: 10-100 mg/dog/day PO or 12.5-50 mg/dog IM or SC/day Cat: 5-30 mg/cat/day PO (up to a maximum dose of 50 mg/cat/day) or 12.5-25 mg/cat IM or SC/day

Thioguanine (6-TG)

Generic

40-mg tablet

40 mg/m2 PO q24h Cat: 25 mg/m2 PO q24hr for 1-5 days, then repeat every 30 days

Thiomalate sodium

See Gold sodium thiomalate

Thiopental sodium

Pentothal

Various size vials from 250 mg to 10 gm (mix to desired concentration)

Dog: 10-25 mg/kg IV (to effect) Cat: 5-10 mg/kg IV (to effect)

Thiotepa

Generic

15-mg injection (usually in solution of 10 mg/ml)

0.2-0.5 mg/m2 weekly, or daily for 5-10 days IM, intracavitary, or intratumor

Thyroid hormone

See Levothyroxine sodium (T4), or Liothyronine

Thyrotropin, thyroidstimulating hormone (TSH)

Thytropar, Thyrogen

10-U vial; old forms difficult to obtain; Thyrogen is 1000 µg/vial

Dog: Collect baseline sample, followed by 0.1 U/kg IV (maximum dose is 5 U); collect post-TSH sample at 6 hr Cat: Collect baseline sample, followed by 2.5 U/cat IM and collect a post-TSH sample at 8-12 hr

Ticarcillin

Ticar, Ticillin

Vials containing 1, 3, 6, 20, and 30 gm

33-50 mg/kg IV, IM q4-6h

Ticarcillin + clavulanate

Timentin

3-gm/vial for injection

Dose according to rate for ticarcillin

Tiletamine + zolazepam

Telazol, Zoletil

50 mg of each component per milliliter

Dog: 6.6-10 mg/kg IM (short term) or 10-13 mg/kg IM (longer procedure) Cat: 10-12 mg/kg IM (minor procedure) or 14-16 mg/kg IM (for surgery)

Tobramycin

Nebcin

40-mg/ml injection

Dog: 9-14 mg/kg IM, IV, SC q24h Cat: 5-8 mg/kg IM, SC, IV q24h

Tocainide

Tonocard

400- and 600-mg tablets

Dog: 15-20 mg/kg PO q8h Cat: No dose established

Toluene

Vermiplex

Tramadol hydrochloride

Ultram and generic

Tramadol immediate-release tablets are available in 50-mg tablets

Dog: 5 mg/kg PO q6-8h Cat: Start with 2 mg/kg q12h PO and increase gradually to 4 mg/kg q8-12h. Cats are more prone to adverse reactions

Trandolapril

Mavik

1-, 2-, and 4-mg tablets

Not established for dogs; human dose is 1 mg/person/day to start, then increase to 2-4 mg/day

Triamcinolone

Vetalog, Trimtabs, Aristocort, generic

Veterinary (Vetalog) 0.5- and 1.5-mg tablets. Human form: 1-, 2-, 4-, 8-, and 16-mg tablets; 10-mg/ml injection

Antiinflammatory: 0.5-1 mg/kg PO q12-24h, then taper dose to 0.5-1 PO mg/kg q48h (however, manufacturer recommends doses of 0.11 to 0.22 mg/kg/day)

Triamcinolone acetonide

Vetalog

2- or 6-mg/ml suspension injection

0.1-0.2 mg/kg IM, SC, repeat in 7-10 days Intralesional: 1.2-1.8 mg, or 1 mg for every cm diameter of tumor q2wk

267 mg/kg PO (of toluene), repeat in 2-4 wk

APPENDIX  I  Table of Common Drugs: Approximate Dosages

Drug Name

Other Names

Formulations Available

Dosage

Triamterene

Dyrenium

50- and 100-mg capsules

1-2 mg/kg PO q12h

Tribrissen

See Trimethoprimsulfadimethoxine combination

1333

Trientine hydrochloride

Syprine

250-mg capsule

10-15 mg/kg PO q12h

Trifluoperazine

Stelazine

10-mg/ml oral solution; 1-, 2-, 5-, and 10-mg tablets; 2-mg/ml injection

0.03 mg/kg IM q12h

Triflupromazine

Vesprin

10- and 20-mg/ml injection

0.1-0.3 mg/kg IM, q8-12h

Tri-iodothyronine

See Liothyronine

Trilostane

Vetoryl

10-, 30-, 60-, and 120-mg capsules; no formulations approved in U.S.; must be imported

Dog: 3-6 mg/kg q24h, PO (adjust dose with cortisol measurements) Cat: 6 mg/kg q24h, PO and gradually increase as needed to 10 mg/kg q24h, PO

Trimeprazine tartrate

Temaril (Panectyl in Canada)

2.5-mg/5 ml syrup; 2.5-mg tablet

0.5 mg/kg PO q12h

Trimethobenzamide

Tigan and others

100-mg/ml injection; 100- and 250-mg capsules

Dog: 3 mg/kg IM, PO q8h Cat: Not recommended

Trimethoprim + sulfonamides (sulfadiazine or sulfamethoxazole)

Tribrissen and others

30-, 120-, 240-, 480-, and 960-mg tablets with trimethoprim to sulfa ratio 1 : 5

15 mg/kg PO q12h, or 30 mg/kg PO q12-24h For Toxoplasma: 30 mg/kg PO q12h

Tripelennamine citrate and Tripelennamine hydrochloride

Pelamine, PBZ

25- and 50-mg tablets; 5 mg/mL oral liquid elixir and 20-mg/ml injection (citrate); Tripelennamine hydrochloride is a 25 mg/mL injection

1 mg/kg PO q12h, or 0.25 mL per 5 kg of tripelennamine hydrochloride

TSH (thyroidstimulating hormone)

See Thyrotropin

Tylosin

Tylocine, Tylan, Tylosin tartrate

Available as soluble powder 2.2 gm tylosin per tsp (tablets for dogs in Canada)

Dog, cat: 7-15 mg/kg PO q12-24h Dog: For colitis: 10-20 mg/kg q8h with food initially, then increase interval to q12-24h

Urofollitropin (FSH)

Metrodin

75 U/vial for injection

75 U/day IM for 7 days

Ursodiol (ursodeoxycholate)

Actigall

300-mg capsule, 250-mg tablets

10-15 mg/kg PO q24h

Valproic acid, divalproex

Depakene (valproic acid); Depakote (divalproex)

125-, 250-, and 500-mg tablets (Depakote); 250-mg capsule; 50-mg/ml syrup (Depakene)

Dog: 60-200 mg/kg PO q8h; or 25-105 mg/kg/day PO when administered with phenobarbital

Vancomycin

Vancocin, Vancoled

Vials for injection (0.5 to 10 gm)

Dog: 15 mg/kg q6-8h IV infusion Cat: 12-15 mg/kg q8h IV infusion

Vasopressin (ADH)

Pitressin

20 U/ml (aqueous)

10 U per animal IV or IM

Verapamil

Calan, Isoptin

40-, 80-, and 120-mg tablet; 2.5-mg/ml injection

Dog: 0.05 mg/kg IV q10-30min (maximum cumulative dose is 0.15 mg/kg)

Vinblastine

Velban

1-mg/ml injection

2 mg/m2 IV (slow infusion) once/wk

Vincristine

Oncovin, Vincasar, generic

1-mg/ml injection

Antitumor: 0.5-0.7 mg/m2 IV (or 0.0250.05 mg/kg) once/wk For thrombocytopenia: 0.02 mg/kg IV once/wk

Viokase

See Pancrelipase

Vitamin A (retinoids)

Aquasol A

Oral solution: 5000 U (1500 RE) per 0.1 ml 10,000-, 25,000-, and 50,000-U tablets

625-800 U/kg PO q24h

Continued

1334

APPENDIX  I  Table of Common Drugs: Approximate Dosages

Drug Name

Other Names

Formulations Available

Dosage

Vitamin B1

See Thiamine

Vitamin B2 (riboflavin)

Riboflavin

Various-size tablets in increments from 10 to 250 mg

Dog: 10-20 mg/day PO Cat: 5-10 mg/day PO

Vitamin B12 (cyanocobalamin)

Cyanocobalamin

Various-size tablets in increments from 25 to 100 µg and injections

Dog: 100-200 µg/day PO Cat: 50-100 µg/day PO

Vitamin C (ascorbic acid)

See Ascorbic acid

Tablets of various sizes and injection

100-500 mg/day

Vitamin D

See Dihydrotachysterol or Ergocalciferol

Vitamin E (alphatocopherol)

Aquasol E, and generic

Wide variety of capsules, tablets, oral solution available (e.g., 1000 units per capsule)

100-400 U PO q12h (or 400-600 U PO q12h for immune-mediated skin disease)

Vitamin K1 (phytonadione, phytomenadione)

AquaMEPHYTON (injection), Mephyton (tablets); Veta-K1 (capsules)

2- or 10-mg/ml injection; 5-mg tablet (Mephyton) 25-mg capsule (Veta-K1)

Short-acting rodenticides: 1 mg/kg/day IM, SC, PO for 10-14 days Long-acting rodenticides: 2.5-5 mg/kg/day and up to 6 wk IM, SC, PO for 3-4 wk Birds: 2.5-5 mg/kg q24h

Warfarin

Coumadin, generic

1-, 2-, 2.5-, 4-, 5-, 7.5-, and 10-mg tablets

Dog: 0.1-0.2 mg/kg PO q24h Cat: Thromboembolism: Start with 0.5 mg/ cat/day and adjust dose based on clotting time assessment

Xylazine

Rompun and generic

20- and 100-mg/ml injection

Dog: 1.1 mg/kg IV, 2.2 mg/kg IM Cat: 5-10 mg/kg q12h, PO or SC

Yohimbine

Yobine

2-mg/ml injection

0.11 mg/kg IV or 0.25-0.5 mg/kg SC, IM

Zidovudine (AZT)

Retrovir

10-mg/ml syrup; 10-mg/ml Injection

Cat: 5-10 mg/kg q12h, PO or SC

Zolazepam

See Tiletamine-zolazepam combination

Zonisamide

Zonegran

100-mg capsule

Dog: 3 mg/kg q8h PO; it has also been administered to dogs at 10 mg/kg q12h PO Cat: Dose not established

APPENDIX 

II

Treatment of Parasites LORA R. BALLWEBER, Fort Collins, Colorado

Species

Target Parasites

Route*

Veterinary Formulations

Emodepside/ Praziquantel

Feline only

Toxocara cati, Ancylostoma tubaeforme, Dipylidium caninum, Taenia taeniaeformis

Topical

Profender

Epsiprantel

Canine and feline

Dipylidium caninum, Taenia spp.

Oral

Cestex

Febantel/ Praziquantel/ Pyrantel pamoate

Canine only

Toxocara canis, Toxascaris leonina, Ancylostoma caninum, Uncinaria stenocephala, Trichuris vulpis, Dipylidium caninum, Echinococcus granulosus, Echinococcus multilocularis, Taenia pisiformis

Oral

Drontal Plus

Fenbendazole

Canine

Toxocara canis, Toxascaris leonina, Ancylostoma caninum, Uncinaria stenocephala, Trichuris vulpis, Taenia pisiformis

Oral

Panacur C, Safe-Guard

Imidacloprid/ Moxidectin

Canine and feline

Toxocara canis, Toxascaris leonina (dog), Toxocara cati (cat), Ancylostoma caninum, Uncinaria stenocephala (dog), Ancylostoma tubaeforme (cat), Trichuris vulpis (dog); Dirofilaria immitis prevention (dog/cat)

Topical

Advantage Multi

Ivermectin

Canine and feline

Ancylostoma tubaeforme, A. braziliense (cat), Dirofilaria immitis prevention (dog/cat)

Oral

Heartgard

Ivermectin/ Praziquantel/ Pyrantel pamoate

Canine only

Toxocara canis, Toxascaris leonina, Ancylostoma caninum, Ancylostoma braziliense, Uncinaria stenocephala, Dipylidium caninum, Taenia pisiformis, Dirofilaria immitis prevention

Oral

Iverhart Max

Ivermectin/ Pyrantel pamoate

Canine only

Toxocara canis, Toxascaris leonina, Ancylostoma caninum, Ancylostoma braziliense, Uncinaria stenocephala, Dirofilaria immitis prevention

Oral

Heartgard Plus, Iverhart Plus, TriHeart Plus, PetTrust Plus

Milbemycin oxime

Canine and feline

Roundworms, Ancylostoma spp., Trichuris vulpis in dogs; Dirofilaria immitis prevention

Oral

Sentinel (with lufenuron), Trifexis (with spinosad)

Praziquantel

Canine and feline

Dipylidium caninum (cat/dog), Echinococcus spp. (dog), Taenia spp. (cat/dog)

Oral, injectable

Droncit

Moxidectin

Canine

Dirofilaria immitis prevention

Injectable

ProHeart6

Praziquantel/ Pyrantel pamoate

Canine and feline

Toxocara canis, Toxascaris leonina (dog), Toxocara cati (cat), Ancylostoma caninum, Ancylostoma braziliense, Uncinaria stenocephala (dog), Ancylostoma tubaeforme (cat), Dipylidium caninum, Taenia spp. (dog/cat)

Oral

Drontal and numerous generic formulations

Pyrantel pamoate

Canine

Toxocara canis, Toxascaris leonina, Ancylostoma caninum, Uncinaria stenocephala

Oral

Nemex 2

Selamectin

Canine and feline

Toxocara cati, Ancylostoma tubaeforme (cat); Dirofilaria immitis prevention (dog/cat)

Topical

Revolution

Drug(s) HELMINTHS

Continued

1335

1336

APPENDIX  II  Treatment of Parasites

Drug(s)

Species

Target Parasites

Route*

Veterinary Formulations

Drug(s)

Species

Target Parasite(s)

Route(s) and Frequency of Administration

Veterinary Formulations

Dinotefuran/ Pyriproxyfen

Canine and feline

Fleas

Topical, monthly

Vectra

Dinotefuran/ Pyriproxyfen/ Permethrin

Canine only

Fleas, ticks, mosquitoes, biting flies, mites (not mange), lice

Topical, monthly

Vectra 3D

Deltamethrin

Canine only

Fleas, ticks

Collar, 6 months

Scalibor Protector Band

Fipronil

Canine and feline

Fleas, ticks, chewing lice

Topical, monthly

Frontline Plus, Parastar, and numerous generic formulations

Fipronil/ Amitraz/SMethoprene

Canine only

Fleas, ticks, sarcoptic mange mites, chewing lice

Topical, monthly

Certifect

Fipronil/ Cyphenothrin

Canine only

Fleas, ticks, chewing lice

Topical, monthly

Parastar Plus

Imidacloprid/ Flumethrin

Canine only

Fleas, ticks, sarcoptic mange mites, lice

Collar, 8 months

Seresto

Imidacloprid/ Pyriproxyfen

Canine and feline

Fleas (dog/cat), chewing lice (dog)

Topical, monthly

Advantage II

Imidacloprid/ Moxidectin

Canine and feline

Fleas (dog/cat), ear mites (cat)

Topical, monthly

Advantage Multi

Imidacloprid/ Permethrin

Canine only

Fleas, ticks, mosquitoes, biting flies, chewing lice

Topical, monthly

Advantix II

Indoxacarb

Canine only

Fleas

Topical, monthly

Activyl

Indoxacarb/ Permethrin

Canine only

Fleas, ticks

Topical, monthly

Activyl Tick Plus

Ivermectin

Feline only

Ear mites

Topical, in ear canal, repeat once as necessary

Acarexx

Nitenpyram

Canine and feline

Fleas

Oral, daily

Capstar

Spinosad

Canine and feline

Fleas

Oral, monthly

Comfortis

Spinosad/ Milbemycin oxime

Canine

Fleas

Oral, monthly

Trifexis

ECTOPARASITES

APPENDIX  II  Treatment of Parasites

1337

Drug(s)

Species

Target Parasites

Route*

Veterinary Formulations

Drug(s)

Species

Target Parasite(s)

Route of Administration and Dosages

Veterinary Formulations

Amprolium

Canine

Cystoisospora spp.

Oral, 100 mg/kg q24h, 7-10 days

Corid

Atovaquone + Azithromycin

Feline

Cytauxzoon felis

Oral, 15 mg/kg q8h + 10 mg/kg q24h, 10 days

Mepron + azithromycin suspension

Azithromycin

Canine and feline

Cryptosporidium

5-10 mg/kg (dog) or 7-15 mg/ kg (cat) q12h, 5-7 days or until clinical signs resolve

Azithromycin suspension

Clindamycin

Canine and feline

Toxoplasma gondii (systemic infections); Neospora caninum

Oral, 10-15 mg/kg q12h, 14-28 days as needed (T. gondii); 7.5-20 mg/kg q12h for 2 weeks beyond clinical resolution (N. caninum)

Antirobe

Doxycycline

Canine and feline

Toxoplasma gondii (systemic infections)

Oral 5-10 mg/kg q12h, 28 days

Vibramycin

Fenbendazole

Canine and feline

Giardia intestinalis

Oral, 50 mg/kg q24h, 3-5 days

Panacur

Furazolidone

Feline

Giardia intestinalis

Oral, 4 mg/kg q12h, 7-10 days

Imidocarb diproprionate

Canine and feline

Babesia spp., Cytauxzoon felis

IM or SC, 6.6 mg/kg, repeat in 14 days (Babesia); 3.5 mg/kg, repeat in 7 days (C. felis)

Imizol

Metronidazole

Canine and feline

Giardia intestinalis

Oral, 15-25 mg/kg q12-24h, 5-7 days

Flagyl

Nitazoxanide

Canine and feline

Giardia intestinalis, Cryptosporidium spp.

Oral, 100 mg/kg q12h, 3 days (G. intestinalis); 25 mg/kg q12h, at least 5 days (Cryptosporidium)

Alinia (Human)

Ponazuril

Canine and feline

Cystoisospora spp., Toxoplasma gondii

Oral, 15 mg/kg q24h, 3 days; 30 mg/kg q24h, 1 day

Marquis (Horses)

Ronidazole

Canine and feline

Giardia intestinalis (dog); Tritrichomonas foetus (cat)

Oral, 30-50 mg/kg q12h, 7 days (G. intestinalis); 30 mg/kg q12h, up to 14 days (T. foetus)

Ridzol

Sulfadiazine and trimethoprim

Canine and feline

Cystoisospora spp., Toxoplasma gondii (intestinal infections)

Oral, 30 mg/kg q12h, 14 days as needed

Tribrissen

Sulfadimethoxine

Canine and feline

Cystoisospora spp., Toxoplasma gondii (intestinal infections)

Oral, 50 mg/kg day 1, then 25 mg/kg q24h for 14-21 days as needed

Albon

Tinidazole

Canine and feline

Giardia intestinalis

Oral, 44 mg/kg q24h, 3 days (dog): 30 mg/kg q12h, 7-10 days (cat)

Tindamax, Fasigyn

Tylosin

Canine and feline

Giardia intestinalis

Oral, 10-15 mg/kg q8h-q12h for 21 days

Tylan

PROTOZOA

*Follow manufacturer’s recommendations for indicated use; see Appendix I, Table of Common Drugs: Approximate Dosages, for extralabel use.

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APPENDIX 

III

AAFCO Dog and Cat Food Nutrient Profiles DAVID A. DZANIS, Santa Clarita, California

The Association of American Feed Control Officials (AAFCO) is a non-governmental body, but it is composed solely of representatives from agencies within individual states and territories, federal agencies such as the U.S. Food and Drug Administration (FDA), and foreign governments such as Canada. A primary function of AAFCO is the publication of a model feed bill, animal feed regulations, and ingredient definitions, all of which a state may adopt as a part of its own feed laws and regulations. A pet food that bears a “complete and balanced”; label claim that does not, in fact, offer adequate nutrition is both misbranded and unsafe. To address this concern, included in the model pet food regulations are means of substantiating nutritional adequacy for complete and balanced dog and cat foods. One method of substantiating nutritional adequacy requires that the product be formulated so that essential nutrient levels meet a prescribed profile. Historically, AAFCO relied on the publications of the National Research Council (NRC) as its authority with respect to the levels of nutrients that constituted a complete and balanced dog or cat food. However, to address several technical concerns regarding the applicability of the NRC recommendations to the practical formulation of pet foods, they were replaced by the AAFCO Dog and Cat Food Nutrient Profiles (Tables 1 and 2) in the early 1990s*. The profiles are the product of the AAFCO Canine Nutrition Expert (CNE) and Feline Nutritional Expert (FNE) Subcommittees, which met in 1990 and 1991, respectively. Nationally recognized experts from both academia and industry were convened to establish practical profiles based on commonly used ingredients. In addition to this author (at that time representing the FDA), members of the CNE included Dr. Jim Corbin, University of Illinois; Dr. Gail CzarneckiMaulden, Westreco, Inc.; Dr. Diane Hirakawa, The Iams Company; Dr. Francis Kallfelz, Cornell University; Dr. Mark Morris, Mark Morris Associates; and Dr. Ben Sheffy, Cornell University. Added to the original members of the CNE were two new members on the FNE to bring additional expertise in the field of cat nutrition; Dr. Quinton Rogers, University of California-Davis; and Dr. Angele Thompson, Kal Kan Foods. Mr. Wenell Kerr of Westreco, Inc., also participated to provide statistical support to both subcommittees. The CNE and FNE met once again in 1995 to review and update both the dog and the cat food profiles. At the time of this writing, a new AAFCO expert panel has been convened to review recent data and recommend revision of the profiles where appropriate. Nutrient levels in the AAFCO Dog and Cat Food Nutrient Profiles are based on the CNE and the FNE members’ knowledge of published and unpublished research, as well as their personal expertise and experiences in practical formulation. Much of the scientific data on nutrient requirements are based on studies using purified diets and the presumption of 100% bioavailability. However, since commercial products are composed of nonpurified, complex ingredients, allowances to account for the effects of ingredients, ingredient interactions, and processing on bioavailability were also considered in establishing nutrient levels. Comments on the bioavailability or the effect of processing and ingredient interaction on some nutrients are also added in the footnotes to tables. In addition to minimum nutrient levels, the AAFCO Dog and Cat Food Nutrient Profiles also set maximum levels of intake of some nutrients. This was done out of concern that the risk of nutrient excess, rather than deficiency, was a concern with some pet foods. Thus maximum limits on the amounts of calcium, phosphorus, magnesium, fat-soluble vitamins, and most trace minerals in dog foods are established. Whereas the list of maximum levels for cat foods is not as extensive as that for dog foods, it should not be inferred that cats are more tolerant of nutrient excesses than dogs. Rather it reflects the paucity of information on the toxic effects of nutrients in cats. Establishing maximum levels arbitrarily might prove worse than no maximum at all. Setting a maximum level implies safety below that level, which the subcommittees could not reasonably ensure. Replacing the previous “meets or exceeds the NRC recommendations” verbiage, the required label wording for reference to the nutrient profiles is that the product is “… formulated to meet the nutrient levels established by the AAFCO Dog (or Cat) Food Nutrient Profiles for …” a given life stage. For both dog and cat foods, there are two separate AAFCO profiles: one for growth and reproduction (gestation and lactation), and one for adult maintenance. This allows foods

*“Revisions of these nutrient profiles are under consideration by AAFCO, and recommendations may change in the future”.

1

APPENDIX  III  AAFCO Dog and Cat Food Nutrient Profiles

TABLE 1  AAFCO Dog Food Nutrient Profiles* Nutrient

Units DM Basis

Growth and Reproduction Minimum

Crude Protein Arginine Histidine Isoleucine Leucine Lysine Methionine-cystine Phenylalanine-tyrosine Threonine Tryptophan Valine

% % % % % % % % % % %

22.0 0.62 0.22 0.45 0.72 0.77 0.53 0.89 0.58 0.2 0.48

18.0 0.51 0.18 0.37 0.59 0.63 0.43 0.73 0.48 0.16 0.39

Crude Fat† Linoleic acid

% %

8.0 1.0

5.0 1.0

% %

0.6 0.5 1 : 1 0.6 0.06 0.09 0.04 80 7.3 5.0 120 1.5 0.11 5,000 500 50 1.0 2.2 10 11.4 1.0 0.18 0.022 1,200

Minerals Calcium Phosphorus Ca:P ratio Potassium Sodium Chloride Magnesium Iron‡ Copper§ Manganese Zinc Iodine Selenium

% % % % mg/kg mg/kg mg/kg mg/kg mg/kg mg/kg

1.0 0.8 1 : 1 0.6 0.3 0.45 0.04 80 7.3 5.0 120 1.5 0.11

Vitamins and Other Vitamin A Vitamin D Vitamin E Thiamine|| Riboflavin Pantothenic acid Niacin Pyridoxine Folic acid Vitamin B12 Choline

IU/kg IU/kg IU/kg mg/kg mg/kg mg/kg mg/kg mg/kg mg/kg mg/kg mg/kg

5,000 500 50 1.0 2.2 10 11.4 1.0 0.18 0.022 1,200

Adult Maintenance Minimum

Maximum

2.5 1.6 2 : 1

0.3 3,000 250 1,000 50 2 250,000 5,000 1,000

*Presumes an energy density of 3.5 kcal ME/g DM, based on the “modified Atwater” values of 3.5, 8.5, and 3.5 kcal/g for protein, fat, and carbohydrate (nitrogen-free extract, NFE), respectively. Rations greater than 4.0 kcal/g should be corrected for energy density; rations less than 3.5 kcal/g should not be corrected for energy. Rations of low-energy density should not be considered adequate for growth or reproductive needs based on comparison to the profiles alone. † Although a true requirement for fat per se has not been established, the minimum level was based on recognition of fat as a source of essential fatty acids, as a carrier of fat-soluble vitamins, and on the amount needed to enhance palatability and to supply an adequate caloric density. ‡ Because of very poor bioavailability, iron from carbonate or oxide sources that are added to the diet should not be considered in determining the minimum nutrient level. § Because of very poor bioavailability, copper from oxide sources that are added to the diet should not be considered in determining the minimum nutrient level. || Because processing may destroy up to 90% of the thiamine in the diet, allowances in formulation should be made to ensure that the minimum nutrient level is met after processing.

formulated for adult dogs or cats to contain lower amounts of some nutrients, eliminating unnecessary excesses. Products that meet only the adult maintenance profile should include “maintenance” as its given life stage. Since products suitable for the more stringent nutrient requirements of growth and reproduction are also presumed to be adequate for adult maintenance, products meeting the growth and reproduction profile can list their intended use for either maintenance, growth, gestation and lactation, or “all life stages.” Nutrient levels in the tables are expressed on a dry matter (DM) basis. To accurately compare levels for a pet food as given in the guaranteed analysis portion of a label or elsewhere on an “as fed” basis, the values must first be corrected 2

APPENDIX  III  AAFCO Dog and Cat Food Nutrient Profiles

TABLE 2  AAFCO Cat Food Nutrient Profiles* Nutrient

Units DM Basis

Growth and Reproduction Minimum

Adult Maintenance Minimum

Crude Protein Arginine Histidine Isoleucine Leucine Lysine Methionine-cystine Methionine Phenylalanine-tyrosine Phenylalanine Threonine Tryptophan Valine

% % % % % % % % % % % % %

30.0 1.25 0.31 0.52 1.25 1.2 1.1 0.62 0.88 0.42 0.73 0.25 0.62

26.0 1.04 0.31 0.52 1.25 0.83 1.1 0.62 0.88 0.42 0.73 0.16 0.62

Crude Fat† Linoleic acid Arachidonic acid

% % %

9.0 0.5 0.02

9.0 0.5 0.02

Minerals Calcium Phosphorus Potassium Sodium Chloride Magnesium‡ Iron§ Copper (extruded)|| Copper (canned)|| Manganese Zinc Iodine Selenium

% % % % % % mg/kg mg/kg mg/kg mg/kg mg/kg mg/kg mg/kg

1.0 0.8 0.6 0.2 0.3 0.08 80 15 5 7.5 75 0.35 0.1

0.6 0.5 0.6 0.2 0.3 0.04 80 5 5 7.5 75 0.35 0.1

Vitamins and Others Vitamin A Vitamin D Vitamin E¶ Vitamin K# Thiamine** Riboflavin Pantothenic acid Niacin Pyridoxine Folic acid Biotin†† Vitamin B12 Choline‡‡ Taurine (extruded) Taurine (canned)

IU/kg IU/kg IU/kg mg/kg mg/kg mg/kg mg/kg mg/kg mg/kg mg/kg mg/kg mg/kg mg/kg % %

9,000 750 30 0.1 5.0 4.0 5.0 60 4.0 0.8 0.07 0.02 2,400 0.1 0.2

5,000 500 30 0.1 5.0 4.0 5.0 60 4.0 0.8 0.07 0.02 2,400 0.1 0.2

Maximum

1.5

2,000

750,000 10,000

*Presumes an energy density of 4.0 kcal ME/g DM, based on the “modified Atwater” values of 3.5, 8.5, and 3.5 kcal/g for protein, fat, and carbohydrate (nitrogen-free extract, NFE), respectively. Rations greater than 4.5 kcal/g should be corrected for energy density; rations less than 4.0 kcal/g should not be ­corrected for energy. Rations of low-energy density should not be considered adequate for growth or reproductive needs based on comparison to the profiles alone. † Although a true requirement for fat per se has not be established, the minimum level was based on recognition of fat as a source of essential fatty acids, as a carrier of fat-soluble vitamins, to enhance palatability, and to supply an adequate caloric density. ‡ If the mean urine pH of cats fed ad libitum is not below 6.4, the risk of struvite urolithiasis increases as the magnesium content of the diet increases. § Because of very poor bioavailability, iron from carbonate or oxide sources that are added to the diet should not be considered in determining the minimum nutrient level. || Because of very poor bioavailability, copper from oxide sources that are added to the diet should not be considered in determining the minimum nutrient level. ¶ Add 10 IU of vitamin E above minimum level per gram of fish oil per kilogram of diet. # Vitamin K does not need to be added unless diet contains more than 25% fish on a dry matter basis. **Because processing may destroy up to 90% of the thiamine in the diet, allowances in formulation should be made to ensure that the minimum nutrient level is met after processing. †† Biotin does not need to be added unless diet contains antimicrobial or antivitamin compounds. ‡‡ Methionine may be used to substitute for choline as a methyl donor at rate of 3.75 parts for 1 part choline by weight when methionine exceeds 0.62%.

3

APPENDIX  III  AAFCO Dog and Cat Food Nutrient Profiles for moisture content. For most dry pet foods (10% moisture), “as fed” values should be multiplied by 1.1. For 75% moisture canned product, values should be multiplied by 4.0. The profiles are also set at presumed energy densities (3.5 kcal ME/g DM for dog foods, 4.0 kcal ME/g DM for cat foods). Since a dog or cat is presumed to eat less of a highcalorie food, the levels of the nutrients must be proportionally higher in order for the animal to meet its needs with lower food intake. Thus products very high in caloric density should also be corrected for energy content before comparisons with the profiles are made. The AAFCO Dog and Cat Food Nutrient Profiles and accompanying information on using the tables are published annually in the AAFCO Official Publication. Information on AAFCO and how to obtain a copy of the AAFCO Official Publication can be found on its website (http://www.aafco.org).

4

Index A A-V block. See Atrioventricular (heart) block AAFCO profiles, during pregnancy and lactation, 964-965, 966f Abamectin for dermatologic disorders, e178 for lung worms, e274-e275 ABCB1 gene, for predicting adverse effects of drug therapy, 175, 330, 433 Abdomen, septic, drainage techniques for, e13-e20 Abdominal effusion(s). See Ascites; Peritoneal effusion Abdominal palpation, for pregnancy diagnosis, 944 Abdominocentesis for ascites from liver disease, 591-592 from refractory heart failure, 781 for malignant effusions, 342 Ablation, for supraventricular tachyarrhythmias in dogs, 744 Abortion. See also Pregnancy, medical termination of from hypothyroidism, e85 infectious causes of, 1218 misoprostol causing, 507 Abscess, orbital, 1198-1199 Abyssinian cat amyloidosis in, 855 arterial thromboembolism in, 812-813 hepatic amyloidosis in, 571b progressive retinal atrophy in, 1195 Acanthomatous ameloblastoma, 363, 365 Acarbose, for diabetes mellitus, in cats, e136f, e136t, e137 Acemannan as cancer immunotherapy, 335, 336t for feline retrovirus infections, 1280t-1281t, 1282 for infectious disease immune therapeutics, 1230, 1230t Acepromazine causing adverse skin reactions, 488t for postpartum agalactia, 958t for tracheal collapse, 664 to calm respiratory distress pets, 47t use of with cardiovascular dysfunction, 64-65 with intracranial pathology, 69

Page numbers followed by “f” indicate figure, “t” indicate tables, “b” indicate boxes, and “e” indicate web chapters.

Acetaminophen (Tylenol) associated hepatotoxicity, 570b, 576-577, 581b N-acetylcysteine for toxicity of, 576-577 S-adenosylmethionine (SAMe) for toxicity of, 577 toxicity from, 117-118 Acetazolamide for craniocervical junction abnormalities, 1102 for glaucoma in dogs, 1173-1174, 1173b for hydrocephalus, 1036 Acetic acid as topical therapy, 441t for Malassezia dermatitis, 442 Acetylcholine receptor (AChR) antibody test, for myasthenia gravis, 1109, 1111-1112, e226 Acetylcholinesterase inhibitor(s) action and use of, for motility disorders, 516-518, 517t from insecticide toxicity, 135 Acetylcysteine (Mucomyst) for canine bronchial diseases, 672 for respiratory diseases, 627 for rhinitis in cats, 647 for Tylenol toxicity, e61t-e66t Acetylsalicylic acid. See Aspirin Achondroplasia, 649 Achromatopsia, 1190 Acid-base disorders compensatory responses with, e2b, e2t diagnosis and treatment of, e1-e8 Acidosis, acid-base disorders and, e1-e8 Acitretin for ichthyosis, 476 for sebaceous adenitis, e211 Acorus toxicity, 124t Acral lick dermatitis, e172-e178 allergy testing with, e175-e176 causes of, e172, e173b diagnosis of, e174-e175 drug therapy for, 482-485 perpetuating factors for, e174 predisposing factors for, e173, e173b treatment of, e175-e178 Acromegaly feline, 216-221, 217f, 217t hypertension from, 727t insulin resistance with, 206b, 207 risk of, with progestin drugs, 985 Acrylonitrile, causing reproductive toxicity, 1027b Actinic dermatoses, 480-482 Actinomycin D, as rescue therapy for canine lymphoma, 382t Activated charcoal for flatulence, e249-e250 for toxin ingestion, 105, 113

Activated clotting time (ACT) in disseminated intravascular coagulation, 294t with anticoagulant rodenticide toxicity, 133 Activated protein C, replacement therapy, for disseminated intravascular coagulation, 295 Acute kidney injury. See Renal failure, acute Acute myeloid leukemia, 314, 318 Acute respiratory distress syndrome (ARDS), 48-51 diagnosis and treatment of, 48-51 differential diagnoses for, 49b rational use of glucocorticoids for, 1301 risk factors for, 49b with feline pancreatitis, 567 Acyclovir, for feline ocular herpesvirus 1, 1158 Adenocarcinoma anal sac, e189-e190 mammary canine, 376 feline, 378-380 nasal in dogs, 641-643, 642f radiation therapy for, 338-340 of ciliary body, in cats, 1209 of the exocrine pancreas, 557 of third eyelid, in dogs, 1203 perianal, 366-369 uterine, 1025-1026 Adenosine triphosphate (ATP), as energy source for brain, 1047 Adenovirus 1, vaccine causing uveitis in dogs, 1164 Adipokines, role in obesity, 254 Adiponectin, role in obesity, 254 Adipose tissue, role in obesity, 254 Adnexal disease, e363-e369 Adrenal disease(s) hyperadrenocorticism imaging for diagnosis of, 171 therapy of, 229 interpretation of tests results for, e97-e102 Adrenal gland(s) imaging of, for diagnosis of endocrine disorder(s), 170-172 incidental mass of, 172 secretion of sex hormone causing hyperadrenocorticism, 221 with feline hyperaldosteronism hyperplasia, 241 neoplasia, 238-239, 241 Adrenal insufficiency illness-related, 78-79, 174-178 with shock, 24-25

1339

1340

Index

Adrenalectomy, for adrenal-dependent hyperadrenocorticism, 229 Adrenocorticotropic hormone (ACTH) ectopic syndrome of, 230-232, 231f stimulation test for illness adrenal insufficiency, 175-176 for occult hyperadrenocorticism, 221 interpretation of, e97-e98 with alopecia X, 478 with hypoadrenocorticism, in dogs, 233-235 with illness-related adrenal insufficiency, 79 Advanced life support, 28-31 Adverse drug experience definition of, e35-e36 reporting of, e36 Adverse drug reactions, cutaneous, 487-490, 488t Adverse events from vaccines, 1249-1256 reporting of, e35-e43 Adverse food reactions causing blepharitis, e365 food elimination diets for, 422-424 Aelurostrongylus abstrusus as bronchopulmonary parasite, e273-e274 common symptoms and syndromes caused by, 1214t-1215t AeroKat and AeroDawg spacers, 623-624, 671, 678-680, 679f, 690, 690f Aerophagia, causing flatulence, e248-e249 Aerosol spray(s), as respiratory toxicants, e46 Afghan hound(s), testicular tumors in, 1022-1023 Aflatoxicosis associated hepatotoxicity, 570b, 581b in dogs, 159-161 African violet(s), 121b Agalactia, 958t postpartum, 959 Agent orange, in pot scrubbing sponges, 98 Aglepristone, for pregnancy termination, 991 Air pollutant(s), e45-e46 Air quality improving indoor, e47-e48 index, e47-e48 Air-purifiers, causing ozone toxicity, e45-e46 Airflow, with brachycephalic airway syndrome, 651 Airway obstruction and evaluation, 26 causes of, 46t large, causing respiratory acidosis, e4b with brachycephalic airway syndrome, 649-653 Airway resistance, 44 Akita(s) hyperkalemia and hyponatremia in, e93 sebaceous adenitis in, e209-e210

Alanine aminotransferase (ALT) elevations from methimazole, e104 monitoring of, before lomustine, 332-333 with feline hepatic lipidosis, 609-610 with hepatobiliary disease, 569-573 with idiopathic vacuolar hepatopathy, 607 Alaskan husky, mitochondrial encephalopathy in, 1048-1051, 1049t, 1051t Alaskan malamute(s) alopecia X in, 477-479 zinc-responsive dermatosis, causing blepharitis in, e365 Alaskan sled dog(s), thyroid hormone differences in, 180t Albendazole for Giardia spp., 530t for lung worms, e276 Albumin, 11 characteristics of, 10t fluid dynamics and, 9-11 Albuminuria, detection and management of, 849-852 Albuterol for bronchial diseases, 671 for feline asthma, 677 for respiratory diseases, 623 inhaler for feline asthma, 675, 677, 680 for respiratory diseases, 623-624 Alcohol for disinfection of methicillin-resistant Staphylococcal sp., 456-457 in ear cleaners, 472t, 473 toxicity, 147 Aldosterone concentrations with atypical hypoadrenocorticism, 233, 235 with feline hyperaldosteronism, 239-240, 240t escape, 854 Aldosterone receptor antagonists, for glomerular disease, 854, 854f Aldosterone-to-renin ratio, 235 Alendronate, for feline idiopathic hypercalcemia, 246-247, 246f Alfentanil, with maintenance anesthetic, 66, 67t Alkaline phosphatase (ALP) bone, e243 corticosteroid, e243 elevations, e242-e246, e245b-e246b algorithm for evaluation of, e244f from methimazole, e104 liver, e243 pathophysiology of, e242-e243 with feline hepatic lipidosis, 609-610 with hepatobiliary disease, 569-573 with idiopathic vacuolar hepatopathy, 606 Alkalosis, acid-base disorders and, e1-e8 Alkylamine, toxicity of, 118-119 Allergen(s) causing flares in atopic dermatitis, 405 exposure to respiratory, e43-e44

Allergen(s) (Continued) extracts, for immunotherapy, 411 house dust mite, e197-e198 Allergen-specific immunotherapy, 411-414 causing adverse skin reactions, 488t client education with, 412b for atopic dermatitis, 407 injection vs. sublingual, 413b schedule adjustments for, 413b with acral lick dermatitis, e176 Allergic reaction anaphylaxis, epinephrine use for, 16 from canine vaccines, 1250-1251 Allergic rhinitis, 636b, 637 Allergy shots, 411-414. See also Allergenspecific immunotherapy Allergy(ies) allergen-specific immunotherapy for, 411-414 associated with eosinophilic pulmonary diseases, 690 causing otitis, and treatment of, 458 conjunctivitis from, 1140 flea dermatitis, 424-425 role of respiratory allergens with, e43-e44 testing of, for diagnosis of canine atopy, 404 Allium plant toxicity, 147-148 Alloantibodies, 311 in cat blood, e145-e146, e145 Allogeneic blood administration, 312 Allopurinol drug interactions with, 677 for American leishmaniasis, e397 for dissolution of urate stones, 902-904, 902f Alopecia association to obesity, 255b bilaterally symmetric, in dogs, 164-166, 165b adrenal sex hormones abnormalities causing, 221-222 from adverse drug reactions, 268, 377, 488t from bacterial folliculitis, 437-438 from cornification disorders, in dogs, 475 from demodicosis, 432-433 from ectoparasitoses, 428, 430-431 from flea allergy dermatitis, 408-409 from imidacloprid, 141 from infection site reactions, 489, 1251 from petroleum hydrocarbons, 155 from topical pyrethrins/pyrethroids, 138 in ferrets with hyperadrenocorticism, e94 nonpruritic, 165b pruritic, 164 Alopecia areata, use of cyclosporine for, 410b Alopecia X causing alopecia, in dogs, 165b, 222-224 diagnosis and treatment of, 477-479, 478b synonyms for, 478b

Index Alpha-agonist(s) causing bradyarrhythmias, 731-732 for feline glaucoma, 1179 Alpha-blocker agent(s), for urinary retention disorders, 918 Alpha-hydroxy acids, in ear cleaners, 472t, 473 Alpha-linolenic acid, requirements during pregnancy and lactation, 963 Alpha2-adrenergic agonist(s) adverse effects of, 60 causing syncope, e328 dosages for, 62t reversal agents for, 30 Alpha2-antagonists, to promote ureterolith passage, 894 AlphaTRAK, point-of-care analyzer, 191-192, 196 Alprazolam for behavior-related dermatoses, 483t, 484 toxicity of, 113-114 Altrenogest, for low progesterone levels during pregnancy, 947-948 Aluminum hydroxide, as antacid therapy, 506b, 507 Aluminum toxicity, from sucralfate, 507 Alveolar-arterial oxygen gradient, calculation of, with acid-base disorders, e3, e3b Amanita mushroom hepatotoxicity, 570b, 581b Amantadine, 61 Amblyomma americanum transmitting cytauxzoonosis, e405 transmitting Ehrlichia ewingii, 1228 Amblyomma maculatum, causing Hepatozoon americanum, 1283-1284 American bulldog(s) actinic dermatoses in, 480 direct mutation tests for, 1018t-1020t nonepidermolytic ichthyosis in, 475 American canine hepatozoonosis diagnosis and treatment of, 1283-1286, 1284f-1285f prognosis for, 1285 American eskimo(s), direct mutation tests for, 1018t-1020t American leishmaniasis, e396-e397 Amikacin causing renal failure, e31-e32 for Bartonella spp., 1266t for infective endocarditis, e294t for methicillin-resistant Staphylococcal skin infections, 444 for nontuberculous cutaneous granulomas, 448t for otitis, 466t for pneumonia, 683t for superficial bacterial folliculitis, 438t Amino acid therapy, for superficial necrolytic dermatitis, 486 Aminobisphosphonates, for osteosarcoma, 391-392 Aminocaproic acid, for treatment of von Willebrand disease, 290-291

Aminoglycoside antibiotics adverse effects of, 34t-35t causing fetal disorders, 1010 causing renal failure, e31-e32 drug incompatibility with, 33t for lower respiratory tract infection(s), 1220t, 1222 for musculoskeletal infections, 1220t, 1222-1223 for Pseudomonas spp. otitis, 466t, 467 for septicemia, 1220t ototoxicity from, 468b, 469 Aminophylline. See also Theophylline for atrial arrhythmias, in cats, 750f-751f for feline bronchitis and asthma, 677 Amiodarone associated hepatotoxicity, 570b, 577, 581b for arrhythmias with congestive heart failure, 764t-765t, 771-772, 783-784 with dilated cardiomyopathy, in dogs, 799 for supraventricular tachyarrhythmias in dogs, 742t, 743-744 for ventricular arrhythmias, 746-748, 747f, 747t for ventricular fibrillation during CPR, 30 Amitraz causing adverse skin reactions, 488t drug interactions with, 34t-35t for demodicosis, 433, 433t for tick control, 1274-1275, 1294 toxicity, 138-139 Amitriptyline for urinary incontinence disorders, 917 to promote ureterolith passage, 894 Amlodipine for glaucoma in dogs, 1173b, 1174 for heart failure in dogs, 764t-765t, 768 for hypertension, 728-729 and kidney disease, 861-862 from acute renal failure, 870 with retinal detachment, 729 for hyperthyroid cats, e103t, e105 for myocarditis, e306 for proteinuria and glomerular disease, 855 rectal use of, 870 toxicity of, use of IV lipid emulsion therapy for, 106 Ammonia for evaluation of hepatobiliary disease, 573 reduction of, for hepatoencephalopathy, 582-583, 593-594, 593b Ammonium urate urolithiasis, 901 Amoxicillin for hepatoencephalopathy, 593-594 for urinary tract infections, 1219-1220, 1220t protocol for helicobacter spp., 511t

1341

Amoxicillin-clavulanate for feline pancreatitis, 567t for infective endocarditis, e294t, e297 for lower respiratory tract infection(s), 1220t, 1222 for musculoskeletal infections, 1220t, 1222-1223 for otitis, 466 for pneumonia, 682t-683t, 683 for pyoderma, 1220t, 1221-1222 for superficial bacterial folliculitis, 438t for upper respiratory tract infections, 1220t, 1222 in cats, 631t for urinary tract infections, 881b, 1219-1220 Amphetamine toxicity, 109-110 Amphotericin drug incompatibilities with, 33t for fungal rhinitis in cats, 647-648, 647t Amphotericin B adverse effects of, 1235 use and protocols for, 1234-1238, 1235t Amphotericin B deoxycholate, use and protocols for, 1234-1238, 1235t Amphotericin B lipid complex, use and protocols for, 1235-1236, 1235t Ampicillin, for infective endocarditis, e294t Amprolium, target parasites and dosage of, 1335-1337 Amputation for osteosarcoma, 389-390 with open fractures, 85 Amylase changes with exocrine pancreatic insufficiency, 558-559 changes with exocrine pancreatic neoplasia, 557 elevations with insecticide toxicity, 137 for the diagnosis of pancreatitis, 554-555 with diabetes and pancreatitis, e77-e78 with feline pancreatitis, 558-559 with leptospirosis, 1287 Amylin, insulin resistance and, 205 Amyloidosis diagnosis and treatment of, 855 hepatic, breeds predisposed to, 571b role of, in diabetic remission, 205 Anaerobes common symptoms and syndromes caused by, 1213t with open fractures, 84-85 Anagen or telogen defluxion, causing alopecia, in dogs, 165b Anal furunculosis, e190 Anal sac(s) anatomy and function of the, e187, e187-e188 apocrine glands tumors, 367-369 impaction, e188-e190 infection and abscess, e188-e189 inflammation, e188-e189 neoplasia, e189-e190

1342

Index

Analgesia constant rate infusions, 61 epidural, 61 in the critical care patient, 59-63 local, 61 transdermal, 61-63 Anaphylaxis, epinephrine use for, 16 Anaplasma phagocytophilum causing nonregenerative anemia, e161, e161b causing polyarthritis, 1225-1226 common symptoms and syndromes caused by, 1214t Anaplasma platys as cause of thrombocytopenia, 281t-282t, 283 common symptoms and syndromes caused by, 1214t Ancyclostoma spp. infection as cause of thrombocytopenia, 281t-282t drugs targeting, 1335-1337 Ancyclostoma tubaeforme, common symptoms and syndromes caused by, 1214t-1215t Ancylostoma caninum, common symptoms and syndromes caused by, 1214t-1215t Androgen receptor blockers, for hyperadrenocorticism in ferrets, e95 Androgen(s) excess, 996 for estrus suppression in the bitch, 985, 987 synthesis or action disorders, 997 Androgenic anabolic steroid associated hepatotoxicity, 581b Anemia causing syncope, e329 diagnostic workup for, 315f feline causing arrhythmias, 750f-751f from cytauxzoonosis, e405-e409 from Mycoplasma haemofelis, e398 from Bartonella spp. infections, 1264 from hypothyroidism, e86 from inflammatory disease, e160 hemolytic autoimmune bone marrow role in, 314-318 immunosuppressive drugs for, 268-274 lymphocytosis associated with, 305 management of, 275-279 nonregenerative, e162 pulmonary thromboembolism with, 705, 708 thromboembolic disease with, 812 treatment of hypercoagulability, 300 triggers for, 275 vaccine-induced, 1250-1251 from cytauxzoonosis, e407 from Mycoplasma haemocanis, e398 infectious causes of, 1217 nonregenerative, e160-e164 diagnostic approach to, e161b

Anemia (Continued) refractory, 317 with chronic kidney disease, 862-863 with thrombocytopenia, 283-284 Anesthesia as cause for esophagitis, e237-e238 causing gastroesophageal reflux, 501, 503 ear-flushing techniques under, 471-472 for cesarean sections, 955t in critical care, 63-70 induction of, 65-66 maintenance of, 66, 67t with cardiovascular dysfunction, 64-68 with intracranial pathology, 68-70, 1040 with respiratory dysfunction, 68 Anesthetic agents, topical, as antipruritic agents, 419 Angioedema, from adverse drug reactions, 488t Angiography with patent ductus arteriosus, e311 with ventricular septal defect, e338 Angiostrongylus vasorum, as cause of thrombocytopenia, 281t-282t Angiotensin II type 1 receptor blockers aldosterone escape with, 854 antihypertensive effect of, 855 for glomerular disease, 854-855, 854f Angiotensin-converting enzyme (ACE) inhibitor(s) adverse effects of, 766-767, 779, 791 aldosterone escape with, 854 antihypertensive effect of, 855 balancing renal function with, 779 for asymptomatic heart disease, 765-766, 775-777, 790 for canine dilated cardiomyopathy, 797-799 for canine heart failure, 763b, 766-768, 777-779 for cardiogenic shock, 783 for feline myocardial disease, 805-809 for glomerular disease, 854-855 for hypertension, 728-729 and kidney disease, 729, 861-862 Aniline, causing reproductive toxicity, 1027b Animal cruelty, and pet poisonings, e51 Animal health diagnostic companies, role of, 306-307 Anion gap calculation of, with acid-base disorders, e2, e3b from ethylene glycol toxicity, 151-152 Anisocoria causes of, e392, e393t diagnosis and treatment of, e388-e395 from optic chiasm lesions, 1137 spastic pupil syndrome causing, e395 types of, e388 Anorexia from chronic kidney disease, 863 from feline hepatic lipidosis, 609 from heart disease, 722 from toxicity of chemotherapeutic drugs, 331 palatability enhancers for, 723-724

Anovulvar cleft, 976-977 Antacid therapy, 505-508 drug incompatibilities with, 33t Anterior uveal melanoma, 1204 Anti-T3 and Anti-T4 antibodies, 184 Anti-Xa assay, for monitoring antithrombotic agents, 707 Antiandrogen(s), for alopecia X, 479 Antiangiogenesis, 354-355 Antiangiogenic therapy, for hemangiosarcoma, 396 Antiarrhythmic drugs during CPR, 30 for arrhythmogenic right ventricular cardiomyopathy, 803, e280 for bradyarrhythmias, 731-737 for dogs, 763b, 764t-765t with congestive heart failure, 771-772, 783 for supraventricular tachyarrhythmias, 741-744, 742t for ventricular tachycardia, 746-748, 747f, 747t Antibiotic therapy during pregnancy complications, 947-948 effect of, on urine cultures, 923-924 for acral lick dermatitis, e175-e176, e175t for acute pancreatitis in dogs, 563 for atopic dermatitis, 405 for canine bronchial diseases, 671-672 for canine parvovirus, 535 for canine respiratory tract infections, 633-634 for enteropathies, 518-522 for feline asthma, 678 for feline pancreatitis, 567t, 568 for feline upper respiratory tract infections, 630, 631t for gall bladder diseases, 603 for gastric dilation-volvulus, e17 for hemotropic mycoplasmosis, e401 for hepatoencephalopathy, 593-594 for infective endocarditis, e294t, e296-e298 for inflammatory bowel disease, 538-539 for methicillin-resistant Staphylococcal skin infections, 444 for neutrophilic cholangitis, 616-618, 617b for open fractures, 84 for pneumonia, 682t, 683, 687 for prostatitis, 1014 for pyothorax, 696 for respiratory diseases, 627-628 for rhinosinusitis in cats, 646 for septic metritis, 958 for shock, 23-24 for superficial bacterial folliculitis, 438, 438t for urinary tract infections with urolithiasis, 881-882, 893-894 ototoxicity from, 468b probiotic therapy with, 527 rational empiric, 1219-1223, 1220t

Index Antibiotic therapy (Continued) topical for corneal ulcers, 1149-1151 for keratoconjunctivitis sicca, 1147 for otitis, 464t with heat-induced illness, 73 with hematologic toxicity from chemotherapeutic drugs, 331 Antibiotic(s) aminoglycoside, causing renal failure, e31-e32 causing adverse skin reactions, 488t formula for interval adjustment with renal failure, 34t-35t tylosin-responsive diarrhea, e262-e265 Antibodies, development of with autoimmune hemolytic anemia, 275 Antibody test(s) for Borrelia burgdorferi, 1272-1273 for canine Bartonella spp., 1264-1265 for canine heartworm disease, 832 for ehrlichiosis, 1292-1293 for feline Bartonella spp., 1269 for feline heartworm disease, 827 for masticatory muscle myositis, 1114 for Toxoplasma gondii, 1296-1297 Anticancer drugs, new, e139-e142. See also under Chemotherapy Anticholinergics, for CPR, 29 Anticoagulant rodenticide toxicity, 133-134 Anticoagulant therapy for arterial thromboembolism, 815 for autoimmune hemolytic anemia, 276-278, 277t for disseminated intravascular coagulation, 296 for hypercoagulable states, 295 for protein-losing enteropathy, 544 for thromboprophylaxis, 708-709 with continuous renal replacement therapy, 873-875 Anticoagulation process, with disseminated intravascular coagulation, 294f Anticollagenase therapy for keratoconjunctivitis sicca, 1147 for keratomalacia, 1151 Anticonvulsant therapy emergent, 1059-1060 for inflammatory central nervous system disorders, 1065 new maintenance, 1054-1057 with intracranial tumors, 1045 Antidepressants and anxiolytics, toxicity of, 112-114 Antidote(s) approved for animal toxicosis, e56t for rodenticide toxicities, 133-135 IV lipid emulsion therapy as, 106-109, 115-116 used to treat toxicities, 101-105, 102t-104t Antiemetic(s) for acute renal failure, 870 for canine parvovirus, 535 for chronic renal disease, 863 for feline cholangitis, 617, 617b

Antiemetic(s) (Continued) for feline pancreatitis, 567t for hepatic lipidosis, 612 Antierythrocyte antibodies, with autoimmune hemolytic anemia, 275 Antifibrotic drug(s) as hepatic support therapy, e257 for chronic hepatitis, 587 Antifreeze. See Ethylene glycol toxicity Antifungal drugs associated hepatotoxicity, 576 augmentation with immunotherapy, 1232 causing fetal disorders, 1010 for dermatophytosis, 449-451, 450t reactions from, 489 shampoos, 450t systemic, 1234-1238 topical for otitis, 465t for pyoderma, 440-441 Antigen receptor gene rearrangements, for feline gastrointestinal lymphoma, 546 Antigen test(s) for canine heartworm disease, 832 for feline heartworm disease, 827 Antigens, causing hypersensitivity reactions to vaccines, 1250-1251 Antihistamine(s) for atopic dermatitis, 405-406 for behavior-related dermatoses, 483, 483t for rhinitis, 637 topical use of, 419, 1031 toxicity of, 118-119 use of, during blood transfusions, 312-313 Antihypertensive drug(s) for cats, 729 for dogs, 729-730 with NSAID causing risk of nephrotoxicity, 865-866, 865t Antiinflammatory drug(s). See also Glucocorticoid(s); Nonsteroidal antiinflammatory drug(s) (NSAID’s) doses of glucocorticoids, 1301t for bronchial diseases, in dogs, 670-671 for canine colitis, 551b for inflammatory bowel disease, 539 for respiratory diseases, 625-627 for rhinosinusitis in cats, 646 potency of systemic glucocorticoids, 461t topical, with acral lick dermatitis, e176-e177 Antileukotrienes, for feline asthma, 678 Antimicrobial susceptibility testing. See also under Culture(s) for superficial bacterial folliculitis, 437-438 Antimicrobial therapy. See also Antibiotic therapy augmentation with immunotherapy, 1232 concentration-dependent, 1219, 1220f for atopic dermatitis, 405

1343

Antimicrobial therapy (Continued) for feline caudal stomatitis, 494 for otitis systemic, 466-467 topical, 462-465, 464t for pyoderma, topical, 439-443, 441t for shock, 23-24 for superficial bacterial folliculitis, 438, 438t topical, 438-439 prophylactic for urinary tract infection, 881-883 rational empiric, 1219-1223, 1220t time-dependent, 1219, 1220f topical, 439-443 for hot spots, e207-e208 Antimüllerian hormone, 1002 Antimuscarinic agents, for urinary incontinence disorders, 917 Antioxidants as hepatic support therapy, e255-e257 for heart disease, 725, 763b, 770, 787 for metabolic brain disorders, 1052 Antiplatelet antibodies, 280-281 Antiprotease therapy, for keratomalacia, 1151 Antipruritic agents, topical, 420t with acral lick dermatitis, e176-e177 Antipyretic agents with heat-induced illness, 73 with vaccine-associated reactions, 1251 Antiseptic(s) ear, 473-474 for pyoderma, 440 ototoxicity from, 468b Antithrombin replacement therapy, for disseminated intravascular coagulation, 295 with disseminated intravascular coagulation, 292, 294f, 294t Antithrombotic agents for arterial thromboembolism, 814-815 for pulmonary thromboembolism, 705-707 monitoring of, 706 Antithyroglobulin antibodies, 182-184 Antitplatelet drug(s) for arterial thromboembolism, 814-815 for pulmonary thromboembolism, 705, 709-710 Antitumor mechanisms, 354-355 Antitussive drugs for canine bronchial disease, 672 for canine respiratory tract infections, 633 for respiratory diseases, 622-623 for tracheal collapse, 664 Antiviral drugs for canine parvovirus, 535 for feline ocular herpesvirus 1, 1158 for feline retrovirus infections, 1277-1280, 1279t for feline rhinosinusitis, 646-647 for feline upper respiratory infections, 630 for papillomatosis, e186 role of interferons in immunity, 1229 Antiyeast drugs. See Antifungal drugs

1344

Index

Anuria, from acute renal failure, 869-870 Anxiety, with behavior-related dermatoses, 484-485 Anxiolytics, toxicity of, 112-114 Aortic body tumor, e167-e168 causing pericardial effusion, 817 Aortic stenosis, prevalence of, in cats, 757t Aplastic anemia, 316, e162 Apocrine gland hidrocystoma, eyelid, 1207 Apocrine glands tumors of the anal sac, 366-369 Apomorphine, for emesis induction, 105 Apraclonidine, for feline glaucoma, 1179 Aqueous flare, 1130-1131, 1131f with canine uveitis, 1162, 1163t with feline uveitis, 1166-1167 Aqueous humor cytology, for canine neoplasia, 1201 misdirection syndrome, 1178 role of, in canine glaucoma, 1170-1171 Aqueous paracentesis, for identification of ocular neoplasia, 1209-1210 Araceae plant toxicity, 121b Arachnoid cysts, intracranial, 1038-1039 Arginine production in cats, 592 Arnica toxicity, 124t Aromatase inhibitors, for hyperadrenocorticism in ferrets, e95 Arrhythmia(s) anesthesia for patients with, 64-68 brady cardiac pacing for, e281-e286 diagnosis and treatment of, 731-737 canine drug therapy for, 764t-765t supraventricular tachy, 737-744, 742t ventricular, 745-748 with dilated cardiomyopathy, 799 cardioversion for, e286-e291 caused by infectious disease, 1212-1213 causing syncope, e326-e329 drugs that stimulate, 677 feline diagnosis and treatment of, 748-755, 750f-751f with cardiomyopathy, 809 from endocarditis, e292-e293 from human drugs of abuse, 109-112 from hypothyroidism, e85-e86 induced right ventricular cardiomyopathy, 801-804, e277-e281 pacemakers for (See Pacemaker) pacing in the ICU setting for, e21-e28, e23f ventricular causing syncope, e326 from dilated cardiomyopathy, 799 in dogs, 745-748 magnesium chloride for, 250-251 with feline cardiomyopathy, 809 with gastric dilation-volvulus, e16-e17

Arrhythmogenic right ventricular cardiomyopathy in cats, e277-e281, e306-e307 in dogs, 801-804, e308 Arsenic associated hepatotoxicity, 570b causing reproductive toxicity, 1027b Artemisia, for canine babesiosis, 1259 Arterial blood gas analysis, use of, 52 Arterial thromboembolism. See under Thromboembolism Arteriosclerosis causing Ischemic strokes, 1119-1120 from hypothyroidism, e86 pulmonary thromboembolism associated with, 705 Arthritis. See also Polyarthritis from borreliosis, 1271 masitinib for, 361t septic common pathogens causing, 1222-1223 empiric antimicrobial therapy for, 1220t with lumbosacral stenosis, 1106-1107 Arytenoid lateralization, 660-661 Asbestos fibers, as respiratory toxicant, e47 Asbestos-free sterilizing talc, for malignant effusions, 342 Ascensia Elite point-of-care analyzer, 196 Ascites from gall bladder disease, 603 from hepatobiliary disease, 572, e257-e258 from liver disease, 591-594, 592f from liver failure, 580-581 with chronic hepatitis, 585f, 587 with nephrotic syndrome, 856 with refractory heart failure, 781 Ascorbic acid. See Vitamin C Asparaginase associated hepatotoxicity, 570b Aspartate aminotransferase (AST), with hepatobiliary disease, 569-573 ASPCA Animal Poison Control Center toxin exposures, 92-93, 92t Aspergillosis antifungal therapy for, 1234-1238 causing aflatoxicosis in dogs, 159-161 causing epistaxis, 1216 common symptoms and syndromes caused by, 1214t nasal in cats, 644-648, 645f in dogs, 636-640, 639f Aspermia/oligospermia caused by retrograde ejaculation, e350-e353, e352f Aspirin as anticoagulant therapy,for autoimmune hemolytic anemia, 277-278, 277t associated hepatotoxicity, 581b causing nephrotoxicity, e32-e33 for arterial thromboembolism, 814 for disseminated intravascular coagulation, 296

Aspirin (Continued) for feline cardiomyopathy, 806t for feline heartworm disease, 830 for feline infectious peritonitis, 1305t for feline thromboembolism, 810, 814 for feline uveitis, 1169t for hypercoagulable states, 299-300 for prevention of cerebrovascular accidents (stroke), 1122 for protein-losing enteropathy, 544 for proteinuria with renal disease, 861 for thromboprophylaxis, 709-710 influence on thyroid function, 181t ototoxicity from, 468b, 471 toxicity of, 116-117 Assault rodenticide toxicity, 134 Assisted ambulation/gait training, e358 Assisted devices, for rehabilitation, e359 Assisted feeding, for patients with cancer, 352-353 Asthma, feline, 673-680 clinical findings with, 674-675 crisis, catecholamine use for, 15t diagnosis and treatment of, 673-680 masitinib for, 361t natural vs. experimentally induced, 673-674 vs. lungworms, e273-e274 Asystole, 29f Ataxia from vestibular disease, 1067 infectious agents that cause, 1212 Atenolol adverse effects of, 34t-35t for asymptomatic heart disease, 766 for feline arrhythmias, 750f-751f, 752 for feline cardiomyopathy, 805-807, 806t for heart failure, in dogs, 764t-765t, 792 for hypertension, 729 for hyperthyroid cats, e103t, e105 for sinus tachycardia, in cats, 749 for supraventricular tachyarrhythmias in dogs, 742t for ventricular arrhythmias, 747-748, 747t in cats, 753-754 Atipamezole, 30 as reversal agent, 60, e56t dosage for, 62t Atlantoaxial subluxation, 1082-1090 anatomy and pathophysiology of, 1082, 1083f-1084f diagnosis of, 1083-1085, 1085f-1086f prognosis for, 1088-1089 treatment of, 1085-1088, 1086f Atlantooccipital overlap in dogs, 1100, 1100f Atopic dermatitis allergen-specific immunotherapy for, 411-414 and food allergy, 403 causing blepharitis, e365 causing conjunctivitis, 1140 causing hot spots, e206-e208

Index Atopic dermatitis (Continued) causing otitis, treatment of, 458 causing perivulvar dermatitis, 971 cyclosporine for, in dogs, 403 diagnosis of, in dogs, 403-404, 404b house dust mites and, e197-e199 treatment of, 405-407 cyclosporine for, 269-271, 405 glucocorticoids for, 415-417 hypoallergenic dietary therapy, 422-424 interventions of no benefit, 406 masitinib for, 361-362, 361t pentoxifylline for, e203-e204 tacrolimus for, 271 topical, 419-421 topical immunomodulators for, e217-e218 with bathing, 405 with interferons, e200-e201, e201 with acral lick dermatitis, e175-e176 Atopica. See Cyclosporine Atovaquone for canine babesiosis, 1257-1260, 1258t for cytauxzoonosis, e408 Atovaquone-azithromycin, target parasites and dosage of, 1335-1337 Atractylis gummifera associated hepatotoxicity, 581b Atrial arrhythmias, in cats, 752-753 Atrial fibrillation, 738, 740f, 741, 742t cardioversion for, e288-e289, e288, e289f from hypothyroidism, e85-e86 in cats, 749-753, 750f-751f with dilated cardiomyopathy, 799 with heart failure, 783-784 in dogs, 770-771 Atrial flutter, 738, 740f, 742t cardioversion for, e290, e290f Atrial natriuretic peptide (ANP), with valvular heart disease, 790 Atrial septal defect, prevalence of in cats, 757, 757t in dogs, 756, 757t Atrial standstill, 733-734 causing syncope, e328, e328f in cats, 750f-751f, 755 Atrial tachycardia, 740f, 742t in cats, 749-753, 750f-751f Atrioventricular (heart) block cardiac pacing for, e281-e286 causing syncope, e328f from hypothyroidism, e85 in cats, 750f-751f, 754-755 second-degree, 734 third-degree, 734-735 temporary pacing for, e25f Atrioventricular conduction abnormalities, 734-735 Atrioventricular node-blocking drugs, for supraventricular tachyarrhythmias, 743 Atrioventricular reciprocating tachycardias, 738, 740f, 742t Atrioventricular septal defect, prevalence of, in cats, 757t

Atropine adverse effects with α2-adrenergic agonist, 60 causing anisocoria or mydriasis, e392 for atrioventricular block, in cats, 755 for bradycardias, 736 for canine uveitis, 1165 for CPR, 29 repeated use of, causing keratoconjunctivitis sicca, 1144 topical for corneal ulcers, 1149, 1151 for feline uveitis, 1169, 1169t use of prior to cesarean section, 955 Atropine response test, with sick sinus syndrome, e330 Audiometry, for evaluation of hearing, 469 Auscultation. See also under Heart murmur(s) for tachyarrhythmias, 738-739 Australian cattle dog(s) direct mutation tests for, 1018t-1020t mitochondrial encephalopathy in, 1048-1051, 1049t, 1051t Australian shepherd(s) avermectin toxicity in, 145 direct mutation tests for, 1018t-1020t Autoagglutination, with blood typing, e144 Autoantibodies for myasthenia gravis, 1109 vaccine-associated, 1255-1256 Autoimmune diseases atrophic lymphocytic pancreatitis, 558 causing inflammatory central nervous disease, 1063-1066 immunosuppressive drugs for, 268-274 of the skin, glucocorticoids for, 416t, 417 Autoimmune hemolytic anemia. See Anemia, hemolytic Automotive product toxins, 92t, 151-155 Autosomal factor deficiencies, 289 Autumn crocus toxicity, 121b Avermectin(s) causing adverse skin reactions, 488t for dermatologic disorders, e178-e184 toxicity, 145-146 Azaglynafarelin, for estrus suppression in the bitch, 988 Azathioprine (Imuran) associated hepatotoxicity, 581b for autoimmune hemolytic anemia, 278-279 for canine colitis, 551b, 552 for canine uveitis, 1165 for immunosuppression, 268 for myasthenia gravis, 1110-1111, e228-e229 for protein-losing enteropathy, 544 for thrombocytopenia, 285t hepatotoxic effects of, 576 use of, with glucocorticoids, 576 Azithromycin (Zithromax) for canine babesiosis, 1257-1260, 1258t, 1265-1266, 1266t

1345

Azithromycin (Zithromax) (Continued) for canine respiratory infection complex, 634 for cytauxzoonosis, e408 for feline babesiosis, 1270 for feline upper respiratory infection, 631t for Giardia spp., 531 for lower respiratory tract infection, 1220t, 1222 for nontuberculous cutaneous granulomas, 448t for pneumonia, 682t for rhinosinusitis in cats, 646 for upper respiratory tract infection, 1220t, 1222 target parasites and dosage of, 1335-1337 Azole antifungals associated hepatotoxicity, 576 Azotemia. See also Renal Failure from amphotericin therapy, 1234-1235 from diabetes mellitus, e76 from heart failure therapy, 779, 791 infectious agents that cause, 1212 predicting, with renal failure, 187 prognostic significance of, with renal failure, 187 with heart disease, anorexia from, 722 B B-cell leukemia, 303-304 B-cell lymphoma, 303-304 Babesia conradae common symptoms and syndromes caused by, 1214t-1215t treatment of, 1258t Babesia gibsoni common symptoms and syndromes caused by, 1214t-1215t treatment of, 1258-1259, 1258t Babesia vogeli common symptoms and syndromes caused by, 1214t-1215t treatment of, 1258t Babesiosis as cause of thrombocytopenia, 281t-282t dosage for and drugs targeting, 1335-1337 rational use of glucocorticoids for, 1300-1301 treatment of canine, 1257-1260, 1258t Bacille Calmette-Guérin (BCG) as cancer immunotherapy, 335, 336t for feline retrovirus infections, 1280t-1281t, 1282 Bacilli, appearance with nontuberculous cutaneous granulomas, 446, 447f Baclofen toxicity, use of IV lipid emulsion therapy for, 108, 115-116 Bacteremia. See also Sepsis as cause of thrombocytopenia, 281t-282t causing endocarditis, e291-e292 common pathogens causing, 1223 empiric antimicrobial therapy for, 1220t

1346

Index

Bacteria. See also Methicillin-resistant Staphylococcal infections appearance with nontuberculous cutaneous granulomas, 446, 447f associated with bronchitis and asthma in cats, 676 causing blepharitis, e363 causing food poisoning associated hepatotoxicity, 581b causing hospital-acquired urinary tract infections, 876-879 causing infective endocarditis, e293-e294 causing myocarditis, e304t causing pneumonia, 681-682, 686 causing pregnancy loss, 1005t, 1006, 1008-1009 causing prostatitis, 1013 causing pyothorax, 695 causing vulvar discharge, 972-973 Helicobacter spp., 508-513, 510f in anal sac fluids, e188 in raw meat diets, 1240-1241 list of, causing various clinical signs, 1213t normal isolates in the female reproductive tract, 970t in the trachea, 682b overgrowth of, in the intestine, 518-522 Bacterial folliculitis, 437-439 Bacterial viruses, for persistent urinary tract infections, 883 Bacteriophages, for persistent urinary tract infections, 883 Bacteriuria from hospital-acquired urinary tract infections, 876-879 with Escherichia coli, causing persistent infection, 880-883 with urolithiasis, 881-882, 893-894 Balanoposthitis, 1030 Balloon valvuloplasty for congenital heart disease, 760-761 for pulmonic stenosis, e317-e318 for subaortic stenosis, e323 Bandage(s) with open peritoneal drainage, e16 with vacuum-assisted wound closure, 88, 89f Barbiturate(s) causing adverse skin reactions, 488t for emergent seizures, 1059-1060 toxicity of, 111 Barium-impregnated polyethylene spheres (BIPS), for evaluation of gastric emptying, 515 Baroreceptor reflex, 732f Bartonella henselae causing infection in humans, 1212, 1266 common symptoms and syndromes caused by, 1213t, 1261-1262 Bartonella rochalimae, common symptoms and syndromes caused by, 1261-1262

Bartonella spp. infection as cause of chronic hepatitis, 584t, 586, 1263b as cause of thrombocytopenia, 281t-282t, 1261-1262, 1263b causing endocarditis, e292, e292-e293, e294-e295, e294t, e296-e298 causing gingivostomatitis, 1216 causing infection in humans, 1266 causing lameness, 1216-1217, 1263b causing myocarditis, e303-e304, e307-e308 causing nervous system signs, 1212, 1263b causing polyarthritis, 1225-1226, 1263b causing systemic disease, 1263b clinical signs of, 1263-1264, 1263b epidemiology of, 1262, 1267-1268 in cats, 1267-1271 in dogs, 1261-1262, 1262t reported diagnoses in dogs, 1263b transmission and risk factors for, 1262, 1267-1268 treatment of, 1265-1266, 1266t, 1269-1270 Bartonella vinsonii causing infection in humans, 1266 common symptoms and syndromes caused by, 1213t Bartonellosis canine, 1261-1267 causing uveitis, 1263b feline, 1267-1271 causing uveitis, 1168 Basenji(s) direct mutation tests for, 1018t-1020t inflammatory bowel disease in, 536 protein losing enteropathy in, 540-541 Basic life support, 26-28 Bassett hound(s)direct mutation tests for, 1018t-1020t Bath oils, for sebaceous adenitis, e210-e211 Bathing, for atopic dermatitis, 406 Baylisascaris procyonis, common symptoms and syndromes caused by, 1214t-1215t Beagle(s) actinic dermatoses in, 480 coagulation factor deficiencies in, 289 direct mutation tests for, 1018t-1020t glaucoma in, 1171b hyperlipidemia in, 261 hypothyroidism in, 178-179 intracranial arachnoid cysts in, 1038 risk of bladder cancer in, 371t thyroid cancer in, 397-398 vestibular disease in, 1068 Bearded collie(s), hypoadrenocorticism in, 233 Beclomethasone dipropionate, inhaled, for respiratory diseases, 626t Bedlington terrier(s) acinar hypoplasia in, 1144 copper-associated liver disease in, 588-590, e231-e236 genetic marker test for copper toxicosis, 1021t

Beef jerky, causing nephrotoxicity, e34 Behavior(s) abnormalities from hydrocephalus, 1034 aggression from hypothyroidism, e85 assessment of, with neuro-ophthalmic exam, e390-e392 concerns regarding, with early age neutering, 982 feline chewing, 913 elimination, 912 environmental enrichment for domestic, 909-914 making changes to minimize problems, 913, 913b observable positive and negative, 911t prey-seeking for food, 911 social interaction, 912-913 Behavior-related dermatoses, 482-485 Belching, e247 Belgian sheepdog(s), atypical pannus in, 1141 Belladonna toxicity, 124t Belt loop gastropexy, for gastric dilationvolvulus, e18 Benazepril adverse effects of, 766-768 for asymptomatic heart disease, 765-766 for cough from bronchial compression, 782 for feline cardiomyopathy, 809 for glomerular disease, 854-855 for heart failure, in dogs, 764t-765t, 766-768, 777-779 balancing renal function and, 779 for hypertension, 729 from acute renal failure, 870 for hyperthyroid cats, e103t, e105 for occult dilated cardiomyopathy, in dogs, 797-798 Bence Jones proteinuria, 849 Benign prostatic hypertrophy, 1012-1015 Benzene, causing reproductive toxicity, 1027b Benzodiazepine(s) adverse effects of, 34t-35t dosing of, with liver disease, 32-33 drug incompatibilities with, 33t for behavior-related dermatoses, 483t, 484 for emergent seizures, 1059 reversal agent for, 30 toxicity of, 112-114 use of with cardiovascular dysfunction, 64-65 with opioids for anesthetic induction in critical patients, 66 Benzoic acid associated hepatotoxicity, 581b Benzopyrene, causing reproductive toxicity, 1027b Benzopyrones, for chylothorax, 699 Benzoyl peroxide, for pyoderma, 440, 441t

Index Benzyl alcohol associated hepatotoxicity, 581b Benzyl benzoate, for dust mite control, e198-e199 Bernese mountain dog(s) cervical spondylomyelopathy in, 1092 direct mutation tests for, 1018t-1020t Bernoulli equation, and pulmonary artery pressure, 713-714 Beryllium, causing reproductive toxicity, 1027b Beta-adrenergic receptor agonists drug interactions with, 677 for respiratory diseases, 623-624, 671 adverse effects of, 624 Beta-blocker(s) causing syncope, e328, e328f for asymptomatic heart disease, 766, 790 for atrial fibrillation, 743 with dilated cardiomyopathy, 799 for dilated cardiomyopathy, in dogs occult, 797-798 with heart failure, 799 for feline arrhythmias, 752 for feline hyperthyroidism, e106 for glaucoma in cats, 1179 in dogs, 1173b, 1174 for heart failure, in dogs, 763b, 770-771, 776, 792 for supraventricular tachyarrhythmias, 742t Beta-cell dysfunction, 205, 216 Beta-lactam antibiotic(s) drug incompatibilities with, 33t for Pseudomonas spp. otitis, 466t, 467 Betamethasone, for otitis systemic, 461t topical, 460t Betaxolol for feline glaucoma, 1179 for glaucoma in dogs, 1173b Bethanechol for myasthenia gravis, e229-e230 for urinary retention disorders, 917t, 918 Bevacizumab (Avastin) for hemangiosarcoma, 396 for malignant effusions, 344 metronomic chemotherapy of, 344 Bicalutamide, for hyperadrenocorticism in ferrets, e95 Bicarbonate. See Sodium bicarbonate Bicarbonate concentration, and acid-base disorders, e1 Bichon Frise, risk of urolithiasis in, 897 Bifidobacterium animalis, as probiotic, 526 Bile acid testing evaluation with alkaline phosphatase elevations, e245-e246 for evaluation of hepatobiliary disease, 572-573 with portal vein hypoplasia, 599-600 Biliary mucoceles, e221-e224 Biliary tract disease diagnostic approach to, 569-575 extrahepatic, management of, 602-605

Biliary tract disease (Continued) feline cholangitis and, 614-618 surgery for, 605 Bilirubinemia, elevations from methimazole, e104 Bimatoprost, for glaucoma in dogs, 1173, 1173b Bioactive enzyme(s), in ear cleaners, 474 Biochemical test(s), for hereditary disorders, 1016 Biologic respiratory contaminants, e43-e44 Biological safety cabinets, for hazardous drugs, 326-327 Biomarkers as outcome predictors for intervertebral disk disease, 1073-1074 for cancer, 356-357 for hemangiosarcoma, 395 for valvular heart disease, 790 Biopsy bone, for osteosarcoma, 388 conjunctival, e386, e386f esophageal, 502 for mammary cancer, 376, 376t for ocular neoplasia, 1201-1202 for protein-losing enteropathy, 540-544 for soft tissue sarcomas, e149 incisional vs. excisional, e170 kidney, for glomerular disease, 849 liver for evaluation of hepatobiliary disease, 574-575 for feline cholangitis, 616 with alkaline phosphatase elevations, e245 with chronic hepatitis, 585f, 586 with feline hepatic lipidosis, 610 with liver failure, 581-582 with portal vein hypoplasia, 600 lung, for interstitial diseases, e268 muscle for canine hepatozoonosis, 1285 for evaluation of dysphagia, 498-499, e261 nasal, 338, e157 in cats, 646 in dogs, 637 nerve, for evaluation of dysphagia, 498-499, e261 postreport conflicts, 325-326 skin for actinic dermatoses, 480 for dermatophytosis, 449 for diagnosis of alopecia, 166 for ichthyosis, 475-476 of acral lick dermatitis lesions, e174 with alopecia X, 478 with superficial necrolytic dermatitis, 486 with vaccine-associated sarcoma, in cats, 1254 specimen collection principles, 322, 323b thyroid, 398

1347

Biopsy and specimen submission, 322-326 Biphosphate(s), for cholecalciferol toxicity, e33-e34 Bipyridyl herbicide toxicity, 130-131 Birch, toxicity of, 125t Bismuth salicylate toxicity, 117 Bismuth subsalicylate for flatulence, e250 protocol for helicobacter spp., 511, 511t Bisoprolol for asymptomatic heart disease, 766 for heart failure, in dogs, 792 Bisphosphonates for feline idiopathic hypercalcemia, 246-247 for multiple myeloma, 385 to prevent postoperative hypocalcemia, e126 Bite wounds causing pyothorax, 695-697 from pets to humans, 1244-1246, 1245t Biting flies, drugs targeting, 1335-1337 Bittersweet toxicity, 124t Black cohosh associated hepatotoxicity, 581b Bladder cancer of the urinary, 370-374 lithotripsy for stones in the, e340e344, e342t-e343t stones (See Urolithiasis) Blast cell, 314 Blastomyces dermatitidis, common symptoms and syndromes caused by, 1214t Blastomycosis antifungal therapy for, 1234-1238 causing nervous system signs, 1212 causing uveitis in cats, 1168 in dogs, 1163-1164, 1164b immunosuppressive therapy for, 1232-1233 Bleach ingestion, 98 Bleeding. See also Hemorrhage testing of, with thromboelastography, 74-77 Bleeding disorders and coagulation factor deficiencies, 286-291 screening questions for, 287b Bleomycin, for pleurodesis, 342 Blepharitis, e363-e365 allergic, e365 bacterial, e363 fungal, e363-e364 iatrogenic, e367 immune-medicated, e366-e367 metabolic-nutritional, e365-e366 neoplastic, e368 parasitic, e364 Blepharospasm, from anterior uveitis, 1163t Blind immunotherapy, 412-413 Blindness assessment of, e390-e391 causes of, 1136t

1348

Index

Blindness (Continued) congenital stationary night, direct mutation test for, 1018t-1020t differential diagnosis for, e382-e383 evaluation of, 1134-1138 from canine uveitis, 1163t from glaucoma, in dogs, 1170 surgical options for, 1176b from hydrocephalus, 1034 from optic tract lesions, 1137f-1138f in briard with congenital retinal dystrophy, 1190 toxicities causing, e383 visual pathway, 1135f, e382 Blisters, from adverse drug reactions, 488t Bloat. See Gastric dilatation-volvulus (GDV) Blood characteristics of, 10t donors, e144-e145 purification with renal replacement therapy, 871-875 Blood chemistry profile, and blood gas measurement, e1 Blood compatibility, 311-312 Blood crossmatching, 311-312 and typing to ensure blood compatibility, e143-e148 procedure, e146-e147 Blood dyscrasias drug induced, e160, e162 from methimazole, e103 Blood film evaluation, in the clinic laboratory, 307 Blood flow during CPR, 27 impairment, in hypercoagulable states, 297, 298f improvement in collateral, 814 Blood gas interpretation, e1-e3 Blood glucose continuous monitoring systems for, 198 home monitoring, 196-197 levels with insulinomas, e130 monitoring of, with diabetes mellitus, 194-195 in cats, 214 in dogs, 191 point-of-care analyzer for, 191-192, 196, 210 values with diabetic ketoacidosis, e79, e80t-e81t, e82 Blood groups, 311 Blood patching, for treatment of pneumothorax, 704 Blood pH, and acid-base disorders, e1 Blood pressure. See also Hypertension; Hypotension for staging of kidney disease, 859-860, 860t indications for measurement of, 727b monitoring in dogs with murmurs, 786 monitoring with nitroprusside therapy, 767-768 tips for measurement of, 727-728

Blood products for treatment of von Willebrand disease, 290t types of, 310-311 Blood testing coagulation testing with thromboelastography, 74-77 with hereditary coagulation factor deficiencies, 286-291 Blood transfusions best practices of, 309-313 causing adverse skin reactions, 488t drug incompatibilities with, 33t effect of liver failure on, 580-581 for disseminated intravascular coagulation, 295 for therapy of shock, 21-22 for treatment of von Willebrand disease, 290, 290t guidelines for, 309-313 indications for, 309-310 monitoring, 312-313 pleural, for treatment of pneumothorax, 704 reactions, 312-313 typing and crossmatching to ensure compatibility of, e143-e148 Blood types in cats, e145-e146, e145t in dogs, e143-e144, e144t Blood typing and crossmatching to ensure blood compatibility, e143-e148 procedure, e144-e145 Blood vessel neoplasia, e167-e168 Bloodroot toxicity, 124t Blue-green algae toxicity, 123, 570b, 581b Body condition score, 38-39, 254-255, 256f-258f with cancer cachexia, 351 Body fat index, 257f-258f Body weight, estimating ideal, 255, 256f-258f Bone grafts, with open fractures, 86 Bone marrow aspirate cytologic evaluation of, 314-315 prior to use of chemotherapeutic drugs, 330 with thrombocytopenia, 284 dyscrasias, 314-318 neoplasia, causing nonregenerative anemia, e164 Bone tumor, from osteosarcoma, 388-392 Boneset toxicity, 124t Boots, for feet protection, e359 Borates, for dust mite control, e199 Borborygmus, e247 Border terrier(s), sebaceous gland hyperplasia in, 476-477 Bordetella bronchiseptica canine bronchopneumonia from, 634, 681, 682t, 687, 1218 causing respiratory infection, 632-633, 1217-1218 causing rhinitis, 636-637, 636b, 1217-1218

Bordetella bronchiseptica (Continued) nebulization of gentamicin for, 628, 634, 671 vaccination, 634-635 causing infection in humans, 1246 common symptoms and syndromes caused by, 1213t feline causing pneumonia, 681, 682t causing upper respiratory infections, 629, 630t, 1217-1218 Boric acid as topical therapy, 441t for otitis, 465t causing reproductive toxicity, 1027b for Malassezia dermatitis, 442 Borreliosis. See Lyme disease Borzoi(s), hypothyroidism in, 178-179 Boston ferns, 121b Boston terrier(s), risk of vaccine hypersensitivity in, 1250-1251 Botanical insecticides, examples of, 136b Botanical oil extract toxicity, 139-140 Botulinum toxin A, for treatment of cricopharyngeal dysphagia, 500 Bougienage, of esophageal structures, 503-504, e240 Bouvier des Flandres, laryngeal paralysis in, 659-661 Bovine cross-linked collagen, for urinary incontinence, e348-e349, e348 Bowen’s disease, topical immunomodulators for, e220 Boxer dog arrhythmogenic right ventricular cardiomyopathy in, 801-804 canine leproid granuloma in, 446 granulomatous colitis in, 519b, 520t, 552-553 indolent corneal ulcers in, 1151-1152 neurocardiogenic syncope in, e326-e327 risk of vaccine hypersensitivity in, 1250-1251 sick sinus syndrome in, 732-733 subaortic stenosis in, e319 testicular tumors in, 1022-1023 ventricular arrhythmia in, 745 Brachycephalic airway obstruction syndrome, 649-653 abnormalities associated with, 650t as risk for heat-induced illness, 71 prognosis of, 652 treatment of, 651-652 Bradyarrhythmias cardiac pacing for, e281-e286 diagnosis and treatment of, 731-737 feline, 750f-751f iatrogenic, 731-732 pathologic, 732-737 physiologic, 731 temporary pacing for, e21-e22 with heart failure, temporary pacing for, e22 Bradycardia(s). See also Bradyarrhythmias atropine response test with, e330 causing syncope, e326-e328, e328, e328f drug induced, e328

Index Bradycardia(s) (Continued) from calcium administration, e126 from hypothyroidism, e85 reflex-mediated, 736 sinus, with syncope, e330 Bradyzoites, from toxoplasmosis, 1295 Brain disorders hydrocephalus, 1034-1037 intracranial arachnoid cysts causing, 1038-1039 intracranial tumors causing, 1039-1047 metabolic, 1047-1053 Brain energy metabolism, 1047-1048 Brainstem auditory evoked response (BAER), for evaluation of hearing, 469 Brake fluid toxicity, 154 Bravo capsule pH test, 502-503 Breathing patterns with respiratory distress, 45-46 with ventilator therapy, 56 work of, 44 Breed(s) affected with von Willebrand disease, 288t predisposed to glaucoma, 1171b predisposed to hepatobiliary disease, 571b thyroid hormone differences in, 180t with reported disorders of sexual development, 995b Breeding and pregnancy loss, 1003-1011 dystocia management from, 948-956 estrus suppression in the bitch and, 984-989 management of the bitch, 930-935 optimal time for breeding, 930-935, 931t nutrition during pregnancy and lactation, 961-966 pregnancy diagnosis in companion animals, 944-948 screening of brucella canis before, 972, e404 soundness exam and normal ejaculation behavior, e353 toxins affecting, 1026-1028 use of endoscopy transcervical insemination, 940-944, 941f Briard(s) congenital night blindness of, 1190 hyperlipidemia in, 261 Brinzolamide for canine glaucoma, 1173-1174, 1173b, e381 for feline glaucoma, 1179, e381 British anti-Lewisite (BAL), for lead toxicity, 158 Brodifacoum rodenticide toxicity, 133-134 Bromadiolone rodenticide toxicity, 133-134 Bromethalin rodenticide toxicity, 134 Bromocriptine, for pregnancy termination, 990-991

Bromovinyldeoxyuridine, for feline ocular herpesvirus 1, 1158 Bronchial compression from heart enlargement, 782 deformities with brachycephalic airway obstruction syndrome, 650t lavage, for feline asthma, 675-676 Bronchial collapse and brachycephalic airway obstruction syndrome, 650t stenting for, 668 Bronchial disease antiinflammatory drugs for, 625-627 chronic, causing pulmonary hypertension, 711, 712t diagnosis and treatment of in cats, 673-680 in dogs, 669-672 Bronchiectasis, 671-672 Bronchitis. See also Bordetella bronchiseptica; Tracheobronchitis chronic in cats, 673-680 in dogs, 669-672 common infectious agents causing, 1218 Bronchoalveolar lavage collection of cytology specimens from, e155 for diagnosis of parasites, e269-e276 for diagnosis of pneumocystosis, e410 for diagnosis of pneumonia, 686 Bronchoconstriction, 44 from feline asthma, 675 Bronchodilator(s) for canine bronchial disease, 671 for feline asthma, 675-680 for pneumonia, 687 for respiratory diseases, 623-625 for tracheal collapse, 664 inhalers, 623-624, 678-680 Bronchogenic carcinoma, causing secondary ocular changes, 1210 Bronchomalacia in dogs, 669-672, 670f Bronchopulmonary parasites, e271-e276 Bronchoscopy, 669, 670f for bronchopulmonary parasites, e271-e276, e271f for eosinophilic pulmonary diseases, 689, 689f for feline asthma, 675-676 for interstitial lung diseases, e267 Broom plant toxicity, 124t Brucella canis aspermia from, e350 causing infection in humans, 1247 causing pregnancy loss, 1005t, 1008, 1218 common symptoms and syndromes caused by, 1213t diagnosis of, 972 screening for, 972 treatment of, 972 Brucellosis, e402-e404 and pregnancy loss, 1004, 1008 causing uveitis in dogs, 1163-1164, 1164b

1349

Brucellosis (Continued) clinical signs of, e402-e403 diagnosis of, e403-e404, e403f prevention of, e404 treatment of, e404 zoonosis of, e402 Buccal mucosa bleeding time, with bleeding abnormalities, 287 Buckeye toxicity, 124t Budd-Chiari syndrome, stenting for, 347 Budesonide, for inflammatory bowel disease, 539 Buffer composition in fluid therapy, 3t Bulking agents, injectable, for urinary incontinence disorders, e345-e350, e347-e348, e347f Bull terrier(s), laryngeal paralysis in, 659-661 Bulldog(s), brachycephalic airway obstruction syndrome in, 650t Bullmastiff(s), direct mutation tests for, 1018t-1020t Buphthalmos, from canine glaucoma, 1171 Bupivacaine, 62t toxicity of, use of IV lipid emulsion therapy for, 106 use of with cesarean section, 955 Buprenorphine dosage for, 62t for epidural analgesia, 61 for feline pancreatitis, 566-567, 567t for the critical patient, 59 for thromboembolism pain, 814 oral transmucosal route for, 59-60 use of, with cardiovascular dysfunction, 65t Buprenorphine SR, 59-60 dosage for, 62t Bupropion toxicity, use of IV lipid emulsion therapy for, 106 Burning bush, Eastern, toxicity of, 124t Burns, fluid movement with, 9t Butorphanol dosage for, 62t for coughing, 622-623, 672 for feline pancreatitis, 567t for heart failure in cats, 808 in dogs, 764t-765t, 790-791 for thromboembolism pain, 814 to calm respiratory distress pets, 47t use of, with cardiovascular dysfunction, 65t Butterfly ingestion, 99 C C-reactive protein, with inflammatory bowel disease, 538 Cabergoline for postpartum puerperal tetany, 958t for pregnancy termination, 990-991 for septic mastitis, 959 for termination of lactation, 960 Cachexia, from cancer, 349-354 Cadmium, causing reproductive toxicity, 1027b

1350

Index

Cairn terrier(s) direct mutation tests for, 1018t-1020t risk of urolithiasis in, 897 Calamus toxicity, 124t Calcidiol, supplement for hypocalcemia, e127-e128, e128t Calcimimetics, for feline idiopathic hypercalcemia, 247 Calcineurin inhibitor(s) as topical immunomodulators, e216-e220, e217f for immunosuppression, 269-271 safety concerns of, e219-e220 Calcinosis cutis, corticosteroid-induced, 489-490 Calcitriol for chronic kidney disease, 862 for hyperparathyroidism, e70-e71 for hypoparathyroidism, e124-e129 measurement for evaluation of hypocalcemia, e125f supplement for hypocalcemia, e127-e128, e128-e129, e128t Calcium. See also Hypercalcemia; Hypocalcemia composition in fluid therapy, 3t concentrations with feline idiopathic hypercalcemia, 242-248, 245f with hyperparathyroidism, e70, e72 with puerperal tetany, 959-960 monitoring during IV injections of, e126 oral formulations of, e127-e128, e127t pathophysiology and risk of oxalate urolithiasis, 897-898 supplementation for tetany or seizures, e126, e126-e127, e126t Calcium carbonate for hypocalcemia, e127-e128, e127t for postpartum puerperal tetany, 958t, 960 Calcium channel blocker(s) causing syncope, e328, e328f drug incompatibilities with, 33t for atrial fibrillation with dilated cardiomyopathy, 799 for dogs, 763b for feline arrhythmias, 752 for hypertension, 728-729 and kidney disease, 861-862 for supraventricular tachyarrhythmias, 742t, 743 toxicity of, use of IV lipid emulsion therapy for, 106 Calcium chloride for hypocalcemia tetany or seizures, e126, e126t monitoring during injection with, e126 oral, for hypocalcemia, e127-e128, e127t Calcium citrate, for hypocalcemia, e127t Calcium EDTA, for lead toxicity, 158 Calcium gluconate drug incompatibilities with, 33t for atrial standstill, 755 for dystocia, 952f, 954

Calcium gluconate (Continued) for hypocalcemia tetany or seizures, e126, e126t for postpartum puerperal tetany, 958t, 960 monitoring during injection with, e126 oral, for hypocalcemia, e127t Calcium lactate, for hypocalcemia, e127t Calcium oxalate crystalluria, 926 from ethylene glycol toxicity, 152 Calcium oxalate urolithiasis, 897-901 and nephroliths, 926 laser lithotripsy for, e341f with hypercalcemia, 244 Calcium-related degenerative keratopathy, 1153 Calicivirus. See Feline calicivirus Callilepis laureola toxicity, 581b Calorie(s) composition in fluid therapy, 3t decreasing intake of, with obesity, 255-260 dietary requirements for, with diabetes mellitus, 202-203, 204t estimating desired intake of, 259 in parenteral nutrition products, 40, 41b-42b needs in patients with cancer, 352 requirements during pregnancy and lactation, 961-963, 966f Calprotectin, with inflammatory bowel disease, 538 Camellias, 121b Camphor, as topical antipruritic agents, 419 Campylobacteriosis, 520 causing diarrhea, 519 causing pregnancy loss, 1005t, 1006, 1008 common symptoms and syndromes caused by, 1213t in raw meat diets, 1240-1241, 1240b treatment for, 520t Canaliculus imperforate, e375-e376 laceration of, e376 obstructed, e376 Cancer. See also Neoplasia adverse effects from therapy of, 330-333 cell targeting, 355 nutrition for the patient with, 349-354 talking to clients about, 318-321, e169-e170 Cancer cachexia, 349-354 Cancer immunotherapy, 334-337 Cancer vaccine, 335, 336t Candida spp. causing hospital-acquired urinary tract infections, 876 causing perivulvar dermatitis, 971 Candidatus mycoplasma haemominutum, e399 Candidatus mycoplasma turicensis, e399 Candidiasis, antifungal therapy for, 1234-1238

Canine adenovirus 1, common symptoms and syndromes caused by, 1215t Canine adenovirus type 2 (CAV-2) causing canine respiratory infection, 632, 1217-1218 common symptoms and syndromes caused by, 1215t Canine atopic dermatitis, 403-404 Canine bartonellosis, 1261-1267 Canine blood groups, 311 Canine breeding management of the female, 930-935 Canine colitis, 550-554 Canine conjunctivitis, 1138-1143 Canine coronavirus, common symptoms and syndromes caused by, 1215t Canine demodicosis, 432-434 Canine distemper virus (CDV) as cause of thrombocytopenia, 281t-282t causing canine respiratory infection, 632, 1217-1218 causing nervous system signs, 1212 causing pregnancy loss, 1005t, 1009 common symptoms and syndromes caused by, 1215t Canine granulocytic anaplasmosis, as cause of thrombocytopenia, 281t-282t Canine hemotropic mycoplasmas, e398-e401 Canine herpesvirus (CHV) as cause of thrombocytopenia, 281t-282t causing canine respiratory infection, 632, 634, 1217-1218 causing conjunctivitis, 634, 1141-1142, 1142f causing pregnancy loss, 1005t, 1009 causing vulvar discharge, 972 common symptoms and syndromes caused by, 1215t Canine hyperlipidemia, diagnosis and treatment of, 261-266 Canine infectious respiratory diseases, 632-635 diagnosis of, 633 treatment and prognosis of, 633-634 Canine influenza virus (CIV) causing canine respiratory infection, 632, 1217-1218 common symptoms and syndromes caused by, 1215t Canine inherited disorders, diagnostic tests for, 1015-1021 Canine leproid granuloma, 445-448, 446f, 448t Canine leukocyte adhesion deficiency, direct mutation test for, 1018t-1020t Canine lymphoma, rescue therapy for, 382t Canine multifocal retinopathy, 1188 direct mutation test for, 1018t-1020t Canine ocular neoplasia, 1201-1206 Canine orthopedic trauma, 80-83 Canine papillomatosis. See Papillomavirus

Index Canine parainfluenza virus (CPiV) causing canine respiratory infection, 632, 1217-1218 common symptoms and syndromes caused by, 1215t Canine parvoviral enteritis, 533-536 Canine parvovirus causing pregnancy loss, 1005t, 1009 common symptoms and syndromes caused by, 1215t use of interferons for, e201 Canine pigmented plaques, e185 Canine respiratory coronavirus (CRCoV) causing canine respiratory infection, 632, 1217-1218 common symptoms and syndromes caused by, 1215t Canine thyroid carcinoma, 397-400, 398f Capillaria aerophilia, e275 Capillaria boehmi, causing nasal discharge, 636-637, 636b Capsaicin, action and use of, for motility disorders, 517-518 Carbamate peroxide, in ear cleaners, 472t Carbamate toxicity, 135-137, 136b Carbamazepine toxicity, use of IV lipid emulsion therapy for, 106 Carbapenem, for pneumonia, 683t Carbimazole, for hyperthyroid cats, e103t, e105 with kidney failure, 188 Carbohydrate(s) dietary, with weight loss diets, 255-259 dietary requirements for, with diabetes mellitus, 200-201, 201t, 204t, 210-215 Carbon dioxide and acid-base disorders, e1 tension, disorders of, e3-e5 Carbon monoxide toxicity, 1027b, e45 Carbon tetrachloride toxicity, 570b Carbonic anhydrase inhibitor(s) causing drug reaction conjunctivitis, 1140 for canine glaucoma, 1173-1174, 1173b, e381 for feline glaucoma, 1178-1179, e381 Carboplatin adverse effects of, 330-331 for osteosarcoma, 391t for thyroid cancer, 400 for urinary bladder cancer, 373 ototoxicity from, 468b Carcinogen, in second-hand smoke, e44-e45 Carcinomatosis, causing malignant effusions, 341 Cardiac effects of potassium supplementation, 253 toxicity from chemotherapeutic drugs, 332 Cardiac atony, and brachycephalic airway obstruction syndrome, 650t Cardiac biomarkers for congenital heart disease, 759 for valvular heart disease, 790

Cardiac cachexia, 722-724 Cardiac hypertrophy, secondary to hypertension, 726 Cardiac neoplasia, e167 Cardiac pacemaker. See Pacemaker Cardiac pump theory, 27 Cardiac tamponade, from pericardial effusion, 816-817 Cardiac troponin I for congenital heart disease, 759 use in respiratory distress, 47 with hemangiosarcoma, 395, 820 with myocarditis, e305, e305f Cardigan Welsh corgi(s), direct mutation tests for, 1018t-1020t Cardiomyopathy arrhythmogenic right ventricular direct mutation test for, 1018t-1020t in cats, e277-e281, e306-e307 in dogs, 801-804, e308 canine classification and staging with, 775-781 dilated cardiogenic shock with, 783 causing pulmonary hypertension, 711 classification and staging with, 775-781 diagnosis and treatment of, 795-800 direct mutation test for, 1018t-1020t genetic marker test for, 1021t nutritional recommendations for, 724 prognosis, 800 treatment of asymptomatic, 775-777 with arrhythmogenic right ventricular, 802 feline, 804-810, 806t asymptomatic, 805-807 dilated, 809 nutritional recommendations for, 724-725 hypertrophic, 807-809 with arrhythmias, 809 with congestive failure, 806t, 808 recurrent, 806t, 809 with thromboembolism, 809-815 nutritional recommendations for, 720-725 pulmonary thromboembolism associated with, 705 Cardioprotective drugs, 762 Cardiopulmonary arrest diagnosis of, 26 epinephrine use in, 15-17, 15t fluid therapy considerations with, 6 temporary pacing for, e22 Cardiopulmonary resuscitation (CPR), 26-31 open chest, 31 post arrest care, 31 prognosis with, 31 Cardiovascular changes, from hypothyroidism, 179

1351

Cardiovascular dysfunction anesthesia for patients with, 64-68 premedication and sedation with, 64-65, 65t Cardiovascular effects, from plants, 121b Cardioversion, e286-e291, e288f for atrial fibrillation, e288-e289, e288, e289f for supraventricular tachyarrhythmias in dogs, 742t, 744 indications and contraindications for, e286-e287 procedure, e287-e288 Carminatives, for flatulence, e249-e250 Carmustine, for intracranial tumors, 1041t, 1044 Carnitine. See L-Carnitine Carotid body tumor, e167-e168 Carotid sinus massage, in cats, 753 Carotid sinus syncope, e328 Carpal hypertension, 80 Carpal trauma in dogs, 81 Carprofen adverse effects of, 60 cutaneous, 489 for canine uveitis, 1165t hepatotoxicity from, 570b, 578, 581b influence on thyroid function, 181t Carts, for rehabilitation, e359 Carvedilol for asymptomatic heart disease, 776 for dilated cardiomyopathy, in dogs occult, 797-798 with heart failure, 799 for heart failure, in dogs, 763b, 764t-765t, 770-771, 792 for myocarditis, e306 for valvular heart disease, 790, 792 toxicity of, use of IV lipid emulsion therapy for, 106 Caspofungin, use and protocols for, 1235t Castor beans toxicity, 121b Castration early age, in dogs and cats, 982-984 for benign prostatic hypertrophy, 1013 for perianal adenoma, 367 risk of prostate cancer and, 1023-1024 Cat fur mite infestation, 431 Cat litter, hypokalemia from ingestion of, 252 Cat(s) population control for, 142-144 temporary pacing in, e28 use of cisplatin in, 333 Cataract(s) causing uveitis, 1184 classification of, 1182t diabetic, 193, 1183, e78 diagnosis and treatment of, 1181-1185, 1182f direct mutation test for, 1018t-1020t hypermature, 1181-1183, 1183f immature, 1181-1183, 1182f mature, 1181-1183, 1182f surgery, 1184-1185

1352

Index

Catecholamine(s) commonly used, 15t for cardiogenic shock, 783 for critical care patients, 14-17 for heart failure, in dogs, 769 for septic shock, 17 hypokalemia from, 251b receptor activities of, 15t Caterpillar ingestion, 99 Cathartic(s), for toxin ingestions, 105 Catheter(s) central venous, with acute respiratory distress syndrome, 50 for parenteral nutrition products, 40-41 pulmonary artery, 19-20 wound, lidocaine use with, 61 Catheterization heart, for diagnosis of pulmonary hypertension, 711 of cervix for breeding, 942 for pyometra treatment, 962-963 urinary antegrade of bladder, 889-891 as risk factor for hospital-acquired urinary tract infections, 877-879 Cationic liposomes, for infectious disease immune therapeutics, 1230t Cattery(ies) multicat outbreaks with dermatophytosis in, 452-454 upper respiratory infection in, 629 Caudal occipital malformation syndrome, 1098 Caval syndrome, 833 Cavalier King Charles spaniel(s) craniocervical junction abnormalities in, 1098-1102 masticatory muscle myositis in, 1113-1114 nonepidermolytic ichthyosis in, 476 otitis media with nasopharyngeal disorders in, 654 strokes in, 812 valvular heart disease in, 784 CCNU. See Lomustine CD34+ cells, causing lymphocytosis, 303 Cefadroxil for pyoderma, 1220t, 1221-1222 for septic mastitis, 959 for superficial bacterial folliculitis, 438t for upper respiratory tract infection(s), 1220t, 1222 for urinary tract infections, 1220-1221, 1220t Cefazolin adverse effects of, 34t-35t before musculoskeletal surgery, 1220t, 1222 for septicemia, 1220t, 1223 for therapy with open fractures, 84-85 Cefovecin, for superficial bacterial folliculitis, 437-438, 438t Cefoxitin, for septicemia, 1220t, 1223 Cefpodoxime, for superficial bacterial folliculitis, 438, 438t

Ceftazidime sodium (Fortaz), for otitis, 466t, 467 Celecoxib toxicity, 116-117 Celinski v. State, e49-e50 Cellulitis, juvenile, use of cyclosporine for, 410b Center of veterinary medicine, FDA, reporting adverse events to, e38, e39f Centipede ingestion, 99 Central nervous system disease from Bartonella spp. infections, 1263b disorder causing dysphagia, 496b disorder from hypothyroidism, e76-e77 infections, use of glucocorticoids for, 1300 noninfectious and inflammatory diseases of, 1063-1066 signs, infectious agents that cause, 1212 vascular disease of, 1119-1126 Central nervous system stimulant(s), toxicity of, 109-112 Centronuclear myopathy, direct mutation test for, 1018t-1020t Cephalexin for feline upper respiratory infection, 631t for methicillin-resistant Staphylococcal infections, 444 for otitis, 466 for pyoderma, 1220t, 1221-1222 for superficial bacterial folliculitis, 438t for upper respiratory tract infection(s), 1220t, 1222 for urinary tract infections, 1220-1221, 1220t Cephalosporin(s) adverse effects of, 34t-35t causing adverse skin reactions, 488t for lower respiratory tract infection(s), 1222 for musculoskeletal infections, 1220t, 1222-1223 for therapy with open fractures, 84-85 Cephalothin adverse effects of, 34t-35t drug incompatibilities with, 33t Ceramide(s), topical, 420t Cerebral blood flow and energy metabolism, 1047-1048 considerations of anesthesia with, 68-70, 69f Cerebral perfusion, with cerebrovascular accidents (stroke), 1120-1123 Cerebrospinal fluid (CSF) acidosis, 67 analysis for inflammatory central nervous system disorders, 1064 analysis with fibrocartilaginous embolism, 1124-1125 biomarkers for intervertebral disk disease, 1073-1074 Cerebrovascular accident (stroke) diagnosis and treatment of, 1119-1126, 1121f

Cerebrovascular accident (stroke) (Continued) hemorrhagic, 1120 ischemic, 1119-1120 thromboembolic disease with, 812 Ceroid lipofuscinosis, direct mutation test for, 1018t-1020t Ceruminolytic(s), for the ear, 472-473, 472t Cervical pain from atlantoaxial subluxation, 1082-1090 from cervical spondylomyelopathy, 1090-1097 from Chiari-like malformation, 1098-1105 Cervical spondylomyelopathy, 1090-1097 algorithm for diagnosis and treatment of, 1095f diagnosis of, 1092-1094 hypothyroidism with, 1094 pathophysiology of, 1090-1091, 1091f-1092f prognosis of, 1096-1097 surgery for, 1094-1096 treatment of, 1094-1096 Cervical vertebral instability. See Cervical spondylomyelopathy Cervix, catheterization of, 942 Cesarean section, anesthesia for, 955t Cetirizine hydrochloride for atopic dermatitis, 406 toxicity of, 118-119 Chagas’ disease, causing myocarditis, e307 Chalazion, e363 Chaparral toxicity, 570b, 581b Chelation therapy for copper-associated liver disease, 588-590, e234-e236 for lead toxicity, 157-158 hypomagnesemia from, 249b Chemical toxins associated with hepatotoxicity, 570b exposure to respiratory, e44-e47 Chemistry analyzers, quality control of, with in-clinic, 307-309 Chemodectoma major vessel, e167-e168 pericardial, 817, 823 Chemoembolization, for malignant obstructions, 348 Chemosis, from conjunctivitis, in dogs, 1139 Chemotherapy adverse effects of, 330 and risk of hospital-acquired urinary infections, 877 antiviral, for feline retrovirus infections, 1277-1280, 1279t associated hepatotoxicity, 575-579, 581b causing adverse skin reactions, 488t client questions about, 318-321 drug handling and safety, 326-329 for feline gastrointestinal lymphoma, 547-548

Index Chemotherapy (Continued) for hemangiosarcoma, 395-396 for insulinoma, e132-e133 for intracranial tumors, 1043t, 1044-1045 for malignant effusions, 343-344 for mammary cancer, 377, 379-380 for multiple myeloma, 385-386 for oral tumors, 364 for osteosarcoma, 390-391, 391t for perianal adenocarcinoma, 368-369 for soft tissue sarcomas, e151 for urinary bladder cancer, 373 intraarterial, 347-348 for lower urinary tract, 890, 891f intracavitary, 343-344 metronomic, 354-357 new anticancer drugs, e139-e142 ototoxicity from, 468b, 469 rescue therapy for canine lymphoma, 381-383, 382t update on masitinib as, 360-362 waste handling, 328-329 Cherry eye. See under Nictitating membrane Chesapeake Bay retriever(s), direct mutation tests for, 1018t-1020t Chest tube. See Thoracostomy tube(s) Chewing behavior in cats, 913 Cheyletiellosis diagnosis and treatment of, 430 treatment options for, 430t use of avermectins for, e182 Chiari-like malformation in dogs, 1098-1105, 1099f Chigger mite(s), diagnosis and treatment of, 431-432 Chihuahua(s), risk of vaccine hypersensitivity in, 1250-1251 Chinese crested(s), direct mutation tests for, 1018t-1020t Chlamydia felis causing feline upper respiratory infections, 629, 630t, 1217-1218 common symptoms and syndromes caused by, 1213t Chlorambucil for feline gastrointestinal lymphoma, 547-548, 548t for feline infectious peritonitis, 1305t for inflammatory bowel disease, 539 for multiple myeloma, 386 metronomic chemotherapy of, 344 Chloramphenicol adverse effects of, 34t-35t causing adverse skin reactions, 488t dosing of, with liver disease, 32-33 drug interactions with, 35t for ehrlichiosis, 1293 for lower respiratory tract infection(s), 1220t, 1222 for methicillin-resistant Staphylococcal skin infections, 444 for superficial bacterial folliculitis, 438t ototoxicity from, 468b topical, for feline ocular herpesvirus 1, 1158 Chlordecone toxicity, 1027b

Chlorhexidine as topical therapy, 441t for disinfection of methicillin-resistant Staphylococcal spp., 455-456 for Malassezia dermatitis, 442 for pyoderma, 440 Chloride composition in fluid therapy, 3t Chloride gap, calculation of, with acid-base disorders, e2 Chlorinated compounds toxicity, 581b Chlorinated hydrocarbon toxicity, 570b Chloroform toxicity, 581b, 1027b Chlorophacinone rodenticide toxicity, 133-134 Chloroprene toxicity, 1027b Chlorothymol, in ear cleaners, 472t Chloroxylenol, as topical therapy for skin infections, 441t Chlorpheniramine causing adverse skin reactions, 488t toxicity of, 118-119 Chlorpromazine for cocaine toxicity, 110 for feline pancreatitis, 567t for vomiting with acute renal failure, 870 Chlortetracycline toxicity, 581b Chocolate enterohepatic recirculation of, 105 toxicity, 98, 148-149, 148t Cholangiocystography, 603 Cholangiohepatitis feline, 614-619 with diabetes mellitus, e77 Cholangioles, reactive, 581-582 Cholangitis complex, 614-615 feline, 614-619, 617b lymphocytic, 618 neutrophilic, 615-618 Cholecalciferol causing nephrotoxicity, e33-e34 supplement for hypocalcemia, e127-e128 Cholecystectomy, 604f-605f for biliary mucoceles, e223 Cholecystitis, 603 Cholecystography, 603 Choledochal stenting, for acute pancreatitis in cats, 568 Cholelithiasis, 603-604, 604f Cholestasis causing alkaline phosphatase elevations, e245b effect on drug metabolism, 33 Cholinergic drug(s) for feline glaucoma, 1179-1180 for keratoconjunctivitis sicca, 1145 Cholinesterase inhibitor(s), 136b for myasthenia gravis, 1110 for urinary retention disorders, 918 Chondrosarcoma, nasal, radiation therapy for, 338-340 CHOP protocol, rescue therapy for canine lymphoma, 381 Chordae tendineae rupture, 790-791, 793

1353

Chorionic gonadotrophin stimulation protocol, 1001, 1002t Chorioretinitis canine, 1162 causing blindness, 1136 causing retinal detachment, in dogs, e371, e371f feline, 1166, 1195-1196 Choristoma, 1153 Choroiditis, canine, 1162 Chromium, for diabetes mellitus, 202, e136t, e137-e138 Chromosomal sex, 993, 995t Chronic axonal degeneration, 1117 Chronic bronchial disorders in dogs, 669-672 Chronic bronchitis in cats, 673-680 in dogs, 669-672, 670f Chronic demyelinating polyradiculoneuritis, 1117 Chronic intestinal pseudo-obstruction, 516 Chronic kidney disease. See under Renal failure, chronic Chronic lymphocytic leukemia, 314 Chronic myeloid leukemia, 314, 317-318 Chylothorax, 695 causes of, 697-698 cytology of fluid from, 698-699 medical treatment of, 699 surgical treatment of, 699-700 Cidofovir for feline ocular herpesvirus 1, 1158 intraocular, with glaucoma eye, 1175-1176 Cigarette toxicity, 119 Cilia abnormalities, 1155 Ciliary body adenoma, 1204-1205, 1205f procedures on, for glaucoma, 1175 Cimetidine (Tagamet) causing adverse skin reactions, 488t drug interactions with, 35t, 37, 677 potency and use of, 505, 506b toxicity of, 119 Ciprofloxacin, for otitis, systemic, 466t Circulation, during CPR, 27, 30 Cirrhosis, 584-585, 585f. See also Liver failure causing ascites, 591-592 Cisapride (Propulsid) action and use of, for motility disorders, 517t for esophagitis, e239-e240 for gastroesophageal reflux, 503 for hepatic lipidosis, 612 for urinary retention disorders, 917t use of, for motility disorders, 516-518 Cisplatin for intrathoracic chemotherapy, 343 for nasal neoplasia, in dogs, 641-643, e158 for osteosarcoma, 391t for urinary bladder cancer, 372-373 intraarterial delivery of, 348 metronomic chemotherapy of, 343 toxicity from chemotherapeutic drugs, 332-333

1354

Index

Citalopram toxicity, 113 Citrate, use of, with continuous renal replacement therapy, 873-875 Citrus aurantium toxicity, 123 Citrus oil, 126 CL/mAb 231, as immunotherapy for lymphoma, 335 Clarithromycin, for nontuberculous cutaneous granulomas, 448t Cleaning associated with hazardous drugs, 328 environments contaminated with resistant Staphylococcal spp., 455-457 for dust mite control, e198 the ear flushing techniques and solutions for, 471-474, 472t with otitis, 458 Cleaning product(s), toxic exposures to, 92t, 95t Client confidentiality, and reporting human drugs of abuse exposure, e52 Client information sheets, for drugs, e41 Client(s) communication of hazardous drug handling, 329 education with allergen immunotherapy, 412b talking about cancer with, 318-321 Climbing structures, to enrich cats environments, 910-911 Clindamycin drug interactions with, 677 for canine babesiosis, 1259 for feline pancreatitis, 567t for feline upper respiratory infection, 631t for lower respiratory tract infection(s), 1220t, 1222 for methicillin-resistant Staphylococcal skin infections, 444 for musculoskeletal infections, 1220t, 1222-1223 for pyoderma, 1220t, 1221-1222 for superficial bacterial folliculitis, 438t for toxoplasmosis, 1167, 1297 target parasites and dosage of, 1335-1337 Clitoral hypertrophy, 972, 978-979, 978f Clofazimine, for nontuberculous cutaneous granulomas, 448t Clomipramine for behavior-related dermatoses, 482-483, 483t influence on thyroid function, 181t toxicity of, 114 use of IV lipid emulsion therapy for, 106 Clonal bone marrow dyscrasias, 316-318 Clonality testing, for evaluation of lymphocytosis, 302 Clonazepam for behavior-related dermatoses, 483t, 484 toxicity of, 113-114

Clopidogrel (Plavix) as anticoagulant therapy, for autoimmune hemolytic anemia, 277-278, 277t causing adverse skin reactions, 488t drug interactions with, 34t-35t for feline cardiomyopathy, 806t for feline thromboembolism, 810 for hypercoagulable states, 300 for prevention of cerebrovascular accidents (stroke), 1122 for protein-losing enteropathy, 544 for thromboprophylaxis, 710, 814-815 to improve collateral blood flow, 814 use of proton pump inhibitors with, 506 Cloprostenol, for pregnancy termination, 990-991 Clorazepate, for behavior-related dermatoses, 483t, 484 Closed system drug transfer devices, 327 Closed-suction drainage, for peritoneal drainage, e12-e13, e12f Clostridium difficile, in tube feeds, e19 Clostridium perfringens, common symptoms and syndromes caused by, 1213t Clostridium spp., 520 associated hepatotoxicity, 581b causing diarrhea, 519 treatment for, 520t Clot formation, with thromboelastography, 74-75 CLOtest, 510, 510f Clotrimazole (Veltrim) for nasal aspergillosis in cats, 648 in dogs, 638-639 topical, for otitis, 465t Clotting abnormalities. See Coagulopathy Cloxacillin, for pyoderma, 1220t, 1221-1222 Coagulase-negative staphylococci, 436 Coagulation factor deficiencies, 286-291 Coagulation testing evaluation of, with thrombocytopenia, 284 with disseminated intravascular disorders, 292-296, 293f, 294t with hereditary factor deficiencies, 287f, 288t with thromboelastography, 74-77 Coagulopathy causing hemothorax, 694 from hydroxyethyl starch solutions, 12-13 from liver failure, 580-582 from methimazole, e104 from rodenticide exposure, 133 hepatic-disease associated, 572, 574, e257 with autoimmune hemolytic anemia, 276 with feline hepatic lipidosis, 610, 612 with gastric dilation-volvulus, e19 Cobalamin absorption, 522-523, 523f

Cobalamin (Continued) factors affecting the concentration of, 523t malabsorption, direct mutation test for, 1018t-1020t measurement of, 523 Cobalamin deficiency for protein-losing enteropathy, 543 in cats, 522-525 with chronic pancreatitis, 564 with exocrine pancreatic insufficiency (EPI), 556, 560 with feline gastrointestinal lymphoma, 546-547 with feline pancreatitis, 567t with hepatic lipidosis, 612 with inflammatory bowel disease, 539 Cocaine toxicity, 110 Cocamidopropyl betaine, in ear cleaners, 472t Coccidioides immitis causing feline uveitis, 1167b common symptoms and syndromes caused by, 1214t Coccidioides spp., causing nervous system signs, 1212 Coccidioidomycosis antifungal therapy for, 1234-1238 causing feline uveitis, 1168 Coccidiomycosis, causing uveitis in dogs, 1163-1164, 1164b Cocker spaniel(s) cardiomyopathy in, 795-796 direct mutation tests for, 1018t-1020t progressive retinal atrophy in, 1188-1190, 1189t sick sinus syndrome in, 732-733 vitamin A-responsive dermatosis in, 476 Cocoa bean or hull toxicity, 98 Cocoa mulch toxicity, 132 Codeine (Methylmorphine), for coughing, 622 Codeine toxicity, 111 Coenzyme Q10 for asymptomatic heart disease, 766 for feline caudal stomatitis, 494 for heart disease, 725 for metabolic brain disorders, 1051, 1051t for mitochondrial encephalopathy, 1051, 1051t for neuromuscular disease, 1118 Coffee toxicity, 98, 148t Coin ingestion, 99-100 Cola toxicity, 98 Colchicine as hepatic support therapy, e257 for amyloidosis, 855 for hepatic fibrosis, 587 Colitis canine causes of, 551t diagnosis and treatment of, 550-554 medical management of, 551b effect of, on gastric emptying, 516 granulomatous, 552-553 antibiotic responsive, 519b, 520t

Index Collagen XXVII, with hemangiosarcoma, 395 Collie(s) avermectin toxicity in, 145 dermatomyositis in, 1115 exocrine pancreatic insufficiency (EPI) in, 558 eye anomaly, 1136-1137 direct mutation test for, 1018t-1020t hyperlipidemia in, 261 ivermectin sensitivity in, e179 progressive retinal atrophy in, 1188-1190, 1189t Colloid fluids characteristics of, 10t clinical use of, 12-13, 12t for acute pancreatitis in dogs, 562 for canine parvovirus, 534 for gastric dilation-volvulus therapy, e15-e16, e16t for protein-losing enteropathy, 543-544 for shock, 21 pharmacology of, 8-11 with crystalloid fluid therapy, 13, e15-e16 with hypertonic saline, 21 Colloid osmotic pressure, 8, 9f conditions that change, 9t Colloidal oatmeal, 420t Colonic stenting, of malignant obstructions, 347 Color dilution alopecia, 164 Coltsfoot toxicity, 124t Combustion-derived toxicant(s), e44-e47 Comfrey toxicity, 570b, 581b Companion animal parasite council, stand on raw meat diets, 1242 Compensation, with acid-base equilibrium, e1-e2, e2b, e2t Complete blood count (CBC) finding with respiratory distress, 47 monitoring, prior to chemotherapeutic drugs, 330-331 with hepatobiliary disease, 569 Compounding drugs, e58 parenteral nutrition products, 40, 41b Computed tomography (CT) attenuation values of normal thyroid gland, 168t for atlantoaxial subluxation, 10841085, 1085f for canine ocular neoplasia, 1201-1206 for cervical spondylomyelopathy, 1093 for congenital hydrocephalus, 1035-1036 for diagnosis of feline hypersomatotropism, 216, 217f, 219 for evaluation of dysphagia, 499 for evaluation of hepatobiliary disease, 574 for evaluation of osteosarcoma, 388 for hemangiosarcoma, 393-395, 394f for inflammatory central nervous system disorders, 1064 for interstitial lung diseases, e266-e267

Computed tomography (CT) (Continued) for intervertebral disk disease, 1073 for lumbosacral stenosis, 1106 for nasal tumors, 338, e158f for nasopharyngeal disorders, 654 for pituitary macroadenoma, e89-e90 imaging for diagnosis of endocrine disorders, 167-174 of adrenal gland(s), 170-172, 171f for hyperaldosteronism in cats, 240-241 of pancreas, 172-174 of pituitary gland, 171f of thyroid gland, 167-170 with fibrocartilaginous embolism, 1124 with nasal discharge in cats, 645-646, 645f in dogs, 636-638, 639f-640f, 640-641, 642f with pericardial effusion, 819, 819f with pneumothorax, 701f with portal vein hypoplasia, 600 Concentration alkalosis, e6-e7 Conditioner(s), for sebaceous adenitis, e210-e211, e211 Conductive hearing loss, 468, 468b treatment and prevention of, 470 Cone degeneration, direct mutation test for, 1018t-1020t Cone-rod dystrophy, 1190 Congenital disease(s) genetic testing for, 1015-1021 hydrocephalus, 1034-1037 nonulcerative corneal, 1153 of the lens, 1181 of the reproductive tract, 993-999 vulvar and vaginal anomalies, 976-980 Congenital heart disease, 756-761 prevalence of, 756-757, 757t prophylaxis with, e297-e298 screening for, 757-759 therapy of, 759-760 Congenital hydrocephalus, 1034-1037 Conjunctiva anatomy and physiology of, 1138 biopsy of, for episcleritis, 1141 changes in, with glaucoma in dogs, 1171t tumors of in cats, 1207-1208 in dogs, 1201, 1203-1204 ulcers of, 1139 Conjunctivitis allergic, 1139f, 1140 canine, diagnosis and treatment of, 1138-1143 frictional irritant, 1140, 1140f from feline herpesvirus 1, 1156-1158 from feline upper respiratory infection, 630t from keratoconjunctivitis sicca, 1143 immune-mediated, 1140-1141 infectious, 1141-1142 traumatic, 1139f, 1142 Contact allergy, pentoxifylline for, e203 Contamination, with methicillinresistant Staphylococcal infections, 455-457, 456t

1355

Continuous glucose monitoring systems, 198 Continuous renal replacement therapy, 871-875, 872f-874f, 875b Contraceptives, in the bitch, 984-989 Conval lily, toxicity of, 124t Convection, 71 Cooling methods, for treatment of heat-induced illness, 72-73 Copper chelator therapy, 588-590 concentrations, e234, e234t-e235t metabolism, e231, e232f restriction, e236 Copper-associated hepatopathy, e231-e236 breeds predisposed to, 571b chelator therapy for, 588-590 diagnosis of, e231, e234t genetic marker test for, 1021t liver biopsy for evaluation of, 575 pathophysiology of, 588 treatment of, e234 Cor triatriatum sinister, prevalence of, in cats, 757t Corgi(s), progressive retinal atrophy in, 1188-1190, 1189t Coring technique for cytology, e154 Cornea. See also under Keratitis; Keratopathy anatomy of, 1148, 1149f changes in, with glaucoma in dogs, 1171t diseases of the, feline, 1156-1161 clinical signs of, 1157b foreign body in, e380 healing of, 1148-1149 laceration of, e380 lipid deposits in, 1153 neoplasia of, 1156 nonulcerative disease of, in dogs, 1152-1156 perforation of, e380 physiology of, 1148 plaque on, 1159f signs of disease in cats, 1157b tumors of in cats, 1207-1208 in dogs, 1204 Corneal edema, with canine uveitis, 1163t Corneal lipidosis, from hypothyroidism, e85 Corneal sequestrum, 1159-1160, 1160f from feline herpesvirus 1, 1157t indications for surgery with, 1161t Corneal ulceration causing uveitis in dogs, 1164 complicated, 1150-1151, e379 diagnosis and treatment of, 1148-1152, e379-e380 diamond burr débridement for, 1152 fluorescein dye for diagnosis of, 1132 from feline herpesvirus 1, 1157t from feline upper respiratory infection, 630t indications for surgery with, 1161t indolent, 1151-1152, e379 keratotomy for, 1151-1152

1356

Index

Corneal ulceration (Continued) simple, 1149-1150, e379 with canine uveitis, 1166 Cornification disorders in dogs, 475-477 Coronavirus enteric, 1303-1304 feline, as cause of thrombocytopenia, 281t-282t Corticosteroid. See Glucocorticoid(s) Corticosteroid alkaline phosphatase (cALP), e243 Corticosteroid insufficiency, illnessrelated, 78-79, 174-178 Cortisol, precursor secretion causing alopecia, 221-222 Cortisol levels with ectopic ACTH syndrome, 230-231, 231f with feline hyperaldosteronism, 240t with hypoadrenocorticism, 233-235 with illness-related adrenal insufficiency, 175-176 with illness-related corticosteroid insufficiency, 175-176 Cortisol-to-ACTH ratio, 235 Corynebacterium parvum (ImmunoRegulin), as cancer immunotherapy, 336t Cosyntropin for testing hypoadrenocorticism, 233-235 for testing illness-related adrenal insufficiency, 78-79, 175-176 Cotton ball vision test, e391 Cough from asthma in cats, 673-674 from bronchial compression with heart disease, 782 induced syncope, e327 infectious causes of, 1217-1218 suppressants (See Antitussive drugs) treatment of, from tracheal collapse, 663-664 with heart disease, 792-793 Coupage, for pneumonia, 687 COX inhibitor(s), for urinary bladder cancer, 372-373 Coxiella burnetii causing infection in humans, 1246 causing pregnancy loss, 1005t, 1009, 1218 common symptoms and syndromes caused by, 1214t Coxofemoral joint trauma in dogs, 82 Cranberry extract, for persistent E. coli urinary tract infections, 881b, 882 Cranial nerve(s) assessment of with neuro-ophthalmic exam, e389, e390-e392 deficits, from vestibular disease, 1067t Craniocervical junction abnormalities in dogs, 1098-1105 diagnosis of, 1102 medical therapy for, 1102-1103 surgery for, 1103-1104, 1103f-1104f Cranioplasty, for Chiari-like malformation in dogs, 1103-1104, 1103f-1104f

Cream(s) as topical therapy for skin infections, 441t for topical antimicrobials, for otitis, 463 potency of topical steroid, 460f Creatine kinase (CK) activity with various myopathies, 1113-1118 in CSF as outcome predictors with intervertebral disk disease, 1073-1074 with heat induced illness, 72 with leptospirosis, 1287 with Neospora caninum, 1290 with toxoplasmosis, 1296 Creatinine as indicator of predicting renal failure with hyperthyroidism, 187 changes with hospital acquired kidney injury, 845-846 for staging of kidney disease, 858, 859t-860t formula for adjustment of drug dosage, 36 formula for adjustment of drug intervals, 36 monitoring of, with ACE inhibitors, 854 Crenosoma vulpis, as bronchopulmonary parasite, e274-e275 Cricopharyngeal achalasia, 499 Cricopharyngeal dyssynchrony, 499 Critical care acid-base disorders, management of, e1-e8 analgesia in, 59-63, 62t anesthesia in, 63-70 catecholamines use in, 14-17 drug Interactions in, 32-38 fluid therapy and, 2-14 hyperthermia and heat-induced illness, 70-74 hypomagnesemia in, 248-251 nutrition in, 38-43 orthopedic trauma in dogs in, 80-83 oxygen therapy in, 52-54 pacing in, e21-e28, e23f respiratory distress in, 44-51 treatment of open fractures in, 83-86 use of thromboelastography in, 74-77 ventilator therapy in, 55-59 Critical-illness related corticosteroid insufficiency, 78-79, 174-178, 177f pathophysiology of, 175 Crossmatching. See Blood crossmatching Cruciate ligament trauma in dogs, 81-82 concerns regarding risk, with early age neutering, 983t Crushing injuries, and wound care, 87-88 Cryo-poor plasma, 310-311 Cryoprecipitate, 310-311 for therapy of shock, 21-22 for treatment of von Willebrand disease, 290, 290t Cryosupernatant, for treatment of factor deficiencies, 290, 290t

Cryotherapy, for glaucoma, 1175 Cryptococcosis antifungal therapy for, 1234-1238 causing epistaxis, 1216 causing feline rhinitis, 644, 648 causing nasopharyngeal disease, 654-656 causing nervous system signs, 1212 causing uveitis in cats, 1168 in dogs, 1163-1164, 1164b immunotherapy for, 1232 Cryptococcus neoformans, common symptoms and syndromes caused by, 1214t Cryptorchidism, 998-999 risk of testicular tumors with, 1022 Cryptosporidium spp. infection common symptoms and syndromes caused by, 1214t-1215t dosage for and drugs targeting, 1335-1337 in raw meat diets, 1240b, 1241 Crystalloid(s). See Fluid therapy Crystalluria, asymptomatic, 926 Culture(s) blood, for endocarditis, e293-e294 ear, for diagnosis of otitis, 463 fecal, bacterial, 519 for Bartonella spp., 1265, e293 feline, 1269 for lagenidiosis, e415 for methicillin-resistant Staphylococcal skin infections, 444 for pythiosis, e413 for septic mastitis, 959 fungal, for dermatophytosis, 449, 452-454 lung, 681-682 with pneumonia, 681-682, 684-686, 684f of brucella canis, e404 prostatic, 1013-1014 respiratory for canine infectious diseases, 633, 671-672 for feline asthma, 676 skin for superficial bacterial folliculitis, 437-438 of acral lick dermatitis lesions, e175 of Staphylococcus spp., 435-436 urine for surveillance of hospital-acquired urinary infections, 877-878 why results are negative FAQ, 923-924 uterine, 938 vaginal, 937, 972-973 wound, 87-88 with open fractures, 84 Cuprate, e56t Curschmann’s spirals, 669-670 Cushing’s disease. See Hyperadrenocorticism Cutaneous adverse drug reactions, 487-490, 488t Cutaneous inverted papilloma, e185

Index Cutaneous pythiosis, e412-e413 Cutaneous vasculitis, topical immunomodulators for, e218-e219 Cuterebra, nasal, 656, e270 Cyanocobalamin. See also Cobalamin; Cobalamin deficiency for cobalamin deficiency, 524 Cyanosis, diagnosis of, 52 Cycad toxicity, 570b, 581b Cyclical flank alopecia, 165b Cyclizine toxicity, 118-119 Cyclocryotherapy, 1175 for feline glaucoma, 1180 Cyclooxygenase inhibitors, in NSAID’s, 37, 60, 116-117 Cyclooxygenase isoenzymes, 863-864 Cyclophosphamide (Cytoxan) causing hemorrhagic cystitis, 332 for feline gastrointestinal lymphoma, 547-548, 548t for hemangiosarcoma, 395-396 for mammary cancer, 377, 379-380 for multiple myeloma, 386 for myasthenia gravis, 1111 metronomic chemotherapy of, 343-344 rescue chemotherapy for canine lymphoma, 381-383 use of, for immunosuppression, 268 Cyclophotocoagulation, 1175 for feline glaucoma, 1180 Cyclosporine adverse effect of, in cats, 409 and risk of ocular squamous cell carcinoma, 1204 as topical immunomodulators, e216-e220, e217 blood level measurement of, 270 contraindications for use of, in cats, 409 drug interactions with, 35t for anal furunculosis, e190 for atopic dermatitis, 406 for autoimmune hemolytic anemia, 278-279 for canine colitis, 551b, 552 for chronic pancreatitis and diabetes, 564 for chronic superficial keratitis (Pannus), 1154 for eosinophilic pulmonary diseases, 690-691 for episcleritis, 1141 for feline asthma, 678 for feline caudal stomatitis, 494 for feline tear film disorders, e387 for inflammatory bowel disease, 539 for inflammatory central nervous system disorders, 1065 for keratoconjunctivitis sicca, 1145, 1155, e387 for myasthenia gravis, 1111 for protein-losing enteropathy, 544 for sebaceous adenitis, e211 for thrombocytopenia, 285t psoriasiform-lichenoid dermatosis from, 489 topical, for eosinophilic keratitis, 1159

Cyclosporine (Continued) use in dermatology, 407-410, 410b use of for immunosuppression, 269-271 with fluconazole, 408 Cyproheptadine for appetite stimulation, 352 for feline asthma, 678 for hepatic lipidosis, 611 for management with GI effects of chemotherapeutic drugs, 331 for selective serotonin reuptake inhibitors toxicity, 113 Cystadenoma, ovarian, 1024-1025 Cystic duct catheterization, 603, 605 Cystic endometrial hyperplasia, 967 causing pregnancy loss, 1005-1006, 1005t Cystic orbital disease, 1199-1200 Cystine crystalluria, 926 Cystinuria, direct mutation test for, 1018t-1020t Cystitis. See Urinary tract infections Cystocentesis, use of ultrasound for, 841, 844 Cystoisospora spp. infection, dosage for and drugs targeting, 1335-1337 Cystolithotomy, percutaneous, 890 Cystometrogram (CMG), e346 Cystoscopy biopsy using, 907-908 for bladder cancer, 371 for delivering injectable bulking agents, e347f guided laser ablation for ectopic ureters, 890-891, 891f interventional strategies for urinary diseases, 884 minilaparotomy-assisted, for urocystoliths, 905-909, 906f-907f Cystourethroscope, for insemination, 940-944 Cytarabine, for inflammatory central nervous system disorders, 1065 Cytauxzoon felis, common symptoms and syndromes caused by, 1214t-1215t Cytauxzoonosis, e405-e409 clinical signs of, e407 diagnosis of, e406f, e407, e407-e408 dosage for and drugs targeting, 1335-1337 pathogenesis of, e405-e407 treatment of, e408 Cytochrome p450, 33-36 and cimetidine, 505 associated with drug induced liver disease, 575, 580 drug interactions based on, 35t Cytokine(s) adverse effects of, 1231 for feline retrovirus infections, 1280t-1281t for immune therapeutics, 335, 1230 inhibitors, for immunosuppression, 271-273 interferon, e200-e201 Cytology airway, with pneumonia, 686

1357

Cytology (Continued) bronchial, 669-670 brush, for Helicobacter spp., 509-510, 510f collection of specimens for, e153-e156 corneal, with complicated ulcers, 1150 ear, for diagnosis of otitis, 458, 463 fecal, for exocrine pancreatic insufficiency, 556 fixation and staining of specimens, e155-e156 for feline asthma, 675-676 for pneumocystosis, e410 for pythiosis, e413 joint, with polyarthritis, 1224-1228 liver, with feline hepatic lipidosis, 610 lung for interstitial lung diseases, e268 for parasites, e269-e276 nasal for parasites, e269-e271 in cats, 644, 645f in dogs, 636-637 nasopharyngeal, 654 of malignant effusions, 342 of skin, for diagnosis of alopecia, 165 of the eye, 1133 pericardial effusion fluid, 817, 820 pleural effusion fluid, characterization of, 692t, 694-696 prostatic, 1013-1014 rectal, 550 uterine, 938 vaginal, 932-933, 933f, 970 for breeding management, 933f for diagnosis of disease, 937 technique for, 937 to detect ovarian remnant syndrome, 1001 with pyometra, 967 with pyometra or mucometra, 947 with septic metritis, 958 with eosinophilic pulmonary diseases, 689 with Malassezia spp., e213-e214 Cytopenias diagnostic workup for, 315f multiple, diagnostic approach to, e161b Cytoprotective agents, action and use of, 506-507 Cytosine arabinoside as rescue therapy for canine lymphoma, 382t for intracranial tumors, 1041t, 1044-1045 D D-dimer level, in disseminated intravascular coagulation, 294t D-limonene, causing adverse skin reactions, 488t D-Penicillamine adverse effects of, e234-e236 for copper-associated hepatitis, e234-e236 Dacarbazine, as rescue therapy for canine lymphoma, 382t

1358

Index

Dachshund(s) direct mutation tests for, 1018t-1020t intervertebral disk disease in, 1071-1072 lymphoplasmacytic rhinitis in, 640 pneumocystosis in, e410 risk of vaccine hypersensitivity in, 1250-1251 sick sinus syndrome in, 732-733 Dacryocystitis, e376 Dacryocystorhinography, e374 Dacryops, e376 Dactinomycin, extravasation and tissue sloughing from, 333 Daily energy requirements, 259 Dairy products, drug incompatibilities with, 33t Dalmatian(s), missing canine red cell antigen(s), 311 Dalteparin (Fragmin), 707, 813 as anticoagulant therapy, for autoimmune hemolytic anemia, 277t for arterial thromboembolism, 815 Dampness and mold, as respiratory allergens, e44 Danazol toxicity, 581b Dantrolene, for urinary retention disorders, 917t, 918 Darbepoetin, for anemia, from chronic kidney disease, 862-863 Dark adaptation test, e391-e392 Dazzle reflex, e391 DEA 1.1 blood type, 311 Deadly nightshade toxicity, 124t Deafness, 468-469 age-related, 469 causes of, 468b from ototoxicity, 468 Débridement for wound care, 83 with open fractures, 85 Decongestants, for respiratory diseases, 627 Decontamination associated with hazardous drugs, 328 from toxins, 104-105 Decoquinate, for canine hepatozoonosis, 1285 DEET mosquito repellent, use of, on pets, 100 Defecation induced syncope, e327 Defibrillation electrical, during CPR, 30 types of units for, 30 Degenerative lumbosacral stenosis, 1105-1108 Degenerative myelopathy, 1075-1081 differential diagnosis for, 1077 direct mutation test for, 1018t-1020t disease progression of, 1076-1077, 1076t exercise with, 1078-1080 rehabilitation considerations with, e360, e362b Degreaser toxicity, 154-155 Dehydration during pregnancy and lactation, 964 estimates of, 5t

Delayed gastric emptying, 514-515, 514b Deltamethrin, 426t target parasites of, 1335-1337 Demecarium bromide causing anisocoria or mydriasis, e392 for glaucoma in cats, 1179-1180 in dogs, 1173b, 1174 Demodex cati, e192-e193 Demodex gatoi, e191-e192 Demodicosis canine, 432-434 treatment options for, 433t, e364 causing blepharitis, e364 feline, e191-e193 use of avermectins for, e182-e183 with sebaceous gland hyperplasia, 476-477 Denaturing agents, for dust mite control, e199 Dental disease antibiotic prophylaxis with, e297-e298 with diabetes mellitus, e77 Dental extractions, for feline caudal stomatitis, 493-494 Deoxyribonucleic acid-based test(s), for hereditary disorders, 1016-1020 Depot deslorelin, for urinary incontinence disorders, 916t Depot leuprolide, for urinary incontinence disorders, 916t Deracoxib adverse effects of, 60 dosage for, 62t for canine uveitis, 1165t for urinary bladder cancer, 372 influence on thyroid function, 181t Dermacentor variabilis, causing cytauxzoonosis, e405 Dermatitis acral lick, e172-e178 atopic (See also Atopic dermatitis) allergen-specific immunotherapy for, 411-414 cyclosporine for, 403-404 from nonsteroidal anti-inflammatory drugs, 489 of the eyelid, e363-e369 perivulvar, 971, 977f concerns regarding risk, with early age neutering, 983t pyotraumatic (See Pyotraumatic dermatitis) scrotal, 1031 superficial necrolytic, 485-487 Dermatologic disorder(s) acral lick dermatitis causing, e172-e178 actinic dermatoses, 480-482 allergen-specific immunotherapy for, 411-414 alopecia X, 477-479 atopy, in dogs, 403-407 bilaterally symmetric alopecia, in dogs, 164-166, 165b cornification disorders in dogs, 475-477 cutaneous adverse drug reactions, 487-490

Dermatologic disorder(s) (Continued) disinfection of environments with staphylococcal sp., 455-457 drugs for behavior-related dermatoses, 482-485 ear-flushing techniques for, 471-474 feline demodicosis causing, e191-e193 feline viral skin, e194-e197 food elimination diets for adverse reactions, 422-424 from Bartonella spp. infections, 1263b from demodicosis, 432-434 from dermatophytosis, 449-451 in multicat environments, 452-454 from ectoparasitoses, 428-432 from hypothyroidism, 179 from superficial bacterial folliculitis, 437-439 from superficial necrolytic dermatitis, 485-487 generalized sebaceous gland hyperplasia, 476-477 glucocorticoids for, 414-418, 416t ichthyosis, 475-476 malassezia causing, e212-e216 nasal parakeratosis, 476 of the anal sac, e187-e190 otitis principles of therapy for, 458-459 systemic antimicrobials for, 466-467 topical antimicrobials for, 462-465 papillomaviruses causing, e184-e187 pentoxifylline for, e202-e205 periocular, e363-e369 pyotraumatic dermatitis causing, e206-e208 sebaceous adenitis causing, e209-e212 staphylococci causing pyoderma, 435-436 topical and systemic glucocorticoid for, 459-462 topical immunomodulators for, e216-e221 topical therapy for, 439-443, 441t with pruritus, 419-421 use of avermectins for, e178-e184 use of cyclosporine for, 407-410 vitamin A-responsive dermatosis, 476 with canine leproid granuloma, 445-446 with feline leprosy syndrome, 446-447 with nontuberculous cutaneous granulomas, 445-448 Dermatomyositis, 1115 pentoxifylline for, e203 Dermatophagoides farinae, e197 Dermatophagoides pteronyssinus, e197 Dermatophyte test medium (DTM), 449 Dermatophytosis as cause of alopecia, 165 causing blepharitis, e363 investigating a multicat outbreak, 452-454 treatment of, 449-451, 450b, 450t-451t Dermatoses actinic, 480-482 behavior-related, 482-485

Index Dermatosis psoriasiform-lichenoid, cyclosporineinduced, 489 sterile neutrophilic, 489 Dermoid, 1153 causing frictional irritant conjunctivitis, 1140 Descemet’s membrane anatomy of, 1148 with descemetocele, 1149 Deslorelin for benign prostatic hypertrophy, 1013 for prostatic abscesses, 1015 Desmopressin acetate (DDAVP) dose adjustments of, e75 for diabetes insipidus, e73-e75 for mammary cancer, 377 for von Willebrand disease, 290 injectable, e74 nasal and ophthalmic, e73-e74 oral, e74 preparations of, e73-e74 Desoxycorticosterone pivalate (DOCP), for hypoadrenocorticism, 236-237 Detemir insulin, 211, 212b storage of, 214 Detrusor atony of urinary bladder, 918 Detrusor-urethral dyssynergia, 918 Dexamethasone adverse effects of, 461 for otitis systemic, 461t topical, 460t for pregnancy termination, 991, 991t use of, with hypoadrenocorticism testing, 234-236 Dexamethasone suppression test for alopecia X, 478 interpretation of, e98-e99 low dose, 221 Dexlansoprazole, action and use of, 505-506 Dexmedetomidine adverse effects of, 60 CRI, 62t dosage for, 62t use of with cardiovascular dysfunction, 64-65 with intracranial pathology, 69 Dexrazoxane, use of, prior to doxorubicin, 332 Dextran 70, for canine parvovirus, 534 Dextroamphetamine and amphetamine (Adderall), toxicity of, 109-110 Dextroamphetamine toxicity, 109-110 Dextromethorphan, for coughing, 623 Dextrose for shock, 24 hypokalemia from, 251b supplementation with diabetic ketoacidosis, e80t-e81t Diabetes insipidus, desmopressin for diagnosis and treatment of, e73-e75 Diabetes mellitus and risk of urinary tract infections, 877 and superficial necrolytic dermatitis, 485

Diabetes mellitus (Continued) canine adjusting therapy with, 191-192 diagnosis and treatment of, 189-193 dietary management of, 199-202 causing alkaline phosphatase elevations, e243-e244 causing cataracts, 1183, 1183f complicated, e76-e83 concurrent with hypothyroidism, e87-e88 diet and, 199-204, 201t feline, 208-215 alternatives to insulin therapy, e135-e138, e136f, e136t diagnosis and treatment of, 208-215 dietary management of, 202-204 pathogenesis of, 208-210 remission, 204-205, 209-210, 213 with acromegaly, 216 hyperadrenocorticism with, 207 hyperosmolar nonketotic, e83 hypertension from, 727, 727t hypokalemia from, 251b hypomagnesemia with, 248 imaging of pancreas for, 172-174 insulin resistance in, 205-208, 206b from feline hypersomatotropism and acromegaly, 216-221 monitoring of, 193-199 nephropathy from, e76 neuropathy from, 1116, e76-e77 pulmonary thromboembolism associated with, 705 retinopathy from, 1192 risk of, with progestin drugs, 985 toxicity of herbal supplements used for, 125 with chronic pancreatitis, 564 Diabetic ketoacidosis (DKA) diagnosis and treatment of, e78-e83, e80t-e81t hypomagnesemia with, 248-250 influence on fructosamine, 194 potassium levels with, 253 role of insulin resistance in, 205 with acute pancreatitis in dogs, 563, e77-e78 Diagnostic test(s) biopsy and specimen submission for, 322-326 for causes of thrombocytopenia, 281t-282t for hereditary disorders, 1015-1021, 1016t interpretation of, for adrenal and thyroid disease, e97-e102 of bone marrow, 314-318 quality control for the in-clinic laboratory and, 306-309 Dialysis use of, with nephroliths and ureteroliths, 895 vs. continuous renal replacement therapy, 871 Diamond burr débridement, 1152 Diaphragmatic rupture, causing pleural effusion, 694

1359

Diarrhea. See also under Colitis antibiotic-responsive, 518-522, 519b chronic diagnostic approach to, e264-e265, e264f idiopathic large bowel, 516 common infectious agents causing, 1213-1215 from Tritrichomonas foetus, 528-530 large bowel, 550-554 causes of, 551t probiotic therapy for, 525-528 tylosin-responsive, e262-e265 Diazepam (Valium) associated hepatotoxicity, 570b, 581b for appetite stimulation, 352 for behavior-related dermatoses, 483t, 484 for emergent seizures, 1059 for urinary retention disorders, 917t, 918 rectal administration of, 1059 toxicity of, 113-114 use of, with cardiovascular dysfunction, 64-65 with fentanyl, for anesthetic induction in critical patients, 66 Diazoxide(s), for insulinomas, e133 Dibromochloropropane toxicity, 1027b Dichlorobenzene toxicity, 1027b Dichloroethane toxicity, 1027b Dichloromethane toxicity, 1027b Dichlorphenamide, for glaucoma in dogs, 1173-1174, 1173b Diclofenac for actinic dermatoses, 481 for canine uveitis, 1165t Dicloxacillin, for pyoderma, 1220t, 1221-1222 Dicyclomine HCl (Bentyl), for canine colitis, 551b Didanosine, for feline retrovirus infections, 1278, 1279t Diesel toxicity, 154-155 Diestrus, drugs for pregnancy termination during, 991-992 Diet and diabetes, 199-204, 201t Dietary supplements for heart disease, 725 of calcium, e127-e128, e127t of potassium, 253 toxicity from, 122-129 Dietary therapy copper-restricted, 590 food elimination, for adverse reactions, 422-424 for acute pancreatitis in dogs, 563-564 for calcium oxalate urolithiasis, 898-899, 899t for cancer, 351-352 for canine colitis, 551b, 552 for canine parvovirus, 535 for chronic diarrhea, e265 for chronic hepatitis, 587-588 for control of hepatoencephalopathy, 593 for copper-associated hepatitis, e236

1360

Index

Dietary therapy (Continued) for exocrine pancreatic insufficiency (EPI), 559-560 for feline diabetes mellitus, e136-e137, e136f for feline hyperthyroidism, e107-e112 for feline idiopathic hypercalcemia, 244-246 for heart disease, 720-725, 777, 790, 792 for hepatic lipidosis, 611-612 for hyperlipidemia, 264 for hypertension and kidney disease, 861-862 for inflammatory bowel disease, 538 for insulinomas, e133-e134 for nephroliths and ureteroliths, 895-896 for obesity, 255-259 for patients with flatulence, e248-e249, e249b for portosystemic shunt, 596 for protein losing enteropathy, 542-543, 543t for urate urolithiasis, 902, 902f, 904, 905b hypoallergenic, 422-424, e176 infectious diseases from raw meat diets, 1239-1243 modification to facilitate gastric emptying, 515 relative to environmental needs of cats, 911-912 sodium restriction, for ascites, from liver disease, 592 Diethylcarbamazine causing adverse skin reactions, 488t for feline retrovirus infections, 1280t-1281t, 1282 Diethylene glycol toxicity, 154, e30-e31 Diethylstilbestrol (DES), for benign prostatic hypertrophy, 1013 Difloxacin, for lower respiratory tract infection(s), 1220t Digital papillomatosis, e185 Digitoxin toxicity, anorexia from, 722 Digoxin adverse effects of, 34t-35t, 791-792 causing bradyarrhythmias, 732 drug incompatibilities with, 33t drug interactions with, 35t for arrhythmia with congestive heart failure, 783 for asymptomatic heart disease, 766 for atrial fibrillation, 743 with dilated cardiomyopathy, 799 for dilated cardiomyopathy, in dogs occult, 797-798 with heart failure, 799 for feline arrhythmias, 752 for heart failure, in dogs, 764t-765t, 768-770, 791-792 for refractory heart failure, 781 for supraventricular tachyarrhythmias, 742t, 743 interaction with GI drugs, 37 monitoring therapy of, 791-792, 799 use of, with hypokalemia, 34t-35t

Dihydrostreptomycin, for brucellosis, e404 Dihydrotachysterol, supplement for hypocalcemia, e127-e128, e128t Diltiazem causing bradyarrhythmias, 732 causing syncope, e328 for atrial fibrillation, 743 with dilated cardiomyopathy, 799 for feline arrhythmias, 752 for feline cardiomyopathy, 805-807, 806t for heart failure, in dogs, 764t-765t with arrhythmias, 772 for supraventricular tachyarrhythmias, 742t, 743 toxicity of, use of IV lipid emulsion therapy for, 106 Dilutional acidosis, e6-e7, e7b Dimenhydrinate for intracranial tumors, 1041t toxicity of, 118-119 Dimethyl sulfoxide (DMSO), for amyloidosis, 855 Dimethylnitrosamine toxicity, 570b Diminazene aceturate, for canine babesiosis, 1258t, 1259 Dinotefuran, 426t Dinotefuran/permethrin/pyriproxyfen, 426t target parasites of, 1335-1337 Dinotefuran/pyriproxyfen, target parasites of, 1335-1337 Dioctyl sodium sulfosuccinate (DSS) ear cleaner, 472-473 in ear cleaners, 472t Dioxane toxicity, 1027b Diphacenone rodenticide toxicity, 133-134 Diphenhydramine (Benadryl) to reduce risk of vaccine hypersensitivity, 1250 topical, 420t for hot spots, e207 toxicity of, 118-119 Diphenoxylate, for canine colitis, 551b Dipivefrin, for glaucoma in dogs, 1173b, 1174 Dipylidium caninum causing infection in humans, 1247 common symptoms and syndromes caused by, 1214t-1215t drugs targeting, 1335-1337 Direct megakaryocytic immunofluorescence assay, evaluation of, with thrombocytopenia, 284 Direct mutation test(s), 1017, 1018t-1020t Dirlotapide, for treatment of obesity, 259-260 Dirofilaria immitis causing infection in humans, 1248 common symptoms and syndromes caused by, 1214t-1215t drugs targeting prevention of, 1335-1337 Dirofilariasis. See Heartworm disease

Discoid lupus erythematosus tacrolimus for, e218 use of cyclosporine for, 410b Discospondylitis, from brucellosis, e403f Disinfection, from Staphylococcal spp., 455-457 Disseminated candidiasis, as cause of thrombocytopenia, 281t-282t Disseminated intravascular coagulation (DIC) diagnosis and treatment of, 292-296 diseases associated with, 294b from heat-induced illness, 71-72 laboratory values supporting, 294t risk of, with pancreatitis in dogs, 562 thrombocytopenia and, 280, 283 Distemper. See Canine distemper virus (CDV) Distichiasis, e369, e377 causing frictional irritant conjunctivitis, 1140 Diuresis for malignant effusions, 342 to promote ureterolith passage, 894 Diuretic(s) for ascites, from liver disease, 591, 592f for heart failure, in dogs, 762-766, 763b loop, ototoxicity from, 469 DNA amplification assay, for Bartonella spp., 1264-1265, 1269 Doberman pinscher(s) cardiomyopathy in, 795, 797 cervical spondylomyelopathy in, 1090-1097 copper-associated liver disease in, 589-590 direct mutation tests for, 1018t-1020t hyperlipidemia in, 261 hypothyroidism in, 178-179 neurocardiogenic syncope in, e327 prostatic disease in, 1012 risk of bladder cancer in, 371t ventricular arrhythmia in, 745 with color dilution alopecia, 164 Dobutamine drug incompatibilities with, 33t for cardiogenic shock, 783 for heart failure in cats, 808 in dogs, 764t-765t, 768-770 receptor activities of, 15t use and dosage of, 15t, 16-17 use of with shock, 23 Docetaxel, e140t, e141 for mammary cancer, 377 hypersensitivity reactions to, 333 Docosahexaenoic acid(s) for heart disease, 722-723 requirements during pregnancy and lactation, 963 Dog erythrocyte antigen, 311 Dolasetron (Anzemet) for acute pancreatitis in dogs, 562-563 for feline cholangitis, 617, 617b for feline pancreatitis, 567t

Index Dolasetron (Anzemet) (Continued) for hepatic lipidosis, 612 for vomiting with acute renal failure, 870 Domperidone, action and use of, for motility disorders, 516-518 Dopamine adverse effects of, with metoclopramide, 34t-35t drug incompatibilities with, 33t for cardiogenic shock, 783 for heart failure, in dogs, 768-770 receptor activities of, 15t use and dosage of, 15t, 16 use of with shock, 22-23 Doppler, fetal monitoring with, 950, 950f Doramectin for demodicosis, 434, e183 for dermatologic disorders, e178, e180 for sarcoptic mange, e182 toxicity of, 145-146 Dorsal laminectomy for intervertebral disk disease, 1073-1074 for lumbosacral stenosis, 1107-1108 Dorzolamide for canine glaucoma, 1173-1174, 1173b, e381 for feline glaucoma, 1179, e381 Dorzolamide/timolol for canine glaucoma, 1173-1174 for feline glaucoma, 1179 Double-outlet right ventricle, prevalence of, in cats, 757t Doxapram, use of, to evaluate laryngeal function, 660 Doxepin for behavior-related dermatoses, 482-483, 483t toxicity of, use of IV lipid emulsion therapy for, 106 Doxil, for hemangiosarcoma, 395-396 Doxorubicin associated hepatotoxicity, 581b cardiac toxicity from chemotherapeutic drugs, 332 causing adverse skin reactions, 488t extravasation and tissue sloughing from, 333 for feline gastrointestinal lymphoma, 547-548, 548t for hemangiosarcoma, 395-396 inhalational, 396 for insulinomas, e132-e133 for mammary cancer, 377, 379-380 for multiple myeloma, 386 for osteosarcoma, 391t hypersensitivity reactions to, 333 induced cardiomyopathy, 795 pegylated liposomal, e139-e140, e140t rescue chemotherapy for canine lymphoma, 381-383 Doxycycline associated hepatotoxicity, 570b for Bartonella spp., 1265-1266, 1266t for Borrelia burgdorferi, 1273-1274 for brucellosis, 972, e404

Doxycycline (Continued) for canine bronchial diseases, 670-672 for canine heartworm disease, 833, 834f, 835 for canine respiratory infection complex, 633-634 for causes of thrombocytopenia, 281t-282t for ehrlichiosis, 1293-1294 for feline heartworm disease, 830 for feline tear film disorders, e387 for feline upper respiratory infection, 630, 631t for hemotropic mycoplasmosis, e401 for infectious polyarthritis, 1225 for infective endocarditis, e294t, e297 for keratomalacia, 1151 for leptospirosis, 1289 for lower respiratory tract infection, 1220t, 1222 for lymphoplasmacytic rhinitis, in dogs, 641 for methicillin-resistant Staphylococcal skin infections, 444 for Mycoplasma spp., 973 for nontuberculous cutaneous granulomas, 448t for pneumonia, 682t for rhinosinusitis in cats, 646 for sebaceous adenitis, e211 for superficial bacterial folliculitis, 438t for upper respiratory tract infection, 1220t, 1222 for urinary tract infections, 1220t, 1221 target parasites and dosage of, 1335-1337 Drainage, techniques for septic abdomen, e13-e20 Drawer motion, 82 Drug dosage(s) formula for adjustment of, with renal failure, 36 table of common, 1307-1334 Drug extravasation, with chemotherapeutic drugs, 333 Drug incompatibilities, 32-38 intravenous administered, 33t Drug interactions, 32-38, 34t-35t Drug labeling, e40-e41 Drug preparation equipment, for hazardous drugs, 326-327 Drug reaction(s) adverse, 32-38, 34t-35t effects of glucocorticoid, 461-462 causing conjunctivitis, 1140 cutaneous, 487-490, 488t Drug therapy(ies) adverse effects of chemotherapy, 330 analgesia, 59-63, 62t antibiotic for enteropathies, 518-522 antiinflammatory potency of systemic glucocorticoids, 461t approved vs. unapproved, e37 associated liver disease, 570b, 575-579 causing alkaline phosphatase elevations, e243-e244, e245b causing blood dyscrasias, e160, e162

1361

Drug therapy(ies) (Continued) causing hyperlipidemia, 262t causing pregnancy loss, 1010 causing renal failure, e30b during CPR, 28-30 effect of topical formulation on glucocorticoid potency, 460f effect of vehicle/formulation on potency of topical glucocorticoids, 460f effect on gastric emptying, 514, 516 effects on thyroid function, 181t for behavior-related dermatoses, 482-485 for causes of thrombocytopenia, 281t-282t for hypothyroidism, 182 for respiratory diseases, 622-628 for treatment of common parasites, 1335-1337 for treatment of obesity, 259-260 for treatment of toxicities, 101-105 hypertension from, 727t immunosuppressive, 268-274 in nutritional support, 43 incompatibilities of, 32-38 lists of approved, extralabel and unapproved, e54-e68 mineralocorticoid activity of systemic glucocorticoids, 461t new maintenance anticonvulsant, 1054-1057 premedication and sedation with cardiovascular dysfunction, 64-65, 65t reporting adverse events from, e35-e43 systemic antimicrobial for otitis, 466-467 to treat animal toxicosis, e56t topical antimicrobials for otitis, 462-465 toxic exposures to, 95t, 96 transdermal (See Transdermal medication(s)) update on masitinib, 360-362 update on toceranib (Palladia), 358-360 use of IV lipid emulsion therapy for toxicities, 106-109 with antacids, 505-508 with topical glucocorticoid for otitis, 460, 460f, 460t Drug toxicity. See also Ototoxicity from antidepressants and anxiolytics, 112-114 from human drugs of abuse, 109-112 over-the-counter, 115-120 Drug(s) compatibility with parenteral nutrition products, 40 formulary of common, 1307-1334 storage, for hazardous drugs, 327 Drug-herb interactions, 127 Drugs of abuse, human, toxicity from, 109-112 and legal considerations, e51 Dry eye. See Keratoconjunctivitis sicca (KCS)

1362

Index

Drying agents, for ears, 472t, 473 Duloxetine, for urinary incontinence disorders, 916t, 917 Duodenal ulceration, associated with Helicobacter spp., 509 Duodenum, deformities with brachycephalic airway obstruction syndrome, 650t Dust mite hypersensitivity and control, e197-e199 Dynamic left ventricular outflow tract obstruction, 805, 806t, 807-808 Dysautonomia causing megaesophagus, e227 effect on gastric emptying, 514, 516 Dysbiosis associated inflammatory bowel disease, 521 of colon, 551 with protein-losing enteropathy, 544 Dyschezia, 550 Dyscrasias of bone marrow, 314-318 Dysfibrinogenemia, coagulation factor abnormalities with, 288t, 289 Dysgranulopoiesis, 314 Dysmyelopoiesis, e163-e164 Dysphagia from gastroesophageal reflux, 501 oropharyngeal, 495-500, e259-e262 causes of, 496b clinical signs of, 496b, e260t history associated with, 497b treatment of, e261-e262 with feline caudal stomatitis, 492 Dyspnea, 45. See also Acute respiratory distress syndrome (ARDS) drugs used with, 47t from acute respiratory distress syndrome, 48-51 Dystocia fetal causes of, 953 management of, 948-956 obstetrical monitoring equipment for, 950f, 953f-954f E EACA. See Aminocaproic acid Ear mites, diagnosis and treatment of, 430-431, 431t. See also Otodectes cynotis Ear(s). See also Otitis antiseptics, 473-474 cleaning solutions, 472-474, 472t ototoxicity of, 474 debris removal agents for, 472-473, 472t flushing techniques for, 471-474 normalizing agents for, 473 Easter lily toxicity, 99, e34 Ebstein’s anomaly, e332 Ecchymosis from adverse drug reactions, 488t with thrombocytopenia, 283 Echinocandins, use and protocols for, 1238 Echinococcus granulosa, common symptoms and syndromes caused by, 1214t-1215t

Echinococcus multilocularis, common symptoms and syndromes caused by, 1214t-1215t Echinococcus spp. infection causing infection in humans, 1247 drugs targeting, 1335-1337 in raw meat diets, 1240b, 1241 Echocardiography for staging heart disease in dogs, 776 with arrhythmogenic right ventricular cardiomyopathy, in cats, e278e279, e278f with dilated cardiomyopathy in dogs, 796-797 with feline heartworm disease, 828-829, 828f with feline myocardial disease, 804-810 with hemangiosarcoma, 393-394 with infective endocarditis, e295 with mitral valve dysplasia, e300-e302, e301f with patent ductus arteriosus, e309-e310, e312f with pericardial effusion, 818-819, 818f-819f with pulmonary hypertension, 711, 712f-713f, 713-714 with pulmonic stenosis, e315-e317, e315f-e316f with subaortic stenosis, e321, e321f with tricuspid valve dysplasia, e333-e334, e334f with valvular heart disease, 788-790, 789f with ventricular septal defect, e337-e338 Eclampsia. See Puerperal tetany Ecology Works Anti-Allergen Solution, for dust mite control, e199 Ectoparasites drugs used to treat common, 1335-1337 treatment of, 428-432 Ectopic ACTH syndrome, 230-232, 231f Ectopic cilia, causing frictional irritant conjunctivitis, 1140 Ectopic ureters cystoscopic-guided laser ablation for, 890-891, 891f ultrasound findings with, 841-842 Ectropion, 1155, e369 Edrophonium chloride challenge test, for myasthenia gravis, 1109 Effusions malignant, 341-344 pleural, 691-700 (See also Pleural effusion) Ehrlichia canis causing nervous system signs, 1212 causing nonregenerative anemia, 1217, e161, e161b causing polyarthritis, 1227-1228 causing renal infections, 1212 common symptoms and syndromes caused by, 1214t immunosuppressive therapy for, 1232-1233

Ehrlichia ewingii causing polyarthritis, 1228 common symptoms and syndromes caused by, 1214t Ehrlichiosis as cause of thrombocytopenia, 281t-282t, 283 canine monocytotropic, 1292-1294 causing uveitis in dogs, 1164b feline monocytotropic, 1294 post-treatment monitoring of, 1293-1294 prevention of, 1294 Eicosapentaenoic acid(s) for heart disease, 722-723 requirements during pregnancy and lactation, 963 Eisenmenger’s physiology, e339 Ejaculation normal antegrade, e351 retrograde aspermia/oligospermia caused by, e350-e353 clinical examples of, e352-e353 spinal reflexes occurring during, e351t Elbow luxation, 80 Elbow trauma in dogs, 81 Electrical-mechanical dissociation, 29f Electrocardiography common arrest rhythms, 29f during CPR, 28 for evaluation of causes of pulmonary hypertension, 713 with arrhythmias in cats, 749, 750f-751f with arrhythmogenic right ventricular cardiomyopathy in cats, e278 in dogs, 801-802 with atrioventricular block, third degree, 735f with baroreceptor reflex, 732f with cardiac pacemaker, e283f-e284f with congenital heart disease, 758-759 with dilated cardiomyopathy in dogs, 797 with mitral valve dysplasia, e300 with myocarditis, e304 with pericardial effusion, 818 with pulmonic stenosis, e315 with sick sinus syndrome, 733f with supraventricular tachyarrhythmias, 739-741, 740f with transvenous pacing, e23-e24, e24f-e25f with tricuspid valve dysplasia, e332-e333, e333f with valvular heart disease, 788 with ventricular arrhythmias, 746f Electrodiagnostic testing, for evaluation of dysphagia, 498, e260-e261 Electrolyte(s) approach to low magnesium, 248-253 approach to low potassium, 248-253 in parenteral nutrition products, 40 Electromyography (EMG), for degenerative myelopathy, 1077

Index Electroretinography, 1133 with progressive retinal atrophy, 1188-1190 Elimination diets, for adverse food reactions, 422-424 Elongated soft palate, and brachycephalic airway obstruction syndrome, 649-653, 650t, 652f Embolism cardiogenic, 812-813 from blood transfusion reaction, 313 Embolization, for malignant obstructions, 348 Embryonic structure, identification by ultrasonography for pregnancy diagnosis, 946t Emergency care gastric dilation-volvulus in, e13-e20 of hypertensive crisis, 730 of open fractures, 83-86 of ophthalmic disorders, e377-e384 of pneumothorax, 700-704 of the eye, e377-e384 pacing in, e21-e28 stabilization of patient with respiratory distress, 44-48 with acute hypoadrenocorticism, 235-236 with laryngeal paralysis, 660 with orthopedic trauma, 80-83 wound care and vacuum-assisted wound closure, 87-90 Emetic drugs for toxin ingestions, 105, 113 to avoid with anesthesia, 68 Emodepside, target parasites of, 1335-1337 Emodepside-praziquantel, target parasites of, 1335-1337 Empiric antimicrobial therapy, 1219-1223 Enalapril (Enacard, Vasotec) adverse effects of, 34t-35t, 766-768 for asymptomatic heart disease, 765-766, 790 for cough from bronchial compression, 782 for feline cardiomyopathy, 809 for glomerular disease, 854-855 for heart failure, in dogs, 764t-765t, 766-768, 777-779 balancing renal function and, 779 for hypertension, 729 for hyperthyroid cats, e103t, e105 for occult dilated cardiomyopathy, in dogs, 797-798 Encapsulated sodium nitrite, for population control, 142-144 Encephalomyelopathy, 1052-1053 End-tidal carbon dioxide (ETCO2), during CPR, 28 Endocardial cushion defects. See Atrioventricular septal defect Endocardial fibroelastosis, prevalence of, in cats, 757t Endocarditis clinical signs of, e292-e293 diagnosis of, e293-e296, e296b

Endocarditis (Continued) differential diagnosis for, e296 infective, e291-e299 pathophysiology of, e292 prognosis for, e298 pulmonary thromboembolism associated with, 705 treatment of, e294t with heart failure, e292, e297-e298 Endocrine causes of hepatobiliary enzyme elevations, 570b disruption, from reproductive toxins, 1028 Endocrine disease(s) acromegaly, feline, 216-221 bilaterally symmetric alopecia, in dogs, 164-166, 165b causing hyperlipidemia, 262t critical-illness related corticosteroid insufficiency, 174-178 diabetes mellitus alternatives to insulin therapy, in cats, e135-e138, e136t and diet, 199-204 complicated, e76-e83 in dogs, 189-193 monitoring of, 193-199 ectopic ACTH syndrome, 230-232 feline idiopathic hypercalcemia, 242-248 feline primary hyperaldosteronism, 238-242 food-dependent hypercortisolism, 230-232 hyperadrenocorticism occult, 221-224 with large pituitary tumor, e88-e91 hyperparathyroidism, e69-e73 hypersomatotropism, feline, 216-221 hyperthyroidism and renal failure, 185-189 medical treatment of, e102-e106 nutritional management of, e107-e112 radioiodine therapy for, e112-e122 hypoadrenocorticism, 233-237 hypoparathyroidism, e122-e129 hypothyroidism, 178-185 imaging for diagnosis of, 167-174 insulinoma, treatment of, in dogs cats and ferrets, e130-e134 interpretation of results for adrenal and thyroid disease, e97-e102 polyglandular, with hypothyroidism, e87-e88 Endocrine pancreatic insufficiency, insulin resistance with, 206b Endometritis, use of renourethroscope for diagnosis of, 943 Endoscopy brush cytology with, 509-510, 510f cervical, 938 for esophagitis and strictures, e238e239, e239f, e240 for feline gastrointestinal lymphoma, 547 for gastric ulcerations, e254

1363

Endoscopy (Continued) for gastroesophageal reflux, 502 for gastrointestinal disorder in brachycephalics, 649-651 for Helicobacter spp., 508-511 for nasopharyngeal disorders, 654 for protein-losing enteropathy, 541-542 interventional strategies for urinary diseases, 884-892 transcervical insemination, 940-944, 941f, 941t uterine, 937-938 vaginal, 934, 936-937 Endothelial dystrophy, 1153 Endotoxemia, as cause of thrombocytopenia, 281t-282t Endotracheal wash, for diagnosis of pneumonia, 686 Energy requirement(s) calculators, 259 during pregnancy and lactation, 961-963, 962f English setter(s), direct mutation tests for, 1018t-1020t English springer spaniel(s) atrial standstill in, 734 mitochondrial encephalopathy in, 1048-1051, 1049t, 1051t Enilconazole for nasal aspergillosis, 638 topical rinse, for dermatophytosis, 450t Enophthalmos, from orbital diseases, 1197, 1198b, 1200 Enoxaparin, 707, 813 as anticoagulant therapy, for autoimmune hemolytic anemia, 277t for arterial thromboembolism, 815 Enrofloxacin (Baytril) causing retinopathy, e383 drug interactions with, 35t, 677 for Bartonella spp., 1266t for brucellosis, 972, e404 for canine bronchial diseases, 671 for canine colitis, 551b, 553 for feline upper respiratory infection, 631t for hemotropic mycoplasmosis, e401 for infective endocarditis, e294t, e297 for lower respiratory tract infection(s), 1220t for otitis systemic, 466t topical, 464t for pneumonia, 682t, 683 for septicemia, 1220t, 1223 for superficial bacterial folliculitis, 438, 438t for therapy with open fractures, 84-85 retinopathy, 1195 Enteral nutrition, 42-43 for acute pancreatitis in cats, 567-568 for acute pancreatitis in dogs, 563-564 for hepatic lipidosis, 611-612 for patients with cancer, 353

1364

Index

Enteritis, effect on gastric emptying, 514, 516 Enterococcus faecium, as probiotic, 527 Enterococcus spp. in raw meat diets, 1240, 1240b in tube feeds, e19 Enterohepatic recirculation, of toxins, 105 Enteropathies, antibiotic-responsive, 518-522, 519b, 519f Enteropathogenic bacterial infection, 520-521 Entropion, 1155, e369 causing frictional irritant conjunctivitis, 1140 Enucleation for feline glaucoma, 1180 of glaucoma eye, 1175-1176 Environment(al) agents associated with hepatotoxicity, 570b associated hepatotoxicity, 581b cleaner for dermatophytosis, 450b control of dermatophytosis, 452-454 control of giardiasis, 532 disinfection from Staphylococcal sp., 455-457, 456t enrichment for domestic cats, 909-914 influences on health of cats, 910-913 Enzyme-linked immunosorbent assay (ELISA) for canine parvovirus, 533-534 for lagenidiosis, e415 for pythiosis, e413 for sarcoptic mange, 428 Eosinophilia, with feline heartworm disease, 826 Eosinophilic granuloma complex, with flea allergies, 424-425 Eosinophilic keratitis, 1157t, 1158-1159, 1159f indications for surgery with, 1161t Eosinophilic meningoencephalitis, 1063-1066 Eosinophilic pulmonary diseases, 688-691, 689f Ephedra toxicity, 123 Ephedrine, for urinary incontinence disorders, 915, 916t Epibulbar melanoma, in cats, 1207-1208 Epichlorohydrin toxicity, 1027b Epidermal hyperplasia, use of interferons for, e200-e201 Epidermoloytic ichthyosis, 475 Epidural analgesia, 61 Epilepsy new anticonvulsants for, 1054-1057 treatment of cluster seizures and status epilepticus, 1058-1063 Epinephrine drug incompatibilities with, 33t for CPR, 28-29 for respiratory diseases, 623 receptor activities of, 15t use and dosage of, 15-16, 15t Epiphora, e374-e377 causes of, e374-e376, e375b, e375f Epirubicin, extravasation and tissue sloughing from, 333

Episcleritis, 1140-1141, 1141f Episiotomy for surgical approach to the vagina, 974-976, 975f with dystocia, 951 Epistaxis from nasal neoplasia in dogs, 641 from rhinitis in dogs, 636 infectious causes of, 1216 Epithelial cell tumors, ovarian, 1024-1025 Epithelial inclusion cyst, 1153 Epithelioma, 1202 Eplerenone, 763-765 Eprinomectin for dermatologic disorders, e178 toxicity of, 145-146 Epsiprantel, target parasites of, 1335-1337 Epulis, 363, 365 Erection. See also Paraphimosis; Priapism physiology of, e354, e355f Ergocalciferol, supplement for hypocalcemia, e127-e128, e128, e128t Erythema, from methimazole, e103-e104 Erythema multiforme causing blepharitis, e367 from drug reactions, 488 use of cyclosporine for, 410b Erythromycin action and use of, for motility disorders, 517t associated hepatotoxicity, 581b for pyoderma, 1220t, 1221-1222 for superficial bacterial folliculitis, 438t topical, for feline ocular herpesvirus 1, 1158 Erythropoietin for anemia, from chronic kidney disease, 862-863 for feline retrovirus infections, 1280t-1281t Escherichia coli causing diarrhea, 519 causing endocarditis, e293-e294, e294t causing oligospermia, e350 causing persistent urinary tract infection, 880-883 causing pneumonia, 681, 682t causing pregnancy loss, 1005t, 1006, 1008 causing prostatitis, 1013 causing pyometra, 967-968 causing septic mastitis, 959 role of with canine colitis, 553 with feline cholangitis, 615 with feline pancreatitis, 568 uropathogenic, 880 Escherichia spp., in raw meat diets, 1240, 1240b Escitalopram, toxicity of, 113 Esmolol for heart failure with arrhythmias, in dogs, 771 for supraventricular tachyarrhythmias in dogs, 742t

Esomeprazole action and use of, 505-506 toxicity from, 118 Esophageal pH monitoring, 502-503 phase of swallowing, 495-496 Esophageal dilation, with myasthenia gravis, 1109-1110 Esophageal perforation, 501-502 Esophageal stenting for malignant obstructions, 347 for strictures, e240-e241, e241f Esophageal strictures, e237-e242, e238, e238-e239, e239f dilation of, 503-504, e240 prognosis with, e241 with gastroesophageal reflux, 503-504 Esophagitis causes of, e237 clinical signs of, e237-e238 diagnosis and treatment of, e237-e242 diagnosis of, e238-e239 from gastroesophageal reflux, 501-504 treatment of, e239-e241 use of sucralfate for, 507 with brachycephalic airway obstruction syndrome, 650t with megaesophagus, e229 Esophagostomy tube(s), for hepatic lipidosis, 611-612 Esophagram contrast, 501-502, e227 for evaluation of esophagitis and strictures, e238-e239, e238f Esophagus deformities with brachycephalic airway obstruction syndrome, 650t disorders of, e225b functional anatomy of, e224-e225 motility of, e237 Essential fatty acids. See Fatty acids Essential oils, toxicity from, 125-127, 126t Essential renal hematuria, 885-886, 886f Estradiol cypionate, for pregnancy termination, 992 Estriol, for urinary incontinence disorders, 915-916, 916t Estrogen concentration to detect ovarian remnant syndrome, 1001-1002 with pyometra, 967 with reproductive neoplasia, 1024-1025 myelotoxicity and and sertoli cell tumors, 1022-1023 therapy and risk of pyometra, 967 therapy for urinary incontinence disorders, 915-916, 916t therapy for vaginitis, 973 Estrogen-receptor-positive breast cancer, 377, 379t Estrus, 931-932 drugs for pregnancy termination during, 991-992 role of, in mammary cancer, 375 suppression, 984-989

Index Eszopiclone toxicity, 113-114 Ethanol for ethylene glycol toxicity, 153 toxicity, 147 Ethanol ablation, ultrasound-guided, for treatment of hyperparathyroidism, e72 Ethanolamine toxicity, 118-119 Ethmoidal turbinate, deformities with brachycephalic airway obstruction syndrome, 650t Ethyl lactate, for pyoderma, 441-442, 441t Ethylene dibromide toxicity, 1027b Ethylene dichloride toxicity, 1027b Ethylene glycol toxicity, 151-153, e30-e31 hepatic metabolism of, 152f metabolism of, e30-e31 Ethylene oxide toxicity, 1027b Ethylenediamine toxicity, 118-119 Ethylenediaminetetraacetic acid (EDTA), for keratomalacia, 1151 Etodolac toxicity, 116-117 Etomidate effect on shock, 25 for anesthetic induction in critical patients, 65 Etoposide for hemangiosarcoma, 396 hypersensitivity reactions to, 333 Etretinate, for sebaceous adenitis, e211 Eucoleus aerophilus, e275 Eucoleus boehmi, e269-e270 causing nasal discharge, 636b Eutrombicula alfreddugesi, 431-432 Evening primrose oil, for sebaceous adenitis, e210-e211 Everolimus, use of, for immunosuppression, 271-272 Everted laryngeal ventricles, and brachycephalic airway obstruction syndrome, 650t, 651-652 Excreta, handling associated with hazardous drugs, 328-329 Exenatide, for diabetes mellitus, in cats, e136t Exercise causing syncope, e329 for degenerative myelopathy, 10781080, 1079f recommendations postop disk herniation, e361b recommendations with degenerative myelopathy, e362b rehabilitation, and physical therapy for neurologic disorders, e357-e362 role of, with obesity, 259 Exercise energy requirements, 259 Exercise induced collapse, direct mutation test for, 1018t-1020t Exocrine pancreatic disorders, feline, 565-568 Exocrine pancreatic insufficiency (EPI) diagnosis and treatment of, 558-560 dietary modification for, 559-560 enzyme replacement therapy for, 559 laboratory testing for, 556-557

Exocrine pancreatic neoplasia, 557 Exophthalmos, from orbital diseases, 1197-1200, 1198b Expectorants, for respiratory diseases, 627 External skeletal fixation, with open fractures, 86 Extracorporeal shockwave lithotripsy, 885 Extractions. See Dental extractions Extrahepatic biliary tract disease, 602-605 Extralabel drug(s) approved, e59t-e61t not approved for use in animals, e61t-e66t unapproved, e67t use of, e57 Extramedullary plasmacytoma, 386-387 Extranasal sinus disorders, causing rhinitis in dogs, 636b Extraocular muscle myositis, 1114-1115 Extraocular polymyositis, 1199 Extravasation of chemotherapeutic drugs, 333 Exudate(s), from malignant effusions, 341-344 Eye diseases of the periocular skin, e363-e369 drops and tear substitutes for, 1146t emergencies, e377-e384 orbital anatomy, 1197 Eyelid dermatitis of, e363-e369 diseases of the, e363-e369 diseases secondary to abnormalities of the, 1155 ectropion of, e369 entropion of, e369 laceration, e378-e379, e379f pigment changes of, e367-e368 tumors in cats, 1207 in dogs, 1201-1206, e368 F Facial excoriation, from methimazole, e103-e104 Facial symmetry, assessment of with neuro-ophthalmic exam, e390-e392 Factor II deficiency, coagulation factor abnormalities with, 288t, 289 Factor IX activity, in hypercoagulable states, 298f deficiency, coagulation factor abnormalities with, 288t, 289 Factor V deficiency, coagulation factor abnormalities with, 288t Factor VII deficiency coagulation factor abnormalities with, 288t, 289 direct mutation test for, 1018t-1020t Factor VIII activity, in hypercoagulable states, 298f deficiency, coagulation factor abnormalities with, 288t, 289

1365

Factor X deficiency, coagulation factor abnormalities with, 288t Factor XI activity, in hypercoagulable states, 298f deficiency coagulation factor abnormalities with, 288t, 289 direct mutation test for, 1018t-1020t Factor XII deficiency, coagulation factor abnormalities with, 288t, 289 Fading puppy, from ventricular septal defect, e336-e337 False pregnancy. See Pseudocyesis Famciclovir, for feline tear film problems, e386 Familial nephropathy, direct mutation test for, 1018t-1020t Famotidine (Pepcid) for feline pancreatitis, 567t for gastric ulceration, e254 for hepatic lipidosis, 612 for vomiting with acute renal failure, 870 potency and use of, 505, 506b protocol for helicobacter spp., 511t toxicity of, 119 Fanconi syndrome, e34 Fanconi’s injury, 580-581 Fat, dietary for diabetes mellitus management, 200-201, 201t, 203, 204t recommendations for, with heart disease, 722-723 Fat overload syndrome, 108 Fatty acids for atopic dermatitis, 406 for sebaceous adenitis, e210-e211 requirements during pregnancy and lactation, 963 role of, in development of feline hepatic lipidosis, 609 topical, 420t, 421 Febentel for Giardia spp., 530t target parasites of, 1335-1337 Febentel/praziquantel/pyrantel, target parasites of, 1335-1337 Febreze, toxic exposure to, 98 Febuxostat, for dissolution of urate stones, 902 Fecal chymotrypsin, 556 contamination from pets to humans causing disease, 1245t, 1246-1247 for detection of bronchopulmonary parasites, e271-e276 oocysts from toxoplasmosis, 1296 pancreatic elastase-1, 556, 559 proteolytic activity (FPA), 556 trypsin, 556 Fecal culture, 519 Feeding protocol during pregnancy and lactation, 965-966 for hepatic lipidosis, 612-613 Feeding tube(s), 42-43 for acute pancreatitis in dogs, 563-564 for patients with cancer, 353

1366

Index

Felbamate associated hepatotoxicity, 578 for seizures, 1055-1056 Felicola subrostratus, 429t Feline acromegaly, 216-221 Feline allergic dermatitis, cyclosporine for, 408-409 Feline asthma. See Asthma Feline bartonellosis, 1267-1271. See also Bartonellosis Feline calicivirus causing pregnancy loss, 1009-1010 causing skin lesions, e194-e195 common symptoms and syndromes caused by, 1215t immunotherapy for, 1232 role in feline stomatitis, 493-494 upper respiratory infection from, 629, 1217-1218 clinical signs of, 630t use of interferons for, e201 Feline cholangitis, 614-619 Feline corneal disease, 1156-1161 Feline coronavirus, common symptoms and syndromes caused by, 1215t Feline cowpox virus, e196 Feline eosinophilic keratitis, cyclosporine for, 269-271 Feline exocrine pancreatic disorders, 565-568 Feline facial pheromone, for behaviorrelated dermatoses, 485 Feline foamy virus (FeFV), management of, 1275-1283 Feline granulocytic anaplasmosis, as cause of thrombocytopenia, 281t-282t Feline hemotropic mycoplasmas, e398-e401 Feline herpesvirus 1 causing blepharitis, e364-e365 causing keratoconjunctivitis, 1156-1158 causing pregnancy loss, 1006, 1009-1010 causing rhinitis, 646-647 causing skin lesions, e194, e364-e365 topical immunomodulators for, e220 causing upper respiratory infection, 629, 630t, 1217-1218 common symptoms and syndromes caused by, 1215t immunotherapy for, 1232 Feline hypersomatotropism, 216-221, 217f Feline immunodeficiency virus (FIV) causing nonregenerative anemia, e161b, e162 causing pregnancy loss, 1005t, 1006, 1009 causing skin lesions, e195 causing thrombocytopenia, 281t-282t causing uveitis, 1168, 1177 common symptoms and syndromes caused by, 1215t immunotherapy for, 1232 in multicat households, 1276 lymphocytosis associated with, 305

Feline immunodeficiency virus (FIV) (Continued) management of, 1275-1283, 1277b, 1279t-1281t vaccination for, 1276 vaccination of, 1276-1277 Feline infectious peritonitis (FIP), 1303-1306 as cause of thrombocytopenia, 281t-282t causing feline uveitis, 1167-1168 causing pleural effusion, 695, 1216 causing pregnancy loss, 1010 diagnosis of, 1304 rational use of glucocorticoids for, 1300 treatment of, 1305t Feline interferon. See also under Interferon for cancer immunotherapy, 336t for feline infectious peritonitis, 1305-1306, 1305t for feline retrovirus infections, 1280t-1281t, 1282 for infectious disease immune therapeutics, 1230t Feline interstitial cystitis (FIC). See Feline lower urinary tract disease (FLUTD) Feline leprosy syndrome, 445-448, 447f, 448t Feline leukemia virus (FeLV) association with lymphoma, 545 causing anemia, 1217 causing feline uveitis, 1168 causing lymphocytosis, 305 causing nonregenerative anemia, e161b, e162 causing pregnancy loss, 1006, 1009 causing skin lesions, e195 causing thrombocytopenia, 281-283, 281t-282t causing uveitis, 1177 common symptoms and syndromes caused by, 1215t immunotherapy for, 1232 in multicat households, 1276 management of, 1275-1283, 1278b, 1279t-1281t vaccination for, 1276 vaccination of, 1276-1277 vaccine-associated sarcomas from, 1253 Feline lower urinary tract disease (FLUTD) environmental enrichment with, 909-914 indications for perineal urethrostomy with, 925 new treatments for, 925 Feline mammary cancer, 378-380 Feline mononuclear ehrlichiosis, as cause of thrombocytopenia, 281t-282t Feline myocardial disease, 804-810, 806t Feline panleukopenia virus causing pregnancy loss, 1005t, 1006, 1009 common symptoms and syndromes caused by, 1215t Feline papillomavirus, causing skin lesions, e195-e196

Feline posttraumatic sarcoma, 1209 Feline primary hyperaldosteronism, 238-242, 240t Feline retrovirus-infections, management of, 1275-1283 Feline sarcoid, e196 Feline scabies, diagnosis and treatment of, 429-430 Feline syncytium-forming virus. See Feline foamy virus (FeFV) Feline triaditis syndrome, 615-616 Feline upper respiratory tract infection, 629-632 causes of, 629, 630t causing pregnancy loss, 1009-1010 clinical signs of, 629 diagnosis of, 630 immunotherapy for, 1232 risk factors for, 629 treatment of, 630, 631t Feline urinary bladder cancer, 374 Feline uveitis, diagnosis and treatment of, 1166-1170, 1169t Feline viral skin disease, e194-e197 Feline(s) blood groups, 311 breed blood types, e145t breed predispositions, with diabetes mellitus, 208-209 environmental enrichment for domestic, 909-914 outbreaks with dermatophytosis in multiple, 452-454 use of glucocorticoids in, 416t Femur trauma in dogs, 82 Fenbendazole for canine colitis, 551b, 552 for Giardia spp., 530t for lung worms, e274-e275, e276 for nasal nematodes, 637, e270 target parasites and dosage of, 1335-1337 Fenoldopam, for oliguria with acute renal failure, 869-870, 869t Fentanyl CRI, 62t for feline thromboembolism, 810 for the critical patient, 59, 62t for thromboembolism pain, 810, 814 toxicity, 111 transdermal, 61-63, 62t with diazepam, for anesthetic induction in critical patients, 66 with maintenance anesthetic, 66, 67t Ferguson reflex, 949 Ferret(s) hyperadrenocorticism in, e94-e97 population control for, 142-144 treatment of insulinoma in, e130-e134 Fertilization period, 930, 931f, 931t Fertilizer toxicity, 96, 130 Fetal complications during pregnancy, 947-948 death, 1003-1011, e85 disorders, 1011 distress, 950 monitoring, 949-951

Index Fetus, reproductive toxins targeting the, 1026-1028 Fever, vs. heat-induced illness, 71-72 Fexofenadine hydrochloride toxicity, 118-119 Fiber dietary requirements for, with diabetes mellitus, 200 diets for feline idiopathic hypercalcemia, 244-246 supplementation with Giardia spp. infections, 531 Fibers, as respiratory toxicants, e46-e47 Fibrates, for hyperlipidemia, 265 Fibrin, abnormalities with disseminated intravascular disorders, 292, 293f Fibrin degradation products (FDP), in disseminated intravascular coagulation, 294t Fibrinogen activity, in hypercoagulable states, 298, 298f in disseminated intravascular coagulation, 294t Fibrinogen deficiency, coagulation factor abnormalities with, 288t Fibrinolysis, with disseminated intravascular disorders, 292, 293f Fibrocartilaginous embolism, 1123-1125, 1123f diagnosis of, 1124-1125 prognosis with, 1125 rehabilitation considerations with, e360 treatment of, 1125 vs. acute disk disease, 1124 Fibromatous epulides, 363 Fibropapilloma, e196 Fibrosarcoma eyelid, 1203f immunotherapy for, 336t nasal, radiation therapy for, 338-340 oral, 365 Filaroides hirthi, as bronchopulmonary parasite, e272-e273 Filaroides milksi, e273 Filgrastim, for feline retrovirus infections, 1280t-1281t Finasteride (Proscar) for alopecia X, 479 for benign prostatic hypertrophy, 1013 for prostatic abscess, 1014-1015 Fine-needle aspiration for cytology specimen collection, e153-e154, e154b of acral lick dermatitis lesions, e174 of bladder tumors, 371 of kidney, use of ultrasound for, 841, 844 of liver, 574 of mammary masses, 376, 378 of masses, client questions about, 319 of perianal mass, 367-368 Finnoff transilluminator, 1128-1129 Fipronil (Frontline), 426t for cheyletiellosis, 430t for Otodectes infestation, 431t for pediculosis, 429t

Fipronil (Frontline) (Continued) for sarcoptic and notoedric mange, 429t target parasites of, 1335-1337 toxicity of, 140-141 Fipronil/amitraz/s-methoprene, target parasites of, 1335-1337 Fipronil/cyphenothrin, target parasites of, 1335-1337 Fipronil/methoprene/amitraz, 426t Firocoxib adverse effects of, 60 dosage for, 62t Fish oils. See also Omega-3 fatty acids for asymptomatic heart disease, 766 for heart disease, 722-723, 777, 781 for hyperlipidemia, 265 Fistulagram, for wound tracts, 87-88 Flail chest, 703 Flatulence, e247-e251 assessment of patients with, e248 feeding plans for patients with, e248-e249, e249b normal production of, e247-e248, e248t Flatus, e247 Flaxseed, for idiopathic vacuolar hepatopathy, 607-608 Flea biology, 424 bite hypersensitivity, 403 infestation, use of avermectins for, e182-e183 transmission of disease by, from pets to humans, 1248 Flea allergy dermatitis, 424-425 flea control for, 424-427 with acral lick dermatitis, e176 Flea control products, 1335-1337 and risk of urinary bladder cancer, 370 drug reactions from, 489 for cats, 426t for dogs, 426t formulations of, dosage for and target parasites of, 1335-1337 toxicity of, 135-141 protocols, 427 strategies, 425-427 with flea allergy dermatitis, 424-427, 426t Flecainide for heart failure, in dogs, 764t-765t with arrhythmias, 771 toxicity of, use of IV lipid emulsion therapy for, 106 Flies, transmission of disease by, from pets to humans, 1248 Florida spots, 1153-1154 Flow cytometry, for evaluation of lymphocytosis, 302 Fluconazole associated hepatotoxicity, 576 for cryptococcosis, 656 for dermatophytosis, 451 for fungal rhinitis in cats, 647-648, 647t

1367

Fluconazole (Continued) for Malassezia spp. infections, e215, e215t for systemic mycoses causing feline uveitis, 1168 use of and protocols for, 1235t, 1236-1237 with cyclosporine, 408 Flucytosine for fungal rhinitis in cats, 647-648, 647t use and protocols for, 1235t, 1238 Fludrocortisone acetate (Florinef), for hypoadrenocorticism, 236-237 Fluid dynamics, 8, 9f, 9t Fluid therapy calculation of requirements for, 5 choice of, 2 colloid, 8-14 for shock, 21 with crystalloid, 13, e15-e16 composition of common, 3t crystalloid, 2-7 during CPR, 30 for acute hypoadrenocorticism, 235 for acute pancreatitis in dogs, 562 for acute renal failure, 868-869 for canine parvovirus, 534 for diabetic ketoacidosis, e81-e82, e82 for disseminated intravascular coagulation, 295 for feline pancreatitis, 566-567, 567t for gastric dilation-volvulus, e15-e17, e16t for heat-induced illness, 73 for hepatic lipidosis, 610-611 for prevention of hospital acquired kidney injury, 847-848 for seizure patients, 1061t for shock, 20-22 resuscitation goals of, 13 routes for, 7 with acute respiratory distress syndrome, 51 with cerebrovascular accidents (stroke), 1122 with nephrotic syndrome, 856 Flumazenil, 30 Flunisolide (AeroBid), inhaled, for respiratory diseases, 626, 626t Flunixin meglumine toxicity, e32-e33 Fluocinolone for otitis, 460 potency of, for otitis, 460t Fluorescein dye testing, 1132 for corneal ulcers, 1149 for mucin deficiency, 1155 Fluorocarbons toxicity, 1027b Fluorocytosine causing adverse skin reactions, 488t for fungal diseases, 1238 Fluoroquinolone(s) adverse effects of, 34t-35t causing adverse skin reactions, 488t causing fetal disorders, 1010 drug incompatibilities with, 33t drug interactions with, 35t for canine respiratory infection complex, 634

1368

Index

Fluoroquinolone(s) (Continued) for hemotropic mycoplasmosis, e401 for infective endocarditis, e297 for lower respiratory tract infection(s), 1220t, 1222 for musculoskeletal infections, 1220t, 1222-1223 for open fractures, 84-85 for pneumonia, 682t for Pseudomonas spp. otitis, 466t interaction with GI drugs, 37 Fluoroscopy for evaluation of esophagitis and strictures, e238-e239 for evaluation of esophagus, 496f, 497-498, 498f, e227-e228 for interventional strategies for urinary disease, 884-892 for placing temporary pacing, e23-e24, e25f for swallowing studies, 497-498, 501-502 Fluorouracil (5-FU) for mammary cancer, 377 toxicity of, 94 use in cats, 333 Fluoxetine HCl (Prozac) for behavior-related dermatoses, 483-484, 483t toxicity of, 113, 483-484 Flurbiprofen for canine uveitis, 1165t, 1184t for feline uveitis, 1169t, 1209-1210 use of, with glaucoma, 1177 Flutamide for benign prostatic hypertrophy, 1013 for hyperadrenocorticism in ferrets, e95 Fluticasone propionate (Flovent) for feline asthma, 679-680 for respiratory diseases, 626, 626t, 671 Follicular dysplasia, causing alopecia, in dogs, 165b Follicular neutrophilic dermatitis, from nonsteroidal anti-inflammatory drug(s), 489 Folliculitis canine bacterial, 165-166 superficial bacterial, 437-439 Fomepizole (4-MP) as antidote, 102t-104t, 154-155, e56t for ethylene glycol toxicity, 153 Food. See also Pet food poisoning bacteria associated hepatotoxicity, 581b probiotic and prebiotic additives in, 525 reporting adverse events of, e35-e43 toxic exposures to, 92t, 93-95, 95t toxicities with human, 147-150 Food allergy. See Atopic dermatitis Food and drug administration (FDA), reporting adverse events to, e35-e43 Food-dependent hypercortisolism, 230-232, 232f Foreign body(s), toxic exposures to, 92t Forelimb trauma in dogs, 80-81

Formaldehyde causing reproductive toxicity, 1027b respiratory irritant from, e46 Formalin, for tissue fixation, 322-324 Formamide toxicity, 1027b Foscarnet, for feline retrovirus infections, 1279, 1279t Fosfomycin, for persistent E. coli urinary tract infections, 881b, 883 Fracture(s) and orthopedic trauma in dogs, 80-83 of the os penis, 1031 open classification of, 83, 84t diagnosis and treatment of, 83-86 in dogs, 82-83 treatment protocol for, 84b, 85-86 orbital, 1200 Francisella tularensis, as cause of thrombocytopenia, 281t-282t French bulldog, granulomatous colitis in, 552-553 Fresh frozen plasma, 310 Fructosamine and insulin resistance, 205-206 for monitoring diabetes mellitus, 194 in dogs, 192 with feline hypersomatotropism and acromegaly, 219f FTY 720, use of, for immunosuppression, 273 Fucosidosis, direct mutation test for, 1018t-1020t Functional residual capacity, 44, 45f Fundic examination, 1131 Fungal culture, for dermatophytosis, 165 Fungal disease(s). See also Dermatophytosis as cause of thrombocytopenia, 281t-282t associated hepatotoxicity, 581b causing blepharitis, e363-e364 causing blindness, 1136 causing chorioretinitis, 1195-1196 causing myocarditis, e304t causing pneumonia, 1218 causing rhinitis in cats, 644, 647-648, 647t in dogs, 636b, 637-640, 639f causing uveitis, 1218 in cats, 1168 in dogs, 1164b common symptoms and syndromes caused by, 1214t immunotherapeutics for, 1230t with dermatophytosis, 449-451 Fur mite infestation in cats, 431 use of avermectins for, e182-e183 Furazolidone, target parasites and dosage of, 1335-1337 Furosemide (Lasix) adverse effects of, 34t-35t, 36-37, 763 for acute heart failure in cats, 808 in dogs, 783, 787t, 790-792 for acute respiratory distress syndrome, 51

Furosemide (Lasix) (Continued) for ascites, from liver disease, 591, 592f, e257-e258 for cough from bronchial compression, 782 for dilated cardiomyopathy, in dogs, 798-799 for feline cardiomyopathy, 806t, 808-809 for heart failure, in dogs, 762-763, 764t-765t, 777-779 for hydrocephalus, 1036 for oliguria with acute renal failure, 869, 869t for pulmonary hypertension, 714 for refractory heart failure, 781 interaction with potassium bromide, 34t-35t, 37 to promote ureterolith passage, 894 G Gabapentin dosage for, 62t for cervical spondylomyelopathy, 1095f for chronic neuropathic pain, 61 for craniocervical junction abnormalities, 1102 for priapism, e356-e357 for seizures, 1054-1055 Gait, assessment of with neuroophthalmic exam, e390-e392 Galactomannan, levels with feline nasal cryptococcosis, 644-645 Galactorrhea, from hypothyroidism, e85 Galactosidase, for flatulence, e250 Galega officinalis, as diabetes supplement, toxicity of, 125 Gallbladder. See also under Biliary anatomy, 602-603 cholecystitis, 603 cholelithiasis, 603-604 mucocele, 604-605, e221-e224, e222f hypertriglyceridemia-associated, 261 risk with hypothyroidism, e86 rupture, 603 stents of, 605 surgery, 604f-605f, 605 Gamma-glutamyl transferase (GGT), with hepatobiliary disease, 569-571 Ganciclovir, for feline ocular herpesvirus 1, 1158 Gapeworm, nasal, 656 Gaps and gradients, calculation of, with acid-base disorders, e2-e3, e3b Garage and automotive product toxicity, 95t, 96, 151-155, e30b Garden products toxicity, 130-132 Garlic toxicity, 98-99, 147-148 Gas(es), as respiratory toxicants, e46 Gasoline toxicity, 154-155 Gastric acid secretion, 505, e251-e252, e252f suppressants, 505-506 Gastric and intestinal motility disorders, diagnosis and treatment of, 513-518 Gastric brush cytology, 509-510, 510f

Index Gastric decompression, for gastric dilation-volvulus, e17-e18 Gastric dilatation-volvulus (GDV) diagnosis and treatment of, e13-e20 effect on gastric emptying after, 514 prognosis for, e14 Gastric Helicobacter spp., 508-513 Gastric stasis, with brachycephalic airway obstruction syndrome, 650t Gastric ulceration, e251-e254 antacid therapy for, 505-508 associated with Helicobacter spp., 509 causes of, e252-e253 from NSAID toxicity, 116-117, e252-e253 influence on gastric emptying, 514 therapy of, e254 use of sucralfate for, 507 Gastric-inhibitory polypeptide (GIP), role in food-dependent hypercortisolism, 231-232, 232f Gastrinoma, imaging for diagnosis of, 174 Gastritis effect on gastric emptying, 514 with Helicobacter spp., 508-513 Gastrocentesis, for gastric dilationvolvulus, e17 Gastroesophageal reflux, 501-504, e237-e242 and brachycephalic airway obstruction syndrome, 649 Gastrointestinal regulation of magnesium, 249-250 regulation of potassium, 251-252 Gastrointestinal disorder(s) antacid therapy for, 505-508 antibiotic therapy for, 518-522 canine colitis, 550-554 canine parvoviral enteritis, 533-536 causes of hepatobiliary enzyme elevations, 570b causing cobalamin deficiency in cats, 523-524 causing hyperkalemia and hyponatremia, e92, e93b cobalamin deficiency in cats, 522-525 drug incompatibilities and interactions with, 37 dysphagia, 495-500 effects from plants, 121b exocrine pancreatic disorders in cats, 565-568 exocrine pancreatic insufficiency (EPI) as, 558-560 feline lymphoma, 545-549 feline stomatitis, 492-495 flatulence as, e247-e251 from cyclosporine, 405 gastric ulceration causing, e251-e254 gastroesophageal reflux, 501-504 Helicobacter spp. causing, 508-513 hypokalemia from, 251b hypomagnesemia from, 249b in dogs with brachycephalic airway obstruction syndrome, 649 inflammatory bowel disease, 536-540

Gastrointestinal disorder(s) (Continued) laboratory testing for the pancreas with, 554-557 motility disorders causing, 513-518 oropharyngeal dysphagia as, e259-e262 pancreatitis in cats, 565-568 in dogs, 561-565 probiotic therapy for, 525-528 protein losing enteropathy, 540-544 protozoal, 528-532 stenting of malignant obstructions due to, 346-347 toxicity from chemotherapeutic drugs, 331-332 tylosin-responsive diarrhea, e262-e265 upset from methimazole, e104 Gastrointestinal hemorrhage from heat-induced illness, 71 from NSAID toxicity, 116 from shock, 24 use of antacid therapy with, 505-508 with chronic hepatitis, 585f Gastrointestinal microbial homeostasis, 519f Gastrointestinal pythiosis, e412 Gastropexy, effect on gastric emptying, 514 Gastrostomy tube(s), for hepatic lipidosis, 611-612 Gel(s), potency of topical steroid, 460f Gemcitabine, e140t, e141-e142 for osteosarcoma, 391t for urinary bladder cancer, 372-373 Gemfibrozil, for hyperlipidemia, 265 Gene therapy, for retinal dystrophy, 1191 Genetic marker test(s), 1017-1020, 1021f, 1021t Genetic test(s) ABCB1, for predicting adverse effects of drug therapy, 330 for arrhythmogenic right ventricular cardiomyopathy, 802 for canine dilated cardiomyopathy, 797 for degenerative myelopathy, 1077 for hereditary disorders, 1015-1021, 1016t, 1017f Genital papillomatosis, e185 Gentamicin (Gentocin) causing adverse skin reactions, 488t causing renal failure, e31-e32 for brucellosis, e404 for otitis systemic, 466t topical, 464t intraocular for feline glaucoma, 1180 fro canine glaucoma, 1175-1176 nebulization of, for respiratory diseases, 628 Geraniums, 121b Geriatric screening tests, 858b Germ cell tumors, 1039-1047 German pinscher(s), direct mutation tests for, 1018t-1020t

1369

German shepherd dog(s) avermectin toxicity in, 145 diarrhea in, 519-520 direct mutation tests for, 1018t-1020t Ehrlichia canis in, 1292 exocrine pancreatic insufficiency (EPI) in, 558 limbal melanomas in, 1204 metatarsal fistulation in, e219 pannus in, 1154 atypical, 1141, 1141f prostatic disease in, 1012 risk of bladder cancer in, 371t subaortic stenosis in, e319 testicular tumors in, 1022-1023 use of cyclosporine for pyoderma in, 410b German shorthaired pointer(s), direct mutation tests for, 1018t-1020t Germander toxicity, 570b, 581b Gestation normal in the bitch, 948-949 normal in the queen, 949 prolonged, 949 Giardia spp. common symptoms and syndromes caused by, 1214t-1215t dosage for and drugs targeting, 1335-1337 in raw meat diets, 1240b, 1241 Giardiasis diagnosis and treatment of, 530-532, 530t probiotics for infections with, 531 with Clostridium perfringens, 530-531 with nematode infection, 531 Gibbs-Donnan effect, 8 Gingival hyperplasia, from cyclosporine, 405 Gingivitis, with feline caudal stomatitis, 492 Gingivostomatitis, infectious causes of, 1216 Glanzmann’s thrombasthenia, direct mutation test for, 1018t-1020t Glargine insulin, 191, 210-211, 212b storage of, 214 Glaucoma canine breed predisposed to, 1171b causes and pathogenesis of, 1171 clinical signs of, 1171t, 1172f diagnosis and treatment of, 11701176, 1173b, e381f, e382-e383 surgery for, 1174-1176, 1176b with uveitis, 1166, 1173t causing blindness, 1136 feline clinical signs of, 1178 diagnosis and treatment of, 11771180, 1178f, e381f, e382-e383 with uveitis, 1177 from toxoplasmosis, 1297 secondary from ocular neoplasia, 1206 Glial tumors, 1039-1047, 1042t-1043t Glimepiride, for diabetes mellitus, in cats, e136t Gliomas, ocular, 1205-1206

1370

Index

Glipizide (Glucotrol), for diabetes mellitus, in cats, 214-215, e135e137, e136f, e136t Glomerular disease causing proteinuria, 850-851 diagnosis and treatment of, 853-857 hypertension and, 727, 727t immune-mediated, immunosuppressive drugs for, 268 prognosis with, 856 Glomerular filtration, effect of nonsteroidal anti-inflammatory drugs on, 865-866 Glomerular filtration rate (GFR), effect of hyperthyroidism on, 185 Gloves, for handling hazardous drugs, 327 Glucagon concentration, with diabetes mellitus in dogs, 189-190 levels, with superficial necrolytic dermatitis, 486 to promote ureterolith passage, 894 Glucagonoma and superficial necrolytic dermatitis, 485-487 insulin resistance with, 206b Glucocorticoid(s) adverse effects of, when given with infectious diseases, 1302 as risk factor for hospital-acquired urinary tract infections, 876-877 associated hepatotoxicity, 581b causing fetal disorders, 1010 causing gastric ulcerations, e253 causing hyperlipidemia, 262t contraindications for, 417-418 deficiency of, with hypoadrenocorticism, 233-237 dose tapering with, 1301-1302 during CPR, 30 effect of vehicle and formulation on topical potency, 460f effect on adrenocorticotropic hormone testing, e97-e98 effect on hepatobiliary enzymes, 570-571 effects on immune system, 414 food-dependent excess, 230-232 for actinic dermatoses, 481 for atopic dermatitis, 405-406 for autoimmune hemolytic anemia, 278 for canine colitis, 551b, 552 for canine uveitis, 1165, 1165t for cervical spondylomyelopathy, 1094 for chronic hepatitis, 586 for cough from tracheal collapse, 664 for craniocervical junction abnormalities, 1102 for dermatologic disorders, 414-418, 416t for ehrlichiosis, 1293 for eosinophilic keratitis, 1159 for eosinophilic pulmonary diseases, 690-691 for esophagitis, e240 for feline asthma, 676

Glucocorticoid(s) (Continued) for feline bronchitis, 676 for feline caudal stomatitis, 494 for feline cholangitis, 616, 617b, 618 for feline idiopathic hypercalcemia, 246f, 247 for feline infectious peritonitis, 1305-1306, 1305t for feline uveitis, 1168-1169, 1169t for gastric dilation-volvulus, e17 for hemotropic mycoplasmosis, e401 for hydrocephalus, 1036 for hypoadrenocorticism therapy, 235-237 for immunosuppression, 269 for infections, 1232-1233, 1299-1303 for inflammatory bowel disease, 539 for inflammatory central nervous system disorders, 1064-1065 for insulinomas, e133 for masticatory muscle myositis, 1114 for myasthenia gravis, 1110-1111 for otitis, topical or systemic, 459-462, 460t-461t for palliative cancer care, client questions about, 321 for prolonged seizures, 1062 for protein-losing enteropathy, 544 for respiratory diseases, 625-626 inhaled, 626, 626t, 671, 678-680 for retinal detachment, in dogs, e373 for rhinosinusitis in cats, 646 for shock, 24-25 for thrombocytopenia, 285 for toxoplasmosis, 1297 hyperadrenocorticism and insulin resistance with, 207 hypertension from, 727t idiopathic vacuolar hepatopathy associated with, 606 induced calcinosis cutis, 489-490 influence on thyroid function, 181t interaction with NSAID’s, 34t-35t monitoring use of, 418 potency and dosing of, 1301t prednisone vs. prednisolone, 415 rational use of, for infectious diseases, 1299-1303 structure of, 414-415 systemic adverse effects of, 461 potency of, 461t topical adverse effects of, 461-462 for hot spots, e207 for keratoconjunctivitis sicca, 1147 potency of, 460f, 460t use of, 419-421, 420t causing alopecia, in dogs, 165 use of, with hypoadrenocorticism testing, 234 use of prednisone in cats, 415 with feline pancreatitis, 568 Glucose. See also Blood glucose composition in fluid therapy, 3t drugs that impair intestinal absorption of, e137

Glucose (Continued) drugs that inhibit hepatic release of, e137 energy metabolism in, 1047-1048 supplementation with liver failure, 582 Glucose curve monitoring of and interpretation, 194-196 vs. home monitoring curve, 197 with diabetes mellitus management in dogs, 192 Glucose nadir interpretation of, 195 with diabetes mellitus management in dogs, 190, 192 Glutaraldehyde cross-linked bovine collagen, for urinary incontinence, e347f-e348f, e348 Glycated hemoglobin, for monitoring diabetes mellitus, 194 Glycemic index, effect of diet on, with diabetes mellitus, 200 Glycerin, in ear cleaners, 472t, 473 Glycerol, for glaucoma in dogs, 11721174, 1173b Glycogen storage disease, idiopathic vacuolar hepatopathy from, 606 Glycopyrrolate adverse effects with α2-adrenergic agonist, 60 use of prior to cesarean section, 955 Golden period, of wound contamination, 85 Golden retriever(s) laryngeal paralysis in, 659-661 Lyme disease in, 1271-1274 nonepidermolytic ichthyosis in, 475-476 pigmentary uveitis in, 1163-1164 risk of bladder cancer in, 371t risk of pyometra with prior pregnancy, 967 subaortic stenosis in, e319 Gonadal sex, 993, 995t Gonadectomy, relationship to obesity, 254 Gonadotrophin(s) for estrus suppression in the bitch, 988 for urinary incontinence disorders, 916-917 levels to detect ovarian remnant syndrome, 1001 Gonadotropin-releasing hormone (GnRH) analogs, for hyperadrenocorticism in ferrets, e95-e96 protocol, 1001, 1002t reproductive toxins affecting, 1027 Gonads, reproductive toxins targeting the, 1027-1028 Gonioimplant, with glaucoma therapy, 1175 Gonioscopy, 1133 Gordon Setter(s), vitamin A-responsive dermatosis in, 476 Gossypol toxicity, 581b Gowns, for handling hazardous drugs, 327

Index Grain aflatoxins, 159-161 Granuloma(s), nontuberculous cutaneous, 445-448 Granulomatous colitis, 520t, 521, 552-553 Granulomatous meningoencephalitis cyclosporine for, 269-270 diagnosis and treatment of, 1063-1066 vestibular signs from, 1069 Granulosa cell tumor, with ovarian remnant syndrome, 1001 Grape and raison toxicity, 98, 121b, 149 Grass, 121b Gravel root toxicity, 124t Greasy scale, topical therapy for, 441t Great Dane dog(s) cardiomyopathy in, 795-796 cervical spondylomyelopathy in, 1090-1097 Great Pyrenees Mountain dog(s) common mutation tests for, 1018t-1020t hyperlipidemia in, 261 Greater celandine toxicity, 581b Green tea extract toxicity, 581b Greenies, danger of, 99 Greyhound(s) atypical pannus in, 1141 canine influenza virus in, 632 pannus in, 1154 thyroid hormone differences in, 180t Grid keratotomy, 1151-1152 Griseofulvin associated hepatotoxicity, 570b, 581b causing adverse skin reactions, 488t causing fetal disorders, 1010 for dermatophytosis, 450 Growth abnormalities, from hypothyroidism, 179 Growth factor inhibitor(s), for immunosuppression, 271-273 Growth factors for feline retrovirus infections, 1280t-1281t for retinal dystrophy, 1191 Growth hormone and feline hypersomatotropism, 216-221 measurement of, 218-219, 219f insulin resistance and, 207 Guaifenesin, for respiratory diseases, 627 Guarana toxicity, 123-124 Gustilo, fractures classification system, 83 Gymnema sylvestre, as diabetes supplement, toxicity of, 125 H H1-antihistamine(s), toxicity of, 118-119 H2-antihistamine(s), toxicity of, 119 H2-receptor antagonists for esophagitis, e240 for gastric ulceration, e254 for gastroesophageal reflux, 503 potency and use of, 505 use with nephroliths and ureteroliths, 894-895 Haemobartonella spp. See under Mycoplasmosis

Hageman trait, coagulation factor abnormalities with, 288t Hair examination for dermatophytosis, 453 photomicrogram of, 165f Hair loss. See Alopecia Halo effect, from ethylene glycol toxicity, 152 Haloperidol, toxicity of, use of IV lipid emulsion therapy for, 106 Halothane-associated hepatotoxicity, 570b, 581b Hamamelis extract, topical, 420t HARDIONS-G acronym, 243b Hazardous drugs, chemotherapeutic, 326-329 Head tilt, from vestibular disease, 1067, 1067t Head trauma colloid use for, 12t fluid therapy considerations with, 6 Hearing loss. See Deafness Heart, Also see under Cardiacmyocardial effects of hypocalcemia on, 252 myocardial effects of magnesium on, 250 Heart block. See Atrioventricular (heart) block Heart disease anesthesia for patients with, 64-68, 65t canine asymptomatic, 775-777, 797-798 at risk for, 775 classifications of, 773-775 stages of and treatment recommendations for, 775-781 valvular, diagnosis and treatment of, 784-794, 785f, 787t, 789f cardioversion with, e286-e291 causing pleural effusion, 694 congenital, 756-761 causing pulmonary hypertension, 711, 712t prevalence of, 756-757 drug incompatibilities and interactions with, 36-37 feline myocardial, 804-810 tachyarrhythmias and, 750f-751f from Bartonella spp. infections, 1263b from heartworms (See Heartworm disease) from infective endocarditis, e291-e299 from mitral valve dysplasia, e299-e302 from myocarditis, e303-e308 from patent ductus arteriosus, e309-e313 from pulmonic stenosis, e314-e319 from subaortic stenosis, e319-e324 from tricuspid valve dysplasia, e332-e335 from ventricular septal defect, e335-e340 insulin resistance with, 206b nutritional management of, 720-725 pulmonary thromboembolism associated with, 705

1371

Heart disease (Continued) syncope from, e324-e331 tips for medication administration with, 721b with hypothyroidism, 184 Heart failure adverse drug effects on, 34t-35t bradyarrhythmias and, temporary pacing for, e22 canine cardiogenic shock from, 783 catecholamine use for, 15t chronic right-sided, 781 classifications of, 773-775 colloid use with, 12t congenital heart disease, 760 drug therapy for, 762-772, 764t-765t, 767f, 778b follow-up examination for, 777-779, 778b from chronic valvular disease, 786-792, 787t from dilated cardiomyopathy, 798-799 from heartworm disease, 832-833 from hypothyroidism, e85 management of, 772-784, 778b overview of, 772-773 persistent cough with, 782 prognosis, 781-782 refractory, 780-781, 780b, 791 treatment of acute, 782-783, 787t, 790-791 with atrial fibrillation, 741 causing hyperkalemia and hyponatremia, e93, e93b feline, with cardiomyopathy, 807-809 from ventricular septal defect, e336-e337 nutritional recommendations for, 720-725 with endocarditis, e292, e297-e298 Heart function, effect of ventricular arrhythmia on, 745 Heart murmur(s) caused by infectious disease, 1212-1213 from mitral valve dysplasia, e300 with congenital heart disease, 757-759 with dilated cardiomyopathy in dogs, 796 with endocarditis, e292-e293 with feline myocardial disease, 804-805 with patent ductus arteriosus, e309 with pulmonic stenosis, e314, e314-e315 with subaortic stenosis, e320-e321 with tricuspid valve dysplasia, e332 with valvular heart disease, 785-786 asymptomatic, 786 with ventricular septal defect, e337 Heartworm disease canine causing uveitis dogs, 1164b classification and staging of, 832-833 diagnosis and treatment of, 831-838 eliminating microfilariae, 836

1372

Index

Heartworm disease (Continued) life cycle of, 831-832 role of Wolbachia in, 826 causing pulmonary hypertension, 711, 712t, 716 causing pulmonary thromboembolism, 705 causing thrombocytopenia, 281t-282t feline diagnosis and treatment of, 824-831, 826t, 828f prevalence of, 825f prevention of, 829, 829t prognosis of, 830 Heartworm prevention for cats, 829, 829t for dogs, 836-837 formulations of, dosage for and target parasites of, 1335-1337 product switching of, 836-837 resistance of, 837 with flea control, 426t Heat ablation, ultrasound-guided, for treatment of hyperparathyroidism, e72 Heat-induced illness, 70-74 Heavy metals associated hepatotoxicity, 570b, 581b causing nephrotoxicity, e30b ototoxicity from, 468b, 469 Heimlich valves, with thoracostomy tubes, 702 Heinz body(ies) from acetaminophen toxicity, 118 from onion/garlic toxicity, 147-148 Helicobacter spp. causing diarrhea, 1213-1215 causing gastric ulcerations, e253 chronic vomiting from, 508-513 common symptoms and syndromes caused by, 1213t diagnostic tests for, 509-511 pathogenesis of, 508-509, 510f treatment failure with, 512 treatment protocols for, 511-513, 511t Heliotropium europaeum toxicity, 124t Helminths, drugs used to treat common, 1335-1337 Hemangiosarcoma clinical staging of, 393b conjunctival, in cats, 1208 cyclophosphamide for, 355-356 diagnosis and treatment of, in dogs, 392-397 immunotherapy for, 334, 336t masitinib for, 361t pericardial, 816-823, e167 Hematocrit, relationship to mean corpuscular hemoglobin concentration (MCHC), 307-308 Hematologic, toxicity from chemotherapeutic drugs, 330-331 Hematology analyzers, quality control of, with in-clinic, 307-309 Hematuria, effect of, on urine protein and albumin, 850 Hemilaminectomy, for intervertebral disk disease, 1073-1074

Hemoabdomen, fluid therapy for, 4 Hemodialysis for ethylene glycol toxicity, e31 slow continuous renal, 873, 874f Hemoglobin, relationship to mean corpuscular hemoglobin concentration (MCHC), 307-308 Hemoglobin-based oxygen carrier solutions, 11 Hemophagocytic syndrome, 316, e163 Hemophilia A and B, 289 Hemophilia B, direct mutation test for, 1018t-1020t Hemoplasmas, canine, e399 Hemorrhage associated with disseminated intravascular coagulation, 292 chronic, anemia from, e160 colloid use with, 12t conjunctival, 1139 from anticoagulant rodenticide toxicity, 133 induced-strokes, 1120 intraocular, secondary to hypertension, 726 postpartum, 957, 958t subconjunctival, 1139, 1139f with open fractures, 84 Hemorrhagic cystitis, from chemotherapeutic drugs, 332 Hemothorax, 694 Hemotropic mycoplasmosis, as cause of thrombocytopenia, 281t-282t Henbane toxicity, 124t Heparin drug incompatibilities with, 33t for arterial thromboembolism, 815 for autoimmune hemolytic anemia, 276-278, 277t for disseminated intravascular coagulation, 296 for hypercoagulable states, 299 for thromboembolism, 813 feline, 810 pulmonary, 706-707, 707t for thromboprophylaxis, 708-709 low-molecular weight vs. unfractionated, 813 low-molecular-weight, 707, 813 monitoring therapy of, 813 unfractionated, 706, 813 use of, with thromboelastography, 706 use with gastric dilation-volvulus, e19 use with IV lipid emulsion therapy, 108 Hepatic disease. See under Liver Hepatic encephalopathy from chronic hepatitis, 587 from feline hepatic lipidosis, 613 from liver disease, 591-594 precipitating factor for, 593b Hepatic fibrosis, 587 Hepatic lipidosis, 608-614 and liver failure, 582-583 diagnosis and treatment of, 608-614 pathogenesis of, 609 prognosis for, 613 with diabetes mellitus, e77

Hepatic necrosis, 580-581 from glucocorticoid(s), 571 from xylitol toxicity, 150 Hepatic nodular hyperplasia, vs. idiopathic vacuolar hepatopathy, 607 Hepatic support therapy, e255-e258 Hepatitis. See also under Liver canine, as cause of thrombocytopenia, 281t-282t chronic immunosuppressive drugs for, 268 therapy for, 583-588, 585f copper-associated, e231-e236 Hepatitis X, 159-161 Hepatobiliary disease breeds predisposed to, 571b diagnostic approach to, 569-575 extrahepatic diseases causing enzyme elevations, 571b function tests for, 572-573 toxins and agents associated with, 570b Hepatocellular carcinoma, associated hepatic injury, 581b Hepatocellular necrosis, 580-583 drug induced, 575-579 therapy of, 583-588 Hepatocellular steatosis, hypertriglyceridemia-associated, 261 Hepatocutaneous syndrome, and superficial necrolytic dermatitis, 485 Hepatopathy, vacuolar, 606-608 Hepatotoxicity agents causing, 570b, 581b drugs causing, 570b, 575-579, 576f, 581b chemotherapeutic, 332-333 mechanism of, 576f methimazole, e104 idiosyncratic, 577-579 mechanisms of injury, 581b pathogenesis of, 577f, 580 Hepatozoon americanum causing myositis, 1115 common symptoms and syndromes caused by, 1214t-1215t diagnosis and treatment for, 12831286, 1284f prognosis for, 1285 Herbal supplement toxicity, 94-95, 99, 122-129, 124t Herbalife toxicity, 581b Herbicide(s) and risk of urinary bladder cancer, 370 causing endocrine disruption, 1028 causing reproductive toxicity, 1027b exposures to, 92t, 96 toxicity, 130-131 Hereditary disorders coagulation factor deficiencies, 286-291, 288t diagnostic tests for, 1015-1021, 1016t Hernia, scrotal, 1031 Herpesvirus. See Canine herpesvirus (CHV); Feline herpesvirus 1 Heska E.R.D. Health Screen urine test, for urine protein and albumin, 850

Index Hetastarch, 11-12 characteristics of, 10t for acute pancreatitis in dogs, 562 for canine parvovirus, 534 for protein-losing enteropathy, 543-544 Heterodoxus spiniger, 429t Hexachlorophene toxicity, 581b Hiatal hernia, 501-502, e238-e239 and brachycephalic airway obstruction syndrome, 650t Hibiscus, 121b Hill’s Science Diet c/d-oxl, for calcium oxalate urolithiasis, 898-899 Hill’s Science Diet SO, for calcium oxalate urolithiasis, 898-899 Hill’s Science Diet u/d, for calcium oxalate urolithiasis, 898-899 Hill’s Science Diet Y/D for hyperthyroid cats with kidney failure, 187-188, e110 transitioning from, to other treatments, e111 transitioning from methimazole to, e111 Himalayan cat(s) corneal sequestrums in, 1159-1160 risk of urolithiasis in, 897 Hip dysplasia, concerns regarding risk, with early age neutering, 983t Histiocytic colitis in boxer dogs, 552-553 in non-boxer dogs, 553 Histiocytic ulcerative colitis, 552-553 Histiocytosis canine reactive, causing eyelid problems, e368-e369 use of cyclosporine for, 410b Histocytocytic sarcoma, associated hepatic injury, 581b Histopathology client questions about, 319-320 for pythiosis, e413 grading of soft tissue sarcomas, e149 identification of Helicobacter spp., 510-511, 510f lesions associated with causes of pulmonary hypertension, 712t of canine colitis, 550-551 of chronic hepatitis, 586 of copper-associated liver disease, 588-589, e233-e234, e235t of feline cholangitis, 614-615 of feline gastrointestinal lymphoma, 545-546 of fibrocartilaginous embolism, 1125 of idiopathic vacuolar hepatopathy, 606 of inflammatory bowel disease, 538 of injection site sarcomas, 1254 of liver, 574 of nontuberculous cutaneous granuloma lesions, 447 of ovarian remnant syndrome, 1002 of portal vein hypoplasia, 600, 601f of skin, for diagnosis of alopecia, 166 staging of mammary cancer, 376t

Histoplasma capsulatum causing anemia, 1217 common symptoms and syndromes caused by, 1214t Histoplasmosis antifungal therapy for, 1234-1238 as cause of thrombocytopenia, 281t-282t causing feline uveitis, 1168 causing nervous system signs, 1212 causing uveitis in dogs, 1164, 1164b immunosuppressive therapy for, 1232-1233 Holter monitoring for arrhythmogenic right ventricular cardiomyopathy, 802-803 for diagnosis of syncope, e329 for supraventricular tachyarrhythmias in dogs, 741-744 for ventricular arrhythmias, 745, 747 in cats, 753-754 with dilated cardiomyopathy, 799 Holz-Celsus procedure, e375 Home-cooked diets, for adverse food reactions, 423 Hop toxicity, 148 Hordeolum, e363 Hormone receptor expression, with mammary cancer, 379t Hormone(s) assays, to detect ovarian remnant syndrome, 1001-1002 role of in mammary cancer, 375 in urinary incontinence, e341 therapy, for mammary cancer, 377 Horner’s syndrome, e395 after ventral bulla osteotomy, 657 Horse chestnut toxicity, 124t Hospital acquired kidney injury, recognition and prevention of, 845-848, 846t acquired pneumonia, 682-683, 683b acquired urinary tract infections, 876-879 contamination with resistant Staphylococcal infections, 456t managing the recumbent patient in the, e360 Hospitalization, as risk factor for hospital-acquired urinary tract infections, 877 Hot spots. See Pyotraumatic dermatitis House dust, as respiratory toxicants, e46-e47 House dust mite control, e197-e199 Household product toxicity, 92t, 95-100, 95t, e30b Human albumin characteristics of, 10t for therapy of shock, 22 use of, 13 Human drugs of abuse legal considerations with, e51 toxicity from, 109-112 Human food toxicities, 147-150 Human γ−globulin, for thrombocytopenia, 285, 285t

1373

Human interferon. See under Interferon Human medication, toxic exposures to, 92t, 94-95 Human recombinant interferon alfa, for infectious disease immune therapeutics, 1230t Humidifiers, for pneumonia, 687 Humidity and dust mite control, e198 effect on heat-induced illness, 70 Hung far oil toxicity, 125t Hyalohyphomycosis, antifungal therapy for, 1234-1238 Hycodan. See Hydrocodone (Hycodan) Hydralazine dosage and formulations of, 764t-765t for chronic valvular heart disease, in dogs, 787t for heart failure, in dogs, 764t-765t, 768, 778b, 783 for hypertension, 730, 862 from acute renal failure, 870 refractory, 729-730 for hypertensive emergencies, 870-871 Hydraulic fluid toxicity, 154 Hydrocephalus, congenital, 1034-1037 Hydrochlorothiazide for calcium oxalate urolithiasis, 900 for dilated cardiomyopathy, in dogs, 798-799 for feline cardiomyopathy, 809 for heart failure, in dogs, 764t-765t, 765-766, 791 for insulinomas, e133 Hydrocodone (Hycodan) for coughing, 622-623, 664, 672 for heart failure, in dogs, 764t-765t for tracheal collapse, 664 toxicity, 111 Hydrocortisone. See also under Glucocorticoid(s) for illness-related corticosteroid insufficiency, 79, 177, 177f potency of, for otitis, 460t Hydrogen peroxide, for emesis induction, 105 Hydrolyzed protein diets, 422-423 Hydromorphone adverse effects of, 60 CRI, 62t dosage for, 62t for the critical patient, 59 for thromboembolism pain, 814 toxicity, 111 use of with cardiovascular dysfunction, 65t with intracranial pathology, 69 Hydromyelia, 1098 Hydronephrosis, ultrasound findings with, 842-843, 843f Hydrostatic pressure, conditions that change, 9t Hydrotherapy, for degenerative myelopathy, 1079-1080 Hydroxyamphetamine, for localization of anisocoria, e395 Hydroxychloroquine, toxicity of, use of IV lipid emulsion therapy for, 106

1374

Index

Hydroxycut associated hepatotoxicity, 581b Hydroxyethyl starch. See Hetastarch; Pentastarch Hydroxyurea, for intracranial tumors, 1041t, 1044 Hydroxyzine causing adverse skin reactions, 488t for atopic dermatitis, 406 Hyoscyamine for atrioventricular block, in cats, 754 for bradycardias, 736 for feline arrhythmias, 750f-751f Hyperadrenocorticism adrenal-dependent gland imaging for diagnosis of, 170-172 therapy of, 229 adverse effects of topical and systemic glucocorticoids and, 461-462 and risk of urinary tract infections, 876-877 causing alkaline phosphatase elevations, e243-e244 causing alopecia, in dogs, 165b clitoral hypertrophy with, 978-979 diabetes mellitus and, 207 hypertension from, 727, 727t idiopathic vacuolar hepatopathy with, 606 in ferrets, e94-e97 insulin resistance with, 206-207, 206b interpretation of tests results for, e97-e102 lymphocytosis associated with, 305 myopathy from, 1116 occult, 221-224 pituitary-dependent imaging for diagnosis of, 171, 173f radiotherapy for, 229 therapy of, 225-228 with large pituitary tumors, e88-e91 pulmonary thromboembolism associated with, 705 surgical treatment options for, 225, 229 testing in cats, e99 therapy of, 225-229 thromboembolic disease with, 812 Hyperalbuminemia, causing nonvolatile ion buffer acid-base abnormalities, e5b Hyperaldosteronism feline primary, 238-242 hypertension from, 727t, 729 with hypertensive retinopathy, in cats, 1194 Hyperbaric oxygen therapy, 54 Hyperbilirubinemia from feline hepatic lipidosis, 609-610, 613 from liver failure, 580-581 Hypercalcemia diagnosis and treatment of, in dogs, e69-e73 feline idiopathic, 242-248 diagnostic plan for, 245f differential diagnosis for, 243b treatment of, 244-247, 244b from cholecalciferol toxicity, e33-e34

Hyperchloremic acidosis, e7, e7b Hypercholesterolemia from hepatobiliary disease, 572 from hypothyroidism, e86 treatment of, 264 with diabetes mellitus, 200-201 Hypercoagulable state(s) causing feline thromboembolism, 811 causing pulmonary thromboembolism, 705, 708 diagnosis and treatment of, 297-301, 298f testing of, with thromboelastography, 74-77 Hypercortisolism. See also under Cortisol ectopic syndrome of, 230-232 food-dependent, 230-232 Hyperestrogenism and sertoli cell tumors, 1022-1023 causing alopecia, in dogs, 165 Hyperglobulinemia, in cats caudal stomatitis, 493 Hyperglycemia. See also Diabetes Mellitus role of insulin resistance in, 205-206 with acute pancreatitis in dogs, 563 Hyperinsulinism, from insulinoma, e130-e134 Hyperkalemia causes of, e93b causing feline arrhythmias, 750f-751f, 755 causing syncope, e328 from acute renal failure, 870 from renin-angiotensin-aldosterone system inhibition, 854-855 from reperfusion after thromboembolism, 810, 813 with hypoadrenocorticism, 233, 234t, 236 with hyponatremia, differential diagnosis for, e92-e93 Hyperlipidemia approach to canine, 261-266 causes of, 261, 262t, 263 causing uveitis in dogs, 1164, 1164b complications of, 263t from hypothyroidism, e85-e86 insulin resistance with, 206b Hypernatremia from activated charcoal use, 105, 137 with feline hyperaldosteronism, 239-240 with hyperthermia, 73 Hyperosmolality from diabetic ketoacidosis, e79 from nonketotic diabetic mellitus, e83 Hyperosmotic(s) for glaucoma in cats, 1179 for glaucoma in dogs, 1172-1174, 1173b Hyperparathyroidism diagnosis and treatment of, in dogs, e69-e73 direct mutation test for, 1018t-1020t hypercalcemia from, in cat, 243b Hyperphosphatemia causing nonvolatile ion buffer acid-base abnormalities, e5, e5b

Hyperphosphatemia (Continued) from xylitol toxicity, 150 with chronic kidney disease, 861-862 with urolithiasis, 892-893 Hyperplastic dermatosis, use of interferons for, e200-e201 Hypersensitivity reactions from canine vaccines, 1250-1251 to chemotherapeutic drugs, 333 with polyarthritis, 1224 Hypersomatotropism, feline, 216-221 Hypertension acute intracranial, 1045 fluid movement with, 9t from acute renal failure, 870 from idiopathic vacuolar hepatopathy, 607 in cats causing hyphema, 1178 retinal detachment from, 1193-1194 retinopathy from, 1193-1194 with hyperaldosteronism, 239 with hyperthyroidism, e105 in dogs causing retinal detachment, e371 causing uveitis, 1164, 1164b retinopathy from, 1192 pulmonary (See Pulmonary hypertension) systemic conditions associated with development of, 727t diagnosis and treatment of, 726-730, 768 with asymptomatic heart disease, 790 with cerebrovascular accidents (stroke), 1121-1122 with kidney disease effects of on staging of, 860t, 861-862 management of, 861-862 with refractory heart failure, 781 Hyperthermia and heat-induced illness, diagnosis and treatment of, 70-74 from adverse effects of hydromorphone, 60, 65t from prolonged seizures, 959-960, 1060 from serotonin syndrome, 34t-35t Hyperthyroidism and renal function, 185-189, 188f, e118 causing feline arrhythmias, 750f-751f causing myopathy, 1115 cobalamin deficiency with, 524 diagnosis of, 169-170, 170f, e101, e107 hypertension from, 727t, 729-730, e105 iatrogenic, 184 insulin resistance with, 206, 206b lymphocytosis associated with, 305 medical therapy for, e102-e106, e103t, e108-e111 nutritional management of, e107-e112 prognosis for, e111 pros and cons of major therapies, e103t

Index Hyperthyroidism (Continued) radioiodine therapy for, e114f (See also under Radioiodine therapy) thyroid physiology of, e107, e108f Hypertonic crystalloids, use of, 2 Hypertonic solutions for cerebral edema from prolonged seizures, 1062, 1062t for seizure patients, 1061t for shock, 21 use of, 2 Hypertriglyceridemia approach to, 261 risk of pancreatitis with, 39-40, 261 treatment of, 264 with diabetes mellitus, 190, 200-201 with hypothyroidism, 179 Hypertrophic cardiomyopathy. See under Cardiomyopathy Hypertrophic osteodystrophy, from adverse reactions to vaccines, 1251 Hyperuricosuria, direct mutation test for, 1018t-1020t Hyperventilation, causing respiratory alkalosis, e4b Hyperviscosity causing retinal detachment, in dogs, e371 causing uveitis in dogs, 1164, 1164b Hypervolemia, fluid movement with, 9t Hyphema causes of, 1178 causing feline glaucoma, 1178 from brucellosis, 1163-1164 with blindness, 1134-1135 with canine uveitis, 1135-1138, 1163-1164 with feline uveitis, 1166-1167 with glaucoma, 1170-1171, 1178 with hypertension, 1193 Hypoadrenocorticism. See also Criticalillness related corticosteroid insufficiency acute, 235-236 adrenal gland imaging for diagnosis of, 171-172 causing nonregenerative anemia, e161b causing syncope, e328 concurrent with hypothyroidism, e87-e88 diagnosis and treatment of, in dogs, 233-237 differential diagnosis for, hyponatremia and hyperkalemia, e92-e93 effect on gastric emptying, 514 interpretation of tests results for, e97-e102 lymphocytosis associated with, 304-305 megaesophagus with, e226, e229 primary vs. secondary, 235 steroid therapy during shock, 25 Hypoalbuminemia causing ascites, 591-592 causing nonvolatile ion buffer acid-base abnormalities, e5, e5b

Hypoalbuminemia (Continued) effect on drug therapy, 36 fluid movement with, 9t from hepatobiliary disease, 572 from liver failure, 580-581 from protein-losing enteropathy, 540-544 human albumin therapy for, 22 interaction with NSAIDs, 34t-35t with acute respiratory distress syndrome, 50 with inflammatory bowel disease, 539 with renal disease, acetylsalicylic acid for, 861 Hypoallergenic dietary therapy, 422-424 Hypocalcemia clinical signs of, e124b conditions causing, e123b diagnostic approach to, e125f during pregnancy and lactation, 963 from blood transfusion reaction, 313 from hypoparathyroidism, e123b, e124 postpartum, 958t, 959-960 supplementation of, for tetany or seizures, e126, e126-e127, e126t with dystocia, 954 with secondary hypercalcemia, e129 Hypocapnia, e3-e4 Hypochloremia, from diuretic therapy, 779 Hypochloremic alkalosis, e6 Hypochlorous acid as topical therapy for skin infections, 441t in ear cleaners, 474 Hypocholesterolemia from hepatobiliary disease, 572 from liver failure, 580-581 Hypocoagulation, testing of, with thromboelastography, 74-77 Hypofibrinogenemia, coagulation factor abnormalities with, 288t Hypoglycemia biochemical, 213-214 during pregnancy and lactation, 963-964 emergency treatment of, e131 from heat-induced illness, 71 from insulinoma, e130-e134 from liver failure, 581-582 from xylitol toxicity, 150 with diabetes mellitus, e78 in dogs, 192-193 remission, in cats, 213 Hypokalemia approach to, 248-253 causes of, 251-252, 251b causing feline arrhythmias, 750f-751f causing myopathy, 1116 from diuretic therapy, 779 from ectopic ACTH syndrome, 230 renal disfunction from, 252 treatment of, 252-253, 253t use of digoxin with, 34t-35t with acute renal failure, 870 with chronic kidney disease, 863 with diabetic ketoacidosis, e79, e80t-e81t, e82

1375

Hypokalemia (Continued) with feline hyperaldosteronism, 239 with gastric dilation-volvulus, e18-e19 with hepatic lipidosis, 611 Hypoluteoidism, 1006 Hypomagnesemia approach to, 248-253, 249b causes of, 249-250 from diabetic ketoacidosis, e79, e80t-e81t treatment of, 250-251 Hyponatremia causes of, e93b from diabetic ketoacidosis, e79 with hyperkalemia, differential diagnosis for, e92-e93 with hypoadrenocorticism, 233, 234t Hypoparathyroidism differential diagnosis for, e122-e123, e123b managing complications with, e128-e129 prognosis for, e129 treatment of, e122-e129 Hypophosphatemia from diabetic ketoacidosis, e79, e80t-e81t, e82 from xylitol toxicity, 150 with hepatic lipidosis, 611 Hypophysectomy for pituitary-dependent hyperadrenocorticism, 225 for treatment of feline hypersomatotropism, 219 Hypoproteinemia from protein-losing enteropathy, 540-544 with open peritoneal drainage, e16-e17 Hypopyon canine, 1162, 1163t, 1164-1165 with blindness, 1134-1135 with uveitis, 1162, 1163t Hyposensitization, for eosinophilic pulmonary diseases, 690 Hypospadias, 998 Hypotension causing gastric ulcerations, e253 fluid therapy for, 2-4 resuscitation in cats, 13 from cardiogenic shock, 783 from gastric dilation-volvulus, e16 from prolonged seizures, 1060, 1061t Hypotestosteronism, causing alopecia, in dogs, 165b Hypothalamus as thermoregulatory center, 70-71 reproductive toxins targeting the, 1027-1028 Hypothermia and hypotension, in cats, fluid therapy for, 13 during CPR, 31 Hypothyroidism causing alopecia, in dogs, 165b causing megaesophagus, e226-e227 causing myopathy, 1115 causing nonregenerative anemia, e161b

1376

Index

Hypothyroidism (Continued) causing vestibular signs, 1068-1069, e84, e86 complications and concurrent conditions with, e84-e88 concurrent illness and, 184 congenital, 179 diagnosis and treatment of, 178-185, 180t, 183f diagnosis of, in dogs, 169 direct mutation test for, 1018t-1020t in cats from over-treatment, 187-189, e111, e119, e119-e121 therapy of, e121 insulin resistance with, 206-207, 206b interpretation of tests results for, e99-e101 monitoring of, 184 myxedema coma from, e86-e87 neuropathy from, 1116 with cervical spondylomyelopathy, 1094 with laryngeal paralysis, 659 Hypotonic crystalloids, 2 Hypoventilation, causes of, 52 Hypovolemia anesthesia for patients with, 64-68 causing gastric ulcerations, e253 Hypoxemia causing feline arrhythmias, 750f-751f clinical signs of, 52 from acute respiratory distress syndrome, 49 from V/Q mismatch, 52 in respiratory acid-base disorders, e3-e5, e3b-e4b with pneumonia, 686 with seizure patients, 1061 Hypoxia, causing respiratory acidosis, e5 Hysteroscopy, transcervical, 937-938 I Ibuprofen. See also Nonsteroidal antiinflammatory drug(s) (NSAID’s) causing nephrotoxicity, e32-e33 toxicity of, 116-117 Ichthyosis, 475-476 Idiopathic vacuolar hepatopathy, diagnosis and treatment of, 606-608 Idoxuridine, for feline ocular herpesvirus 1, 1158 Ifosfamide, e139, e140t toxicity from chemotherapeutic drugs, 332 IgA deficiency, diarrhea with, 519-520 Ileus, post-surgical, effect of, on gastric emptying, 516-518 Illicit human drug toxicity, 109-112 Illness-related corticosteroid insufficiency, 78-79 Imaging, for diagnosis of endocrine disorders, 167-174, 168b IMHA. See Anemia, hemolytic Imidacloprid for lung worms, e274 for pediculosis, 429t toxicity, 140-141

Imidacloprid-flumethrin, 426t target parasites of, 1335-1337 Imidacloprid-moxidectin, 426t target parasites of, 1335-1337 Imidacloprid-permethrin, target parasites of, 1335-1337 Imidacloprid-permethrin-pyriproxyfen (K9 Advantix II), 426t Imidacloprid-pyriproxyfen (Advantage II), 426t target parasites of, 1335-1337 Imidapril, for heart failure, 763b, 766-767, 777-779 Imidocarb for canine babesiosis, 1258, 1258t for cytauxzoonosis, e408 target parasites and dosage of, 1335-1337 Imipenem for infective endocarditis, e294t for otitis, 466t, 467 Imipramine, for urinary incontinence disorders, 916t, 917 Imiquimod as topical immunomodulators, 335, 336t, e220-e221 for actinic dermatoses, 481 for papillomatosis, e186 Immune-mediated disease(s) causing blepharitis, e366-e367 causing endocarditis, e292 causing myocarditis, e304t causing neuropathies, 1117 causing nonregenerative anemia, e161b causing pregnancy loss, 1007 causing retinal detachment, in dogs, e371 causing uveitis in dogs, 1162-1165, 1164b topical immunomodulators for, e217-e218 vaccines causing, 1250-1251 Immune-mediated hemolytic anemia. See Anemia, hemolytic Immune-mediated thrombocytopenia diagnosis and treatment of, 280-281, 281t-282t, 285t secondary, 280-281 Immune-stimulatory therapy. See Immunotherapy ImmuneFx, 335 Immunity and risk of hospital-acquired urinary tract infections, 876-879, 881b concerns regarding, with early age neutering, 982 impairment from diabetes mellitus, e77 impairment from hypothyroidism, e86 role of interferons in, 1229 Immunodeficiency direct mutation test for, 1018t-1020t immunotherapy for, 1231-1232 Immunofluorescent antibody test for American leishmaniasis, e396-e397 for Borrelia burgdorferi, 1272-1273 for feline Bartonella spp., 1269

Immunoglobulin E causing hypersensitivity reactions, to vaccines, 1250-1251 for autoimmune hemolytic anemia, 279 Immunohistopathology, for feline gastrointestinal lymphoma, 545-546 Immunologic transfusion reactions, 312-313 Immunomodulators. See under Immunotherapy Immunosuppression contributing to pneumonia, 681 from topical glucocorticoids, 461 Immunosuppressive drugs, 268-274 doses of glucocorticoids, 1301t for infectious diseases, 1229, 1232-1233 for inflammatory bowel disease, 539 for inflammatory central nervous system disorders, 1065 for myasthenia gravis, 1110-1111 for thrombocytopenia, 285t Immunotherapy adverse effects of, 1231 allergen-specific, 411-414 and risk of ocular squamous cell carcinoma, 1204 for cancer, 334-337 for canine parvovirus, 535 for feline infectious peritonitis, 1304-1306, 1305t for feline retrovirus infections, 1280-1283, 1280t-1281t for hemangiosarcoma, 396 for infectious diseases, 1229-1233, 1230t for intracranial tumors, 1045-1046 for keratoconjunctivitis sicca, 1145 for Malassezia spp. infections, e215-e216 for oral tumors, 364 for papillomatosis, e186 for persistent infections in dogs, 1231-1232 viral, in cats, 1232 metronomic chemotherapy and, 355 to augment antimicrobial and antifungal therapy, 1232 topical, 421, e216-e221 Imperforate canaliculus, e375-e376 Imperforate punctum, e375 Imprint cytology, e153 Inactivated parapoxvirus, for infectious disease immune therapeutics, 1230t Inappropriate elimination. See also Urinary incontinence disorders and litter box care with environmental enhancement for cats, 912 Incretins, for diabetes mellitus, in cats, e138 Indirect calorimetry, with cancer cachexia, 350 Indirect fluorescent antibody (IFA) test, for ehrlichiosis, 1292-1293 Indolent corneal ulcers, 1151-1152 Indomethacin causing nephrotoxicity, e32-e33 toxicity of, 116-117

Index Indoxacarb, 426t target parasites of, 1335-1337 Indoxacarb/permethrin, 426t target parasites of, 1335-1337 Infections. See also Methicillin-resistant staphylococcal infections causing canine respiratory disease, 632-635 causing chronic hepatitis, 584t causing diarrhea, 519 causing dysphagia, 496b causing feline respiratory disease, 629-632 causing hepatobiliary enzyme elevations, 570b causing myositis, 1115 causing nasal discharge, 636b causing polyarthritis, 1224-1228 causing renal failure, e30b differentials of, for medical problems, 1212-1218 disinfection of environments with staphylococcal sp., 455-457 drug incompatibilities and interactions with, 37 empiric antibiotic therapy for, 1219-1223, 1220t risk of, with diabetes mellitus, e77 septic abdomen causing, drainage techniques for, e13-e20 skin from staphylococci causing pyoderma, 435-436 glucocorticoids for, 415-417 secondary to demodicosis, 433 superficial bacterial folliculitis, 437-439 topical therapy for, 439-443, 441t use of glucocorticoids for, 1300-1301 with cholangitis in cats, 615 with complicated corneal ulcers, 1150-1151 with dermatophytosis, 449-451 with nontuberculous cutaneous granulomas, 445-448 Infectious bronchitis in dogs, 669-672 Infectious disease(s) causing canine uveitis, 1164b causing feline uveitis, 1167-1168 causing nonregenerative anemia, e161-e162, e161b from American leishmaniasis, e396-e397 from babesia, 1257-1260 from Bartonella spp., 1261-1271 from canine brucellosis, e402-e404 from feline cytauxzoonosis, e405-e409 from feline retrovirus, 1275-1283 from Hepatozoon americanum, 1283-1286 from leptospirosis, 1286-1289 from monocytotropic ehrlichiosis, 1292-1294 from Neospora caninum, 1290-1291 from pets to humans, 1244-1249 (See also Zoonosis) from raw meat diets, 1239-1243 from toxoplasmosis, 1295-1298

Infectious disease(s) (Continued) hemotropic mycoplasmosis causing, e398-e401 immunosuppressive therapy for, 1232-1233 immunotherapy for, 1229-1233, 1230t lagenidiosis causing, e412-e415 pneumocystosis causing, e409-e411 pythiosis causing, e412-e415 rational use of glucocorticoids for, 1299-1303 zoonoses spread from animals to humans, 1245t Infective endocarditis, e291-e299 Inflammation gastric, effect on gastric emptying, 514 intestinal, effect on gastric emptying, 514 role of, with glomerular disease, 849 with feline caudal stomatitis, 493 Inflammatory bowel disease and canine colitis, 550-551 antibiotic-responsive, 519b classification of, 536 cyclosporine for, 269-270 diagnosis and treatment of, 536-540 prognosis for, 539 with cholangitis, in cats, 615-616 with dysbiosis, 521 Inflammatory diseases causing anemia, e160 causing neuropathies, 1117 causing pregnancy loss, 1005-1006, 1005t, 1008-1010 of the liver, in cats, 614-619 Inflammatory mammary carcinoma, 375, 378 Inflammatory myopathies, 1113-1115 Inhaler(s) for eosinophilic pulmonary diseases, 690, 690f for feline asthma, 675, 678-680, 679f for respiratory diseases, 623-624, 626, 626t, 671 Inheritance pattern for coagulation factor deficiencies, 288t Injection site reactions, 489 sarcomas, 1252-1255 Inking, specimens for evaluation, 324b Insane root toxicity, 124t Insect bite(s) causing allergic conjunctivitis, 1140 exposures to, 92t Insect growth regulator toxicity, 140-141 Insecticide toxicoses, 135-141, 136b causing adverse skin reactions, 488t toxic exposures to, 92t Insemination, use of endoscopy transcervical, 940-944, 941f, 941t Insulin. See also Insulin resistance CRI for diabetic ketoacidosis, e80te81t, e82 determining dose and frequency for, 191-192 drugs that enhance peripheral sensitivity of, e137-e138

1377

Insulin (Continued) drugs that enhance secretion of, e135-e137 for cats, 210, 212b alternatives to, e135-e138, e136t for dogs, 190-192 for treatment of hyperkalemia, 236 hypokalemia from, 252 IV incompatibility, 33t long-term monitoring of, 192 resistance, hypertriglyceridemiaassociated, 261 with oral hypoglycemics, e138 Insulin resistance, 205-209, 206b hypersomatotropism and acromegaly as causes, in cats, 216-221 Insulin-like growth factor-1, for feline retrovirus infections, 1280t-1281t Insulinoma imaging for diagnosis of, 174 prognosis with, e134 treatment of, in dogs cats and ferrets, e130-e134 Intensity-modulated radiation therapy, for nasal tumors, 338-339, 340f Interferon type 1, role of, in antiviral immunity, 1229 Interferon(s) applications in dermatology, e200-e201 α, e200 β, e200 γ, e200-e201 ω, e201 balanced production of, with effective immune therapies, 1229-1230 classification of, e200 for cancer immunotherapy, 336t for feline caudal stomatitis, 494 for feline infectious peritonitis, 1305-1306, 1305t for feline retrovirus infections, 1280t-1281t, 1281-1282 for infectious disease immune therapeutics, 1230t for papillomatosis, e186 γ, role of, in antibacterial and antifungal immunity, 1229 importance of production of, 1230 mode of action of, e200 Intermittent positive pressure ventilation, in critical care, 66-67 International renal interest society, 857-863 Interstitial cell tumors, 1022-1023 Interstitial lung diseases, e266-e269, e267b Interventional oncology, 345-349 Interventional radiology, 345-349 Interventional strategies for urinary disease(s), 884-892 Intervertebral disk disease, 1070-1075 glucocorticoids for, 1074 herniation causing, 1071 neuroprotective agents for, 1074 pathophysiology of, 1070-1071 rehabilitation considerations with, e360, e361b

1378

Index

Intervertebral disk disease (Continued) risk of urinary tract infections with, 876-877 spinal cord injury scale with, 1072, 1072t surgery for, 1073-1074 vs. fibrocartilaginous embolism, 1124 Intestinal bacterial overgrowth, antibiotic-responsive, 518-522, 519b Intestinal gas, e248t Intestinal microbiota, 525-526 with inflammatory bowel disease, 537 Intestinal motility disorders, diagnosis and treatment of, 513-518 physiology, 516 Intestinal mucosal immune system, 537 Intraarterial chemotherapy for lower urinary tract, 890, 891f for malignant obstructions, 347-348 Intracranial arachnoid cysts in dogs, 1038-1039 Intracranial elastance curve, 68f Intracranial hypertension, 1045 Intracranial pathology, anesthesia with, 68-70, 69f Intracranial pressure elevations from prolonged seizures, 1061-1062, 1062t with cerebrovascular accidents (stroke), 1120, 1122 Intracranial tumors, 1039-1047, 1041t-1042t Intracranial volume, 68 Intradermal testing, for Malassezia hypersensitivity, e214 Intralesional injection, with acral lick dermatitis, e177 Intranasal vaccinations accidental injection of, 635 canine, 634-635 feline, 631-632 Intraocular pressure (IOP) measurement of, 1130 normal values, 1130 in cats, 1166-1167 with canine glaucoma, 1170, 1174 and uveitis, 1173t with feline glaucoma, 1177 Intraperitoneal chemotherapy, 343-344 Intrathoracic chemotherapy, 343-344 Intravascular fluid therapy, 4, 8 Intravenous, drug incompatibilities, 33t Intravenous fat embolism. See Intravenous lipid emulsion therapy Intravenous lipid emulsion therapy, 106-109, 115-116 Intravesical therapy, for urinary bladder cancer, 373 Iodinated contrast agents, for hyperthyroid cats, e106 Iodine restriction, for feline hyperthyroidism, e109-e111 Ion gap, calculation of, with acid-base disorders, e2 Iopanoic acid, for hyperthyroid cats, e103t, e106

Ipilimumab, as cancer immunotherapy, 334 Ipronidazole, for Giardia spp., 530-531, 530t Iridociliary adenoma, 1204-1205 in cats, 1209 Iris melanoma, in cats, 1208-1209, 1208f Iris nevus, 1208f Iris swelling, with canine uveitis, 1163t Irish setter(s) direct mutation tests for, 1018t-1020t progressive retinal atrophy in, 1188-1190, 1189t Irish wolfhound(s), cardiomyopathy in, 795-796 Iron deficiency anemia, e160 Ischemic myelopathy, 1123-1125 renal injury, causing renal failure, e30b strokes, 1119-1120 Isoflurane anesthesia in critical care, 66 use of with cesarean section, 955 Isoproterenol, for bradycardias, 736-737 Isospora spp., common symptoms and syndromes caused by, 1214t-1215t Isotretinoin, for sebaceous adenitis, e211 Itraconazole (Sporanox) adverse effects of, 1236 associated hepatotoxicity, 576 drug reactions from, 489 for dermatophytosis, 451, 451t for fungal rhinitis in cats, 647t for lymphoplasmacytic rhinitis in dogs, 641 for Malassezia spp. infections, e215, e215t for nasal aspergillosis, 639-640 for nasopharyngeal cryptococcosis, 656 for otitis, 467 use and protocols for, 1235t, 1236 Ivermectin adverse reactions to microfilariae from, e180 causing adverse skin reactions, 488t enterohepatic recirculation of, 105 for cheyletiellosis, 430t, e182 for demodicosis, 433-434, 433t, e182 for dermatologic disorders, e178, e179-e180 for feline demodicosis, e192-e193 for fur mite infestation, e183 for lung worms, e275 for nasal mites, 637, 655-656 for Otodectes, 431t, e182 for pediculosis, 429t for sarcoptic and notoedric mange, 429t for sarcoptic mange, e181 for tick infestation, e183 target parasites of, 1335-1337 Ivermectin toxicity, e179 causing blindness, 1136, e383 direct mutation test for, 1018t-1020t drug interactions potentiating, e179 use of IV lipid emulsion therapy for, 106, 108, 115-116

Ivermectin/praziquantel/pyrantel, target parasites of, 1335-1337 Ivermectin/pyrantel, target parasites of, 1335-1337 Ixodes spp. ticks transmitting Anaplasma phagocytophilum, 1225-1226 transmitting Borrelia burgdorferi, 1227 transmitting Ehrlichia canis, 1292-1294 J Jack Russell terrier(s) mitochondrial encephalopathy in, 1048-1051, 1049t, 1051t nonepidermolytic ichthyosis in, 475-476 Jaundice and approach to hepatobiliary disease, 569 from acute liver failure, 580-581 from drug-associated liver disease, 576, 578-579, 647t from feline hepatic lipidosis, 609 with chronic hepatitis, 585f, 587 with feline pancreatitis, 566, 568 Jejunostomy feeding tubes for canine pancreatitis, 563-564 for feline cholangitis, 617 for feline pancreatitis, 568 for nutrition in critical care, 24, 42-43 for the cancer patient, 353 Jimsonweed causing anisocoria or mydriasis, e392 toxicity, 124t Jin Bu Huan toxicity, 570b Joe Pye weed toxicity, 124t Joint effusion collection of cytology specimens from, e155 with infective endocarditis, e293 with orthopedic trauma, 81 with polyarthritis, 1224-1228 Joint function and rehabilitation, e357-e358 Jones test, 1132 Junctional tachycardia, 740f, 742t Juvenile cellulitis causing eyelid dermatitis, e368 rational use of glucocorticoids for, 1301 K Kalanchoe toxicity, 121b Kanamycin, causing renal failure, e31-e32 Kaopectate toxicity, 117 Kava toxicity, 570b, 581b Keeshond direct mutation tests in, 1018t-1020t risk of urolithiasis in, 897 Kennel cough. See Tracheobronchitis Keratectomy for corneal dermoid, 1153 lamellar, for corneal sequestrum, 1159-1160 Keratinization disorders in dogs, 475-477

Index Keratitis in cats cyclosporine for, 269-271 eosinophilic, 1158-1159, 1159f from herpesvirus 1, 1156-1158, 1157t from upper respiratory infection, 630t indications for surgery with, 1161t in dogs causing uveitis, 1164b chronic superficial (Pannus), 1154 from keratoconjunctivitis sicca, 1143 pigmentary, in the pug, 1154 superficial punctate, 1153 Keratoconjunctivitis feline herpesvirus 1, 1156-1158 proliferative, 1158-1159 Keratoconjunctivitis sicca (KCS) cyclosporine for, 269-271 diagnosis and treatment of, 1143-1147, 1154-1155 from feline herpesvirus 1, 1157t, 1158 hypothyroidism with, e85 indications for surgery with, 1161t Schirmer tear test for evaluation of, 1132 surgery for, 1147 tear substitutes for, 1146t with corneal ulcers, 1150 Keratomalacia, 1151 Keratopathy calcium-related degenerative, 1153 lipid, 1153 Keratotomy diamond burr, 1152 grid, 1151-1152 multiple punctate, 1152 Kerosene toxicity, 154-155 Kerry blue terrier(s), direct mutation tests for, 1018t-1020t Ketamine CRI, 62t dosage for, 62t for feline pancreatitis, 567t use in critical care, 60 use of, with intracranial pathology, 69 Ketamine/valium combination, for anesthetic induction in critical patients, 65 Ketoconazole adverse effects of, 1237-1238, 1301-1302 as topical therapy for skin infections, 441t associated hepatotoxicity, 570b, 576, 581b drug interactions with, 35t for anal furunculosis, e190 for dermatophytosis, 450 for ichthyosis, 476 for Malassezia spp. infections, 442, e214-e215, e215t for nasopharyngeal cryptococcosis, 656 for otitis, 467 topical, 465t

Ketoconazole (Continued) for pituitary-dependent hyperadrenocorticism, 228 use and protocols for, 1235t, 1237-1238 use of, with cyclosporine, 270, 408 Ketone, measurement with diabetic ketoacidosis, e81 Ketoprofen adverse effects of, 60 dosage for, 62t for feline uveitis, 1169t influence on thyroid function, 181t toxicity of, 116-117 Ketorolac for canine uveitis, 1165t toxicity of, 116-117 Kidney aspirate of, 841, 844 biopsy, for glomerular disease, 849 injury, hospital acquired, 845-848, 846t interventional approach to nephrolithiasis, 884-889 normal size of, 841-842 ultrasound of, 840-845, 841f Kidney disease. See Renal disease Kidney failure. See Renal failure Killed Propionibacterium (ImmunoRegulin), for infectious disease immune therapeutics, 1230, 1230t Klebsiella spp. causing pneumonia, 682t, 1216, 1222 causing prostatitis, 1013 causing thrombocytopenia, 281t-282t causing urinary infections, 1217, 1219-1221 isolates in feline airways, 676 in trachea of healthy animals, 682b in vagina of healthy dogs, 970t KOH prep, 164 Kratom toxicity, 124 Kwan loon medicinal oil toxicity, 125t L L-2-Hydrooxyglutaricaciduria, 1052 L-2-Hydroxyglutaricaciduria, direct mutation test for, 1018t-1020t L-Asparaginase as rescue therapy for canine lymphoma, 382t associated hepatotoxicity, 581b for feline gastrointestinal lymphoma, 548t hypersensitivity reactions to, 333 L-Carnitine for asymptomatic heart disease, 721-722, 724 for diabetes mellitus, 201 for feline hepatic lipidosis, 609, 613 for heart failure, 777 for liver disease, 582-583 for mitochondrial encephalopathy, 1051, 1051t for neuromuscular disease, 1118 requirements with heart disease, 724

1379

L-Deprenyl, 228 L-Lysine. See Lysine L-MTP-PE as cancer immunotherapy, 336t for hemangiosarcoma, 396 Labor and delivery dystocia, 948-956 monitoring of, 951, 953f normal, in the bitch and queen, 948-949 Laboratory quality control for the in-clinic, 306-309 techniques for biopsy and specimen submission, 322-326 techniques for collection of cytology specimens, e153-e156 tests for hereditary disorders, 1015-1021 Laboratory test(s) for disseminated intravascular coagulation, 294t for evaluation of lymphocytosis, 302 for heartworm disease in cats, 826-827, 826t for hepatobiliary disease, 569-575 for hypercoagulable states, 298 for hypothyroidism, 179-182, 180t of the exocrine pancreas, 554-557 Labrador retriever(s) atrioventricular conduction abnormalities in, 734 carprofen toxicity in, 578 copper-associated liver disease in, 589-590 craniocervical junction abnormalities in, 1098-1100 direct mutation tests for, 1017, 1018t-1020t encephalomyelopathy in, 1052-1053 hyperthermia in, 71-72 laryngeal paralysis in, 659-661 limbal melanomas in, 1204 lumbosacral stenosis in, 1105, 1106f Lyme disease in, 1271-1274 nasal parakeratosis in, 476 obesity in, 254 osteosarcoma in, 388 pericardial effusion in, 817 portosystemic vascular anomalies in, 571b progressive retinal atrophy in, 1188-1190, 1189t risk of pyometra with prior pregnancy in, 967 testicular dysgenesis in, 997 vitamin A-responsive dermatosis in, 476 von Willebrand disease in, 288t Lacrimomimetic(s), for keratoconjunctivitis sicca, 11451147, 1146t Lacrimostimulant(s), e386-e387 for keratoconjunctivitis sicca, 1145 Lactate as indicator for temporary pacing, e21 effect of fluid therapy on, 2 levels in shock, 19 with gastric dilation-volvulus, e14, e18

1380

Index

Lactated Ringer’s solution (LRS), drug incompatibilities with, 33t Lactation antibiotics during, 958t hypomagnesemia from, 249b nutrition during, 961-966 termination of, 960 Lactitol, for hepatoencephalopathy, 593 Lactobacillus probiotic(s) for persistent urinary tract infections, 882 for treatment of vaginitis, 973 therapy, 525, 527 Lactoferrin as topical therapy for skin infections, 441t for feline retrovirus infections, 1280t-1281t, 1282-1283 Lactoperoxidase, as topical therapy for skin infections, 441t Lactulose enema with liver failure, 582-583 for hepatoencephalopathy, 593, 596 use of, with feline hepatic lipidosis, 613 Lagenidiosis, e412-e415, e414-e415 clinical findings with, e414 diagnosis of, e414-e415 treatment of, e415 Lagerstroemia speciosa, as diabetes supplement, toxicity of, 125 Lagophthalmos, 1155 Lameness from bartonellosis, 1263-1264, 1263b from cervical spondylomyelopathy, 1092 from craniocervical junction abnormalities, 1101 from Cushing’s myopathy, 1116 from degenerative myelopathy, 1076-1077 from Hepatozoon americanum, 1284 from lumbosacral stenosis, 1105-1106 from Lyme disease, 1213t, 1271 from obesity, 255b from osteosarcoma, 388 from polyarthritis, 1224-1228 from trauma, 80-82 from various infectious agents, 1213t-1215t, 1216-1217 Lamivudine, for feline retrovirus infections, 1278, 1279t Lansoprazole (Prevacid) action and use of, 505-506 for esophagitis, e240 for gastric ulceration, e254 toxicity from, 118 Lantus. See Glargine insulin Laparoscopic surgery cholecystectomy, 605 for gastric dilation-volvulus, e18 Laparotomy, to detect ovarian remnant syndrome, 1002, 1003f Laryngeal collapse, with brachycephalic airway obstruction syndrome, 652, 661 Laryngeal diseases, diagnosis and treatment of, 659-662

Laryngeal masses, 661-662 Laryngeal paralysis causing megaesophagus, e227 from hypothyroidism, e76 in cats, 661 in dogs, 659-661 with heat-induced illness, 71, 73 Laryngoscopy for evaluation of dysphagia, 498 for evaluation of laryngeal paralysis, 660 Larynx, deformities with brachycephalic airway obstruction syndrome, 650t, 652 Laser procedures ablation for actinic dermatoses, 481 of ectopic ureters, 890-891, 891f for acral lick dermatitis, e176 for glaucoma, 1174-1175 lithotripsy for uroliths, e340-e344 Latanoprost causing anisocoria or mydriasis, 1163t, e392 for glaucoma in cats, 1180 for glaucoma in dogs, 1173, 1173b, 1173t for lens instability, 1186 Lavage for open fractures, 85 for open wounds, 87-88 Lawn and garden product(s) risk of urinary bladder cancer from, 370 toxic exposures to, 92t, 95-96 toxicity of, 130-132 Lead toxicity, 156-159, 1027b Leflunomide for autoimmune hemolytic anemia, 279 for immunosuppression, 272-273 Left atrial tear or splitting, 793 Legal, considerations with pet poisoning, e49-e52 Leiomyoma, uterine, 1025-1026 Leiomyosarcoma, uterine, 1025-1026 Leishmaniasis American, diagnosis and treatment of, e396-e397 diagnosis of, e396-e397 associated hepatotoxicity, 581b causing myositis, 1115 causing nonregenerative anemia, e161b causing thrombocytopenia, 281t-282t common symptoms and syndromes caused by, 1214t-1215t Lens capsule rupture, 1183, 1183f changes in, with glaucoma in dogs, 1171t disorders, diagnosis and treatment of, 1181-1187 implantation, 1185, 1185f induced uveitis, 1184, 1184t luxation, 1185-1187, 1186f normal structure and function of, 1181 trauma, 1187

Lens-induced uveitis, 1164 Lenticular sclerosis, 1181, 1182f Lentigo simplex, e367 Leonberger(s) chronic axonal degeneration in, 1117 hypoadrenocorticism in, 233 Leopard’s bane toxicity, 124t Leptin, role in obesity, 254 Leptospirosis, 1286-1289 associated hepatotoxicity, 581b causing infection in humans, 1247-1248 causing pregnancy loss, 1005t, 1006, 1008 causing renal infections, 1212 causing thrombocytopenia, 281t-282t causing uveitis in dogs, 1164b common symptoms and syndromes caused by, 1213t diagnosis of, 1287-1289 effect of vaccination on, 1288 treatment of, 1289 uncommon manifestations of, 1287 Leukemia, 317-318 associated hepatotoxicity, 581b causing lymphocytosis, 302-305 nonregenerative anemia from, e164 Leukopenia, from canine parvoviral enteritis, 533 Leukotriene inhibitors, for respiratory diseases, 626-627 Levamisole causing adverse skin reactions, 488, 488t for feline retrovirus infections, 1280t-1281t, 1282 Levetiracetam (Keppra) for emergent seizures, 1060 for intracranial tumors, 1041t for seizures, 1056 Levey-Jennings control chart, 308 Levorphanol toxicity, 111 Levosimendan, for heart failure, in dogs, 768-770 Levothyroxine causing adverse skin reactions, 488t for hypothyroidism, 179, 183f, 184-185 with complications or concurrent disease, e84-e88 for myxedema coma, e87 use of, with cardiac disease, 184 Lhasa apso hydrocephalus in, 1034-1035 intracranial arachnoid cysts in, 1038 risk of urolithiasis in, 892, 897 Lice infestation. See Pediculosis Licorice associated hepatotoxicity, 581b Lidocaine adverse effects of, 34t-35t CRI, 62t dosage for, 62t for feline arrhythmias, 750f-751f for feline pancreatitis, 567t for heart failure, in dogs, 764t-765t with arrhythmias, 771, 783 for local analgesia, 61

Index Lidocaine (Continued) for supraventricular tachyarrhythmias, 742t, 743 for ventricular arrhythmias, 746-747, 747f, 747t for ventricular fibrillation during CPR, 30 toxicity of, use of IV lipid emulsion therapy for, 106-107 transdermal patch, 62t, 63 use, with gastric dilation-volvulus, e18 Lily of the valley toxicity, 124t Lily toxicity, 121b Limb salvage surgery, for osteosarcoma, 390 Limbal melanomas, in cats, 1207-1208 Limbus tumors, 1204 Lime sulfur dip for cheyletiellosis, 430t for dermatophytosis, 450t for feline demodicosis, e192-e193 for pediculosis, 429t for sarcoptic and notoedric mange, 429t Lincomycin drug interactions with, 677 for pyoderma, 1220t, 1221-1222 for superficial bacterial folliculitis, 438t Linguatula serrata, nasal mite, e270-e271 Linognathus setosus, 429t Lipase. See also Pancreatic lipase immunoreactivity (Spec cPL) for the diagnosis of pancreatitis, 554-555, 561 Lipemia, causing hyperkalemia and hyponatremia, e93 Lipid emulsion for parenteral nutrition, 39-40 therapy, 106-109 Lipid keratopathy, 1153 Lipid metabolism, with diabetes mellitus, 200-201 Lipid(s) approach to canine hyperlipidemia, 261-266 as emulsion therapy, 106-109 Lipogranulomas, for protein-losing enteropathy, 544 Lipoic acid, associated hepatotoxicity, 581b Liposome based immunotherapy, 334, 336t Lipstick ingestion, 99-100 Lithotripsy extracorporeal shockwave, 885 for uroliths, e340-e344 complications of, e344 indications for, e342-e343 limitations, e343-e344, e343t procedure for, e341-e342, e342t Litter box, care and environmental enrichment for domestic cats, 912 Liver bile duct anatomy of, 602-603 biopsy, 574-575 for feline cholangitis, 616 with chronic hepatitis, 585f, 586 with feline hepatic lipidosis, 610

Liver (Continued) with liver failure, 581-582 with portal vein hypoplasia, 600 enzyme elevations, 569-573 of the alkaline phosphatase, e242-e246 with biliary mucocele, e221-e224 with copper-associated hepatitis, e233 with feline cholangitis, 614-619 with feline hepatic lipidosis, 609-610 with hepatobiliary disease, 569-573, 570b with hepatotoxicity, 575-579 with idiopathic vacuolar hepatopathy associated, 606-607 with liver failure, 580-581 function tests, 572 with portosystemic shunt, 595 Liver disease and superficial necrolytic dermatitis, 485-486 associated with hypertriglyceridemia, 261, 262t causing nonregenerative anemia, e161b copper-associated, 588-590, e231-e236 drug-associated, 575-580, 576f, 581b effect on drug therapy, 32-36 extrahepatic biliary tract disease, 602-605 feline cholangitis, 614-619, 617b from Bartonella spp. infections, 1263b from feline hepatic lipidosis, 608-614 from heat-induced illness, 71 from leptospirosis, 1287 from plants, 121b hepatic support therapy for, e255-e258 hepatitis (See Hepatitis) idiopathic vacuolar hepatopathy, 606-608 insulin resistance with, 206b portal vein hypoplasia, 599-602 portosystemic shunt (See Portosystemic shunts (PSS)) toxin-associated, 581b treatment of ascites from, 591-594, e257-e258 treatment of hepatoencephalopathy from, 591-594 with concurrent feline pancreatitis, 566 with diabetes mellitus, e77, e79 Liver failure acute, 580-583 drug effects on, 34t-35t from aflatoxins, 159-161 treatment of ascites with, 591-592 treatment of hepatoencephalopathy with, 592-594 Lomustine as rescue therapy for canine lymphoma, 382t associated hepatotoxicity, 332-333, 570b, 577, 581b for hemangiosarcoma, 396 for intracranial tumors, 1041t, 1044 for multiple myeloma, 386 metronomic chemotherapy of, 343-344

1381

Loperamide for canine colitis, 551b toxicity, 111 Loratadine toxicity, 118-119 Lorazepam for behavior-related dermatoses, 483t, 484 toxicity of, 113-114 Losartan, as hepatic support therapy, e257 Lotion(s) for Malassezia spp. infections, e215 for topical antimicrobials, for otitis, 463 potency of topical steroid, 460f Low fat diets, for hyperlipidemia, 264 Lower motor neuron, signs with degenerative myelopathy, 1077 Lower respiratory tract infection(s). See also under Pneumonia; Respiratory tract infection(s) common pathogens causing, 1222 empiric antimicrobial therapy for, 1220t Lufenuron for dermatophytosis, 451 for Malassezia spp. infections, e215 toxicity, 136b, 140-141 Lumbosacral stenosis, 1105-1108 diagnosis of, 1105-1106 medical treatment for, 1106-1108 surgery for, 1107-1108 Lung acute inflammatory disorder of, 48-51 injury from ventilator therapy, 58 Lung diseases causing respiratory acidosis, e4b causing respiratory alkalosis, e4b from leptospirosis, 1287 interstitial, e266-e269 diagnosis of, e266-e268 Lung lobe torsion, causing pleural effusion, 694, 698 Lung neoplasia, e165 Lung volume, 44 Lungworms, e269-e276 Luteinizing hormone measurement of, 934-935 surge, 930-931, 931f and ovulation timing, 931t and pregnancy complications relative to, 947-948 and pregnancy diagnosis using abdominal palpation, 944 and pregnancy diagnosis with relaxin concentrations, 947 to detect ovarian remnant syndrome, 1001-1002 Lyell’s syndrome, from drug reactions, 489 Lyme disease, 1271-1275 causing infection in humans, 1216 causing lameness, 1216-1217 causing myocarditis, e307 causing nephritis in dogs, 1272 causing polyarthritis, 1227 causing uveitis in dogs, 1164b

1382

Index

Lyme disease (Continued) common symptoms and syndromes caused by, 1213t, 1271 diagnosis of, 1272-1273 differential diagnosis for, 1273 prevention of, 1274-1275 renal infections with, 1212 treatment of, 1227, 1273-1274 vaccination, 1274-1275 Lymph node(s) involvement in mammary cancer, 375, 380t involvement of, with of thyroid tumors, 398-399, 399t involvement with perianal tumors, 368-369 role in cancer surgery, e170-e171 Lymphatic abnormalities causing chylothorax, 697-698 involvement with mammary cancer, 376, 376t obstruction, causing malignant effusions, 341 Lymphocytic cholangitis, 617b, 618 Lymphocytic plasmacytic colitis, 551-552 Lymphocytic plasmacytic enteritis, 550 Lymphocytic portal hepatitis, 615 Lymphocytic-plasmacytic stomatitis, in cats, 492-495 Lymphocytosis diagnosis and treatment of, 301-305 in cats, 305 in dogs, 302-305 nonneoplastic, 305 Lymphoma associated hepatic injury, 581b association with bipyridyl herbicide toxicity, 131 causing eyelid changes, e368 causing hyperlipidemia, 262t causing lymphocytosis, 302-305 causing malignant effusions, 341-342 causing retinal detachment, in dogs, e371 causing secondary ocular neoplasia, 1206, 1206f, 1209-1210 causing uveitis, in cats, 1168 gastrointestinal cobalamin deficiency with, 523-524 feline, 545-549 prognosis, 548-549, 548t protocols, 548t immunotherapy for, 334-335, 337 mediastinal, e166-e167 myocardial, feline, e167 nasopharyngeal, 658 nonregenerative anemia from, e164 ocular, in cats, 1168 of the exocrine pancreas, 557 rescue therapy for canine, 381-383, 382t Lymphoplasmacytic rhinitis, in dogs, 637, 640-641, 640f Lymphoproliferative disorders, causing lymphocytosis, 302 Lynxacarus radovskyi, 431

Lysine for feline ocular herpesvirus 1, 1158 for feline upper respiratory infections, 630 for rhinosinusitis in cats, 646-647 Lysozyme, as topical therapy for skin infections, 441t M Ma huang toxicity, 123 Maalox toxicity, 117 Macadamia nut toxicity, 98-99, 148 Macroadenoma(s), pituitary, e88 Macrolides, causing adverse skin reactions, 488t Macropalpebral fissure, 1155 Macrophage depletion therapy, 335-337 Macules, from adverse drug reactions, 488t Magnesium approach to low levels of, 248-253, 249b chloride supplementation, 250-251 composition in fluid therapy, 3t dietary, recommendations for, with heart disease, 723 ionized, 248, 250-251 physiologic role and function of, 248-249 role in parathyroid hormone production, e123 Magnesium hydroxide, as antacid therapy, 506b, 507 Magnesium sulfate cathartic, for toxin ingestions, 105 Magnetic resonance imaging (MRI) for atlantoaxial subluxation, 10841085, 1086f for canine ocular neoplasia, 1201-1206 for cerebrovascular accidents (stroke), 1121f for cervical spondylomyelopathy, 1093 for Chiari-like malformation in dogs, 1098-1102, 1099f for congenital hydrocephalus, 1035-1036, 1035f for degenerative myelopathy, 1077 for diagnosis of feline hypersomatotropism, 216, 219 for evaluation of dysphagia, 499 for evaluation of hepatobiliary disease, 574 for evaluation of nasal discharge, in dogs, 636-637 for evaluation of pericardial effusion, 819 for fibrocartilaginous embolism, 1124, 1125f for inflammatory central nervous system disorders, 1064 for intervertebral disk disease, 1073 as outcome predictors, 1073-1074 for intracranial arachnoid cysts in dogs, 1038, 1039f for lumbosacral stenosis, 1106, 1107f for myocarditis, e305 for nasal tumors, 338 for pituitary macroadenoma, e89-e90

Magnetic resonance imaging (MRI) (Continued) for portal vein hypoplasia, 600 imaging for diagnosis of endocrine disorders, 167-174 of adrenal gland(s), 170-172 for hyperaldosteronism in cats, 240 of pancreas, 172-174 of pituitary gland, 172, 173f of thyroid gland, 167-170 to evaluate for causes of dysphagia, e260, e261f Maine coon cat blood type of, e145t diabetes mellitus in, 208 myocardial disease in, 804 Major vessel neoplasia, e167-e168 Malassezia infection(s) causing blepharitis, e364 dermatitis, e212-e216 perivulvar, 971 topical therapy for, 441t, 442-443 otitis, e212-e216 topical therapy for, 463-464 Malignancy. See also Neoplasia causing hypercalcemia, in cats, 243, 243b Malignant effusions, 341-344 Malignant glaucoma, 1178 Malignant histiocytosis cancer immunotherapy for, 336t nonregenerative anemia from, e164 Malignant obstruction(s) interventional oncology for, 345-347 urethral stenting for, 889-890 Malnutrition, in critical care, 38 Malonic aciduria, 1052-1053 Maltese glaucoma in, 1171b, 1176f hepatobiliary disease in, 571b mammary tumors in, 375, 377-378 portosystemic shunts in, 594 protein-losing enteropathies in, 540-541 risk of urolithiasis in, 897 von Willebrand disease in, 288t Mammary neoplasia cancer immunotherapy for, 336t comparison between canine and feline, 379t diagnosis and treatment of, 375-380 immunotherapy for, 336t in cats, 378-380, 380t risk of, with progestin drugs, 985 Mammomonogamus ierei, nasal, 656, e270 Manchester terrier(s), direct mutation tests for, 1018t-1020t Mandibular tumors, 363-364 Mandrake toxicity, 124t Manganese toxicity, 1027b Mannitol for cerebral edema from prolonged seizures, 1061-1062, 1062t for cerebrovascular accidents (stroke), 1122 for glaucoma in cats, 1179, e381 for glaucoma in dogs, 1172-1174, 1173b, e381

Index Mannitol (Continued) for intracranial tumors, 1041t for oliguria with acute renal failure, 869, 869t to promote ureterolith passage, 894 Manometry, for evaluation of the esophagus, e227-e228 Marbofloxacin drug interactions with, 35t for otitis systemic, 466t topical, 464t for superficial bacterial folliculitis, 438, 438t Marijuana enterohepatic recirculation of, 105 toxicity, 110-111 Maropitant (Cerenia) for canine pancreatitis, 562-563 for feline cholangitis, 617, 617b for feline pancreatitis, 567t for hepatic lipidosis, 612 for management with GI effects of chemotherapeutic drugs, 331 for vomiting with acute renal failure, 870 with canine parvovirus, 535 Masitinib, 360-362 Mast cell tumor(s) associated hepatic injury, 581b causing eyelid changes, e368 immunotherapy for, 336t masitinib for, 360-362, 361t scrotal, 1023 Mastication, role in swallowing, 495-496 Masticatory muscle myositis, 1113-1114, 1199 Mastiff(s) cervical spondylomyelopathy in, 1092 colitis in, 553 cystine crystalluria in, 926 hereditary tests for, 1018t-1020t retinopathies in, 1188 Mastitis, septic, 959, 959f Maternal causes of pregnancy loss, 1005-1010 Matrix metalloproteinase 9, with intervertebral disk disease, 1073-1074 Maxillary tumors, 363-364 Mayapple toxicity, 124t Mayflower toxicity, 124t MDR-1 gene, predicting adverse effects of drug therapy, 330 Meadowsweet toxicity, 125t Mean arterial pressure, and intracranial dysfunction, 68-69, 69f Mean corpuscular hemoglobin concentration (MCHC), and in-clinic laboratory quality, 307-308 Mebendazole associated hepatotoxicity, 570b, 581b Mechanical occluder devices for urinary incontinence, 919-923, 920f Mechlorethamine, as rescue therapy for canine lymphoma, 382t Meclizine for intracranial tumors, 1041t for vestibular disease, 1045

Medetomidine, use of with cardiovascular dysfunction, 64-65 with intracranial pathology, 69 Mediastinal mass lymphocytosis associated with, 304 neoplasia, e166-e167 Medical records, considerations of, with legal claim with poisonings, e50-e52 Medication error(s), e37 Medications. See under Drug(s) Medroxyprogesterone acetate adverse effects of, 1013 for benign prostatic hypertrophy, 1013 for estrus suppression in the bitch, 986-987 Medulloepitheliomas, 1205 Megacolon, feline idiopathic, 516 Megaesophagus, e224-e230 acquired, e226-e227 causes of, e225b congenital, e226 diagnosis of, e227-e228 from hypothyroidism, e76 functional anatomy of, e224-e225 idiopathic, e227 prognosis of, e230 treatment of, e228-e230 Megestrol acetate (Ovaban) for benign prostatic hypertrophy, 1013 for eosinophilic keratitis, 1159 for estrus suppression in the bitch, 984-986 Meglumine antimoniate, for American leishmaniasis, e397 Meibomian gland adenoma, e368 function of, 1143-1144 infection, e363-e365 tumors, 1202, 1202f-1203f Melaleuca oil, 126-127, 140 Melanocytoma, uveal, 1204 Melanoma limbal, 1204 masitinib for, 361t ocular, in cats, 1207-1209, 1208f oral, treatment of, 364-365 tumor vaccine for, 335 uveal, 1204 Melarsomine dihydrochloride (Immiticide) adverse effects of, 835 for heartworm disease in cats, 829-830 in dogs, 833-835, 834f Melatonin for alopecia X, 479 for hyperadrenocorticism in ferrets, e96 for idiopathic vacuolar hepatopathy, 607-608 Meloxicam adverse effects of, 60 dosage for, 62t for canine uveitis, 1165t for feline uveitis, 1169t for kidney disease, 865-866 influence on thyroid function, 181t toxicity of, 116-117

1383

Melphalan (Alkeran) as rescue therapy for canine lymphoma, 382t for multiple myeloma, 385-386 Memantine, for glaucoma in dogs, 1173b, 1174 Membranoproliferative glomerulonephritis, 855-856 Membranous glomerulopathy, 855 Menace test, 1134-1135, e390-e391 Meningioma, 1039-1047, 1042t-1043t of the optic nerve, 1205 Meningitis, use of glucocorticoids for, 1232-1233 Menthol, as topical antipruritic agents, 419 Meperidine toxicity, 111 use of, with cardiovascular dysfunction, 65t Mepivacaine, toxicity of, use of IV lipid emulsion therapy for, 106 Mercury toxicity, 1027b Meropenem, for otitis, 466t, 467 Mesalamine, for canine colitis, 551b Mesenteric portography, with portal vein hypoplasia, 600 Mesna, given with ifosfamide, e139 Mesothelioma, e165-e166 causing malignant effusions, 341 causing pleural effusion, 694-695 pericardial, 817, 820 Metabolic causes of dysphagia, 496b complications of hypomagnesemia, 250 Metabolic acidosis causing hyperkalemia and hyponatremia, e93, e93b common causes of, e7b compensatory response to, e2t from diabetic ketoacidosis, e79, e80t-e81t, e82 management of acid-base disorders and, e5-e8 sodium bicarbonate for, 67-68 with acute kidney disease, 870 with chronic kidney disease, 862 with gastric dilation-volvulus, e16 with hypoadrenocorticism, treatment of, 236 with maintenance anesthetic, 67 Metabolic alkalosis common causes of, e8b compensatory response to, e2t from diuretic therapy, 779 from hyperthermia, 70-71 hypokalemia and, 252 management of acid-base disorders and, e5-e8 Metabolic brain disorders, 1047-1053 Metabolic disorder(s) causing pregnancy loss, 1007 causing seizures, 1058 Metabolism, and cancer cachexia, 350 Metaflumizone/amitraz (ProMeris), drug reactions from, 489 Metaldehyde toxicity, 96

1384

Index

Metatarsal fistulation, topical immunomodulators for, e219 Metatarsal sinus tracts, use of cyclosporine for, 410b Metatarsal trauma in dogs, 81 Metergoline, for pregnancy termination, 990 Metformin, for diabetes mellitus, in cats, e136t, e137 Methadone adverse effects of, 60 dosage for, 62t for feline thromboembolism, 810 for the critical patient, 59 to calm respiratory distress pets, 47t toxicity, 111 use of, with cardiovascular dysfunction, 65t Methanol in ear cleaners, 472t toxicity, 151 Methazolamide, for glaucoma in dogs, 1173-1174, 1173b, e381 Methemoglobinemia from acetaminophen toxicity, 118 from onion/garlic toxicity, 147-148 Methenamine hippurate, for persistent E. coli urinary tract infections, 881b, 882 Methicillin-resistant Staphylococcal infections causing pyoderma, 435 diagnosis and treatment of, 443-445 disinfection of environments with, 455-457, 456t from raw meat diets, 1240-1241 resistance, 435 topical therapy for, 440, 441t, 442 vaginal, 973 Methimazole (Tapazole) adverse reactions from, 488t, 489, e103-e104 associated hepatotoxicity, 578, 581b clinical monitoring of, e104 for hyperthyroid cats, e102-e106, e103t, e108-e111 with kidney failure, 188 transdermal, e104-e105 transitioning to limited-iodine diets from, e111 Methoprene toxicity, 140-141 Methotrexate associated hepatotoxicity, 570b for feline gastrointestinal lymphoma, 548t use of, for immunosuppression, 268-269 Methoxyflurane toxicity, 581b Methyl chloroform toxicity, 1027b Methyl ethyl ketone toxicity, 1027b Methyl n-butyl ketone toxicity, 1027b Methylmalonic aciduria, 1052-1053 Methylphenidate toxicity, 109-110 Methylprazole (4-MP), for ethylene glycol toxicity, 153, e31 Methylprednisolone. See also under Glucocorticoid(s) drug incompatibilities with, 33t

Methylprednisolone (Continued) for feline asthma and chronic bronchitis, 676 for feline caudal stomatitis, 493-494 for feline gastrointestinal lymphoma, 547 for intracranial tumors, 1041t for otitis, systemic, 461t for respiratory diseases, 626 structure and use of in dermatology, 414-418 Methylxanthine(s) for atrioventricular block, in cats, 754 for feline asthma, 677 for respiratory diseases, 624-625, 671 toxicity, 148-149, 148t Metipranolol, for glaucoma in dogs, 1173b Metoclopramide (Reglan) action and use of, for motility disorders, 516-518, 517t adverse effects of, 34t-35t with dopamine, 34t-35t drug incompatibilities with, 33t for acute pancreatitis in dogs, 562-563 for esophagitis, e239-e240 for feline pancreatitis, 567t for gastroesophageal reflux, 503 for hepatic lipidosis, 612 for vomiting with acute renal failure, 870 use of prior to cesarean section, 955 Metoprolol for asymptomatic heart disease, 766 for heart failure, in dogs, 770-771, 792 for supraventricular tachyarrhythmias in dogs, 742t Metritis causing pregnancy loss, 1005-1006, 1005t postpartum, 958, 958t Metronidazole (Flagyl) adverse effects of, 34t-35t dosing of, with liver disease, 32-33 for antibiotic-responsive diarrhea, 519 for canine colitis, 551b, 552 for epiphora, e375 for Giardia spp., 530t for hepatoencephalopathy, 593-594 for protein-losing enteropathy, 544 protocol for helicobacter spp., 511t target parasites and dosage of, 1335-1337 toxicity, causing vestibular signs, 1068-1069 Metronomic chemotherapy, 354-357 for hemangiosarcoma, 396 with soft tissue sarcomas, e151 Mexiletine for arrhythmia with congestive heart failure, 783 for arrhythmia with dilated cardiomyopathy, in dogs, 799 for heart failure, in dogs, 764t-765t for ventricular arrhythmias, 747-748, 747t with arrhythmogenic right ventricular cardiomyopathy, 803

Mibolerone (Cheque drops), for estrus suppression in the bitch, 984 Miconazole for Malassezia spp. infections, 442, e215 for otitis, topical, 463-464, 465t for pyoderma, 440-441 for skin infections, topical, 441t Microalbuminuria, 850 from diabetes mellitus, e76 Microbial homeostasis, gastrointestinal, 519f Microfilarial test for canine heartworm disease, 832 for feline heartworm disease, 826-827 Micronutrient, supplementation of, with diabetes mellitus, 201-202 Microscopic agglutination test (MAT) titers, for leptospirosis, 1287-1289 Microscopy, for Bartonella spp., 1265 Microsomal triglyceride transfer protein inhibitors, 260 Microsporum spp. causing blepharitis, e363-e364 causing dermatophytosis, 449-451 in multicat environments, 452-454 Microvascular dysplasia. See Portal vein hypoplasia Midazolam adverse effects of, 34t-35t drug interactions with, 35t for emergent seizures, 1059 toxicity of, 113-114 use of, with cardiovascular dysfunction, 64-65 Mifepristone, for pregnancy termination, 991 Milbemycin oxime for cheyletiellosis, e182 for demodicosis, 433t, 434, e183 for dermatologic disorders, e178, e180-e181 for lung worms, e275 for nasal mites, 637, 655-656, e270 for Otodectes infestation, 431t for sarcoptic and notoedric mange, 429t for sarcoptic mange, e181 target parasites of, 1335-1337 toxicity of, 145-146 Miliary dermatitis, 424-425 Milk thistle. See Silymarin Milrinone, for heart failure, in dogs, 763, 768-770 Mineralization, from high phosphorus and calcium, 244 Mineralocorticoid(s) activity of systemic glucocorticoids, 461t deficiency of, with hypoadrenocorticism, 233-237 excess, with feline hyperaldosteronism, 238 for hypoadrenocorticism therapy, 236-237 Miniature pinscher(s), direct mutation tests for, 1018t-1020t

Index Miniature schnauzer(s), vitamin A-responsive dermatosis in, 476 Minilaparotomy-assisted cystoscopy for urocystoliths, 905-909, 906f Minimum inhibitory concentration, with antimicrobial therapy, 1219 Minocycline, for feline upper respiratory infection, 631t Miosis causes of, e392 from canine uveitis, 1163t Miotic(s), for glaucoma in dogs, 1173b, 1174 Mirtazapine adverse effects of, 34t-35t dosage with renal failure, 34t-35t for hepatic lipidosis, 611 for management of GI effects with chemotherapeutic drugs, 331 Misoprostol action and use of, 506-507 for gastric ulceration, e254 for pregnancy termination, 990 Mistletoe associated hepatotoxicity, 581b Mite(s), drugs targeting, 1335-1337 Mithramycin associated hepatotoxicity, 581b Mitochondrial encephalopathy, 10481051, 1049t, 1051t Mitocidal therapies, for demodex, 433-434, 433t Mitomycin C for esophageal strictures, e240-e241 for urinary bladder cancer, 373 Mitotane (o,p’-DDD, Lysodren) associated hepatotoxicity, 581b for adrenal-dependent hyperadrenocorticism, 229 for alopecia X, 479 for hyperadrenocorticism in ferrets, e95 for idiopathic vacuolar hepatopathy, 607-608 for pituitary-dependent hyperadrenocorticism, 225-229 monitoring therapy of, e98 Mitoxantrone as rescue therapy for canine lymphoma, 381-383, 382t for intrathoracic chemotherapy, 343 for mammary cancer, 379-380 for urinary bladder cancer, 373 Mitral regurgitation. See also Valvular heart disease asymptomatic, 765-766, 790 atrial tear from, 793 heart failure from, 766-768, 790-792 neurocardiogenic syncope with, e326-e327 Mitral valve disease causing pulmonary hypertension, 711, 712t diagnosis and treatment of, chronic, 784-794, 785f staging of, 787t Mitral valve dysplasia diagnosis and treatment of, e299-e302, e301f

Mitral valve dysplasia (Continued) prevalence of in cats, 757, 757t in dogs, 756, 757t prognosis for, e302 Mitratapide, for treatment of obesity, 259-260 Moisturizers, as antipruritic agents, 419, 420t Mold(s) as respiratory allergens, e44 immunotherapy for, 411 Mometasone furoate, potency of, for otitis, 460t Momordica charantia, as diabetes supplement, toxicity of, 125 Monoclonal antibody therapy, for mammary cancer, 377-378 Montelukast, for feline asthma, 678 Morgagnian cataract, 1181-1183, 1183f Morphine adverse effects of, 60 CRI, 62t dosage for, 62t drug incompatibilities with, 33t for epidural analgesia, 61 for the critical patient, 59 to calm respiratory distress pets, 47t toxicity, 111 use with cardiovascular dysfunction, 65t use with intracranial pathology, 69 Mosapride action and use of, for motility disorders, 516-518, 517t for esophagitis, e239-e240 Mosquito(s) drugs targeting, 1335-1337 prevention products, pet exposure to, 100 transmission of disease by, from pets to humans, 1248 Motilin agonists, action and use of, for motility disorders, 516-518, 517t Motility disorders, gastric and intestinal, 513-518 Moxidectin causing adverse skin reactions, 488t for cheyletiellosis, 430t for demodicosis, 433t, 434, e183 for dermatologic disorders, e178, e181 for lung worms, e274-e275 for Otodectes, 431t, e182 for sarcoptic and notoedric mange, 429t for sarcoptic mange, e181-e182 target parasites of, 1335-1337 toxicity of, 145-146, e181 use of IV lipid emulsion therapy for, 106, 108 Moxidectin/imidacloprid, target parasites of, 1335-1337 Mucin deficiency, 1155 Mucinolytic agent(s), for keratoconjunctivitis sicca, 1147 Mucoceles, of the gall bladder, 604-605, e221-e224

1385

Mucolytic drug(s) for canine bronchial diseases, 672 for pneumonia, 687 for respiratory diseases, 627 Mucometra, 947 Mucopolysaccharidosis IIIB, direct mutation test for, 1018t-1020t Mucopolysaccharidosis VI, direct mutation test for, 1018t-1020t Mucopolysaccharidosis VII, direct mutation test for, 1018t-1020t Mucosa-associated lymphoid tissue (MALT) lymphoma, Helicobacter spp associated, 509 Mulch toxicity, 131-132 Müllerian agenesis or hypoplasia, 996 Müllerian duct syndrome, persistent, 997-998, 998f Multicat household(s) conflict in, 912-913 environmental enrichment for, 909-914 management of retrovirus infections in, 1276 outbreaks with dermatophytosis in, 452-454 upper respiratory infection in, 629 Multidrug resistance (MDR-1) gene, avermectin toxicity and, 145-146, e179 Multiple myeloma, 384-386 causing secondary ocular neoplasia, 1206 diagnosis and treatment of, 384-386, 385b nonregenerative anemia from, e164 Mupirocin for hot spots, e207-e208 for lick granulomas, e178 for skin infections, 441t, 442 Murmurs. See Heart murmur(s) Muscle atrophy, with degenerative myelopathy, 1079 disorder as cause of dysphagia, 496b injury as cause of hepatobiliary enzyme elevations, 570b Musculoskeletal concerns regarding, with early age neutering, 983 problems, empiric antimicrobial therapy for, 1220t Musculoskeletal disorder(s) degenerative myelopathy, 1075-1081 infectious causes of polyarthritis, 1224-1228 Musculoskeletal infection(s) common pathogens causing, 1222-1223 infectious causes of polyarthritis, 1224-1228 treatment of neuropathies and myopathies, 1113-1118 Mushroom toxicity, 94, 95t Mustargen, extravasation and tissue sloughing from, 333 Myasthenia gravis acquired, from methimazole, e104 causing megaesophagus, e226, e228

1386

Index

Myasthenia gravis (Continued) diagnosis of, 1109, e226 immunosuppressive drugs for, 268 monitoring the course of, 1111-1112, e228-e229 therapy of acute fulminating, 1111 treatment of autoimmune, 1109-1112, e228-e229 Mycobacterium causing nontuberculous cutaneous granulomas, 445-448 using immunotherapy for, 1232 Mycophenolate mofetil for autoimmune hemolytic anemia, 279 for myasthenia gravis, 1111 for thrombocytopenia, 285t use of, for immunosuppression, 272 Mycoplasma haemocanis, 1213t Mycoplasma haemofelis, 1213t, e399 Mycoplasma haemominutum, 1213t Mycoplasma hematoparvum, 1213t Mycoplasma turicensis, 1213t Mycoplasmosis as cause of thrombocytopenia, 281t-282t carrier status of, e399, e400f causing canine respiratory infection, 632-633, 1217-1218 causing feline upper respiratory infections, 629, 1217-1218 causing pneumonia, 681, 683t, 687-688 causing pregnancy loss, 1005t, 1006, 1010, 1218 causing thrombocytopenia, 281t-282t causing vaginitis, 972-973 common symptoms and syndromes caused by, 1213t diagnosis of, e400-e401 features of, e399 hemotropic, e398-e401 in feline airways, 676 in the female reproductive tract, 938 normal isolates in healthy dogs, 973b rational use of glucocorticoids for, 1300-1301 treatment of, e401 with feline asthma and bronchial disease, 678 Mycotoxin(s), exposures to, 95t Mydriasis, causes of, e392 Mydriatic(s), for canine uveitis, 1165t Myelin basic protein, with intervertebral disk disease, 1073-1074 Myelodysplastic syndrome, 314, 317, e163-e164 Myelofibrosis, secondary, e163 Myelography for cervical spondylomyelopathy, 1093 for intervertebral disk disease, 1073 for lumbosacral stenosis, 1106, 1106f with fibrocartilaginous embolism, 1124 Myeloid to erythroid ratio, 315f Myelonecrosis, e162-e163 Myelopathy degenerative, 1075-1081 ischemic, 1123-1125

Myelosuppression, from chemotherapeutic drugs, 330-331 Myelotoxic drug(s), for immunosuppression, 268-269 Myocardial disease, feline, 804-810 Myocardial infarction as cause of sudden death, 782 causing hypokalemia, 251b, 252 with cardiogenic shock, 783 with corticosteroid insufficiency, 174 with feline myocardial disease, 804 Myocarditis, e303-e308 atrial, e308 causes of, e304t diagnosis of, e304-e306 feline, e306-e307 pathophysiology of, e303-e304 treatment of, e306 Myopathy(ies) from hyperadrenocorticism, 1116 from hyperthyroidism, 1115 from hypokalemia, 1116 from hypothyroidism, 179, 1115, e76 from steroids, 1116 rehabilitation considerations with, e360-e362 treatment of, 1113-1118 Myositis dermato-, 1115 extraocular muscle, 1114-1115 masticatory muscle, 1114, 1199 poly-, 1114 Myotomy, for cricopharyngeal achalasia, 499-500 Myotonia congenita, direct mutation test for, 1018t-1020t from hyperadrenocorticism, 1116 Myxedema coma, e86-e87 Myxosarcoma, scrotal, 1023 N N-acetylcysteine for acetaminophen toxicity, 118, 576-577 for liver failure, 582 N-methyl-D-aspartate antagonist(s), use in critical care, 60-61 N-terminal pro-B-type natriuretic peptide (NT-proBNP) in asymptomatic cats, 805 in dogs with murmurs, 786-787 with canine DCM, 797 with congenital heart disease, 759 with feline arrhythmias, 750f-751f with feline myocardial disease, 804-805 with respiratory distress, 47, 793 with valvular heart disease, 790 Nabumetone toxicity, 116-117 Nail bed epithelial inclusion cyst, e185 inverted squamous papillomas, e185 Naloxone, 30 as antidote, e56t dosage for, 62t for opioid toxicity, 111 Naproxen toxicity, 116-117, e32-e33

Narcolepsy, direct mutation test for, 1018t-1020t Narcotic(s), use of prior to cesarean section, 955 Nasal deformities with brachycephalic airway obstruction syndrome, 650t disease from Bartonella spp. infections, 1263b parasites, 636b, 655-656, e269-e271 Nasal arteritis, use of cyclosporine for, 410b Nasal biopsy, 637 Nasal catheter, for oxygen administration, 53 Nasal discharge in cats, 644-648 in dogs, 635-643, 636b Nasal neoplasia, e157-e159 chemoembolization for, 348, 348f in cats, 644, 648, e159 in dogs, 641-643, 642f radiation therapy for, 338-340 staging of, e157 Nasal parakeratosis, 476 Nasal polyps, 656-657 in dogs, 641-643 Nasoesophageal tube(s), for hepatic lipidosis, 611 Nasogastric tube(s), and risk of aspiration pneumonia, 685 Nasolacrimal apparatus cannulation of, 1132-1133 obstruction of, e376 testing of, 1132 Nasopharyngeal disorders, 653-658 cysts, 657-658 diagnosis of, 654-655 foreign bodies causing, 655 mucous, 655 neoplasia, 658 parasites causing, 655-656 turbinates, 657 Nasopharyngeal polyps, 656-657 causing vestibular signs, 1068 Nasopharyngoscopy, for evaluation of nasal neoplasia in dogs, 641 Nasopharynx deformities with brachycephalic airway obstruction syndrome, 650t surgical access to, 655 Nebulization for pneumonia, 687 of gentamicin, 628, 634, 671 Nebulizers for canine bronchial diseases, 672 for respiratory diseases, 623-624 Neck pain from atlantoaxial subluxation, 1082-1090 from cervical spondylomyelopathy, 1092-1093 from Chiari-like malformation, 1098-1105 Necrolytic dermatitis, 485-487 Necrotizing leukoencephalitis, 1063-1066 Necrotizing meningoencephalitis, 1063-1066

Index Nemotodal, causes of thrombocytopenia, 281t-282t Neomycin causing adverse skin reactions, 488t causing drug reaction conjunctivitis, 1140 for hepatoencephalopathy, 593-594 topical, for otitis, 464t Neonatal corneal dystrophy, 1153 Neoplasia adrenal gland, with feline hyperaldosteronism, 241 associated hepatic injury, 581b association of, with Helicobacter spp., 508 association with herbicide toxicity, 131 biopsy and specimen submission for, 322-326 bladder diagnosis and treatment of, 370-374, 371t ultrasound findings with, 843, 844f blepharitis, e368 bone marrow, anemia from, e164 cardiac, e167 causing neuropathies, 1117 causing nonregenerative anemia, e161b causing pleural effusion, 694-695 causing pregnancy loss, 1007 causing pulmonary hypertension, 711, 712t causing retinal detachment, in dogs, e371, e372f collection of specimens for cytology with, e153-e156 ectopic ACTH syndrome with, 230 effusions from, 341-344 exocrine pancreatic, 557 hemangiosarcoma, 392-397 immunotherapy for, 334-337 incomplete resection and local recurrence, e172 insulin resistance with, 206b interventional oncology and, 345-349 intraarterial chemotherapy for, 347-348 lower urinary tract, 890, 891f intracranial, 1039-1047, 1042t laryngeal, 661-662 lung, e165 ectopic ACTH syndrome with, 230 from second-hand smoke, e44 lymphoma (See Lymphoma) major vessel, e167-e168 mammary, 375-380 comparison between canine and feline, 379t mediastinal, e166-e167 metronomic chemotherapy for, 354-357 multiple myeloma, 384-386 nasal, e157-e159 from second-hand smoke, e44 in cats, 644, 648 in dogs, 641-643, 642f radiation therapy for, 338-340 nasopharyngeal, 658

Neoplasia (Continued) new anticancer drugs for, e139-e142 ocular corneal, 1156 in cats, 1207-1210 causing glaucoma, 1177-1178 in dogs, 1201-1206 causing uveitis, 1164, 1164b orbital, 1199 oral, diagnosis and treatment of, 362-366 osteosarcoma, 388-392 palliative vs. curative surgery, e171 perianal, 366-369 perineal, 366-369 plasma cell, 384-387 plasmacytoma, 386-387 pleural space, e165-e166 pulmonary, e165-e168 pulmonary thromboembolism associated with, 705 renal, ultrasound findings with, 842, 843f reproductive, 1022-1026 soft tissue sarcomas, e148-e152 stenting for obstructions caused by, 345-347, 889-890 talking to clients about, 318-321 thromboembolic disease with, 812 thyroid tumors, 397-400 toceranib (Palladia) update for, 358-360 urethral, ultrasound findings with, 844f vaccine-associated, in cats, 1252-1255 vaginal, 972 with diabetes mellitus, e77 Neoplastic obstruction(s), interventional oncology for, 345-347, 889-890 Neoral, 270 Neorickettsia helminthoeca, common symptoms and syndromes caused by, 1214t Neorickettsia risticii, common symptoms and syndromes caused by, 1214t Neorickettsial, causes of thrombocytopenia, 281t-282t Neospora caninum, 1290-1291 causing myositis, 1115 causing nervous system signs, 1212 causing pregnancy loss, 1218 common symptoms and syndromes caused by, 1214t-1215t diagnosis of, 1290 dosage for and drugs targeting, 1335-1337 in raw meat diets, 1240b, 1241-1242 treatment of, 1290-1291 Neotrombicula autumnalis, 431-432 Nepafenac, for canine uveitis, 1165, 1165t Nephrolithiasis concurrent infections with, 893-894 interventional approach to kidney and ureter, 884-889 lithotripsy for, 884-889 medical management of, 892-896 percutaneous removal of, 885f when they should be treated, 925-926

1387

Nephropathy. See also Protein-losing nephropathy familial, direct mutation test for, 1018t-1020t from diabetes mellitus, e76 Nephroscopy, interventional strategies for urinary diseases, 884 Nephrostomy percutaneous, for ureteral obstructions, 887, 888f tubes, use of, with nephroliths and ureteroliths, 895 Nephrotic syndrome causing hyperkalemia and hyponatremia, e93 diagnosis and treatment of, 853-857 Nephrotic-range proteinuria, 853 Nephrotomy, effect on glomerular filtration, 884-885 Nephrotoxicity causes of, e29-e34, e30b from amphotericin, 1234-1235 from nonsteroidal anti-inflammatory drugs, 864, 865t, 866-867 Nerve, lesions causing anisocoria or mydriasis, e390, e390f, e393t Nerve conduction velocities, for degenerative myelopathy, 1077 Nerve injury, peripheral, rehabilitation considerations with, e360-e362 Nerve sheath tumor, eyelid, 1207 Netilmicin, causing renal failure, e31-e32 Neural tumors, 1039-1047 Neurally mediated syncope, e326-e327, e327f Neuro-ophthalmic examination, e388-e395 Neurodiagnostic testing, for degenerative myelopathy, 1077 Neuroepithelial tumors, 1039-1047 Neurologic disorder(s) causing anisocoria or mydriasis, e392-e395 causing dysphagia, 496b craniocervical junction abnormalities in dogs, 1098-1105, 1099f degenerative myelopathy, 1075-1081 drug incompatibilities and interactions with, 37 from atlantoaxial subluxation, 1082-1090 from cerebrovascular accidents (stroke), 1119-1126 from cervical spondylomyelopathy, 1090-1097 from congenital hydrocephalus, 1034-1037 from encephalomyelopathy, 1052-1053 from intervertebral disk disease, 1070-1075 from lumbosacral stenosis, 1105-1108 from malonic aciduria, 1052-1053 from methylmalonic aciduria, 1052-1053 from mitochondrial encephalopathy, 1047-1053 from myasthenia gravis, 1109-1112 from organic acidopathies, 1052-1053

1388

Index

Neurologic disorder(s) (Continued) infectious agents that cause, 1212 inflammatory diseases of the CNS, 1063-1066 intracranial arachnoid cysts in dogs, 1038-1039 intracranial tumors, 1039-1047 new anticonvulsants for, 1054-1057 physical therapy and rehabilitation for, e357-e362 secondary to hypertension, 726 treatment of cluster seizures and status epilepticus, 1058-1063 treatment of neuropathies and myopathies, 1113-1118 vestibular, 1066-1070 with pituitary macroadenoma, e89 with pituitary-dependent hyperadrenocorticism, 228 Neuromuscular disease adjunctive therapy for, 1117-1118 causing respiratory acidosis, e4b Neuronal ceroid lipofuscinosis, direct mutation test for, 1018t-1020t Neuropathy(ies) from diabetes mellitus, e76-e77 from hypothyroidism, e84-e85 ototoxicity from, 468b treatment of, 1113-1118 Neuroprotective agent(s) for glaucoma in dogs, 1173b, 1174 for intervertebral disk disease, 1074 Neutering early age, in dogs and cats, 982-984 summary of risks, 983t for benign prostatic hypertrophy, 1013 for treatment of alopecia X, 479 risk of prostate cancer and, 1023-1024 Neutral protamine Hagedorn (NPH) insulin, 190-191, 210 Neutropenia diagnostic workup for, 315f from canine parvoviral enteritis, 533 from chemotherapeutic drugs, 330-331 from methimazole, e103 Neutrophilic cholangitis, 615-618, 617b Newfoundland dog(s) cardiomyopathy in, 795-796 dilated cardiomyopathy in, 724, 795-796 direct mutation tests in, 1018t-1020t laryngeal paralysis in, 659 polymyositis in, 1114 subaortic stenosis in, e319 Niacin, for hyperlipidemia, 265 Niacinamide, causing adverse skin reactions, 488t Nicotine toxicity, 119-120 Nictitating membrane neoplasia of in cats, 1207 in dogs, 1203 prolapsed gland of, 1203 Nightshade toxicity, 124t Nitazoxanide for Giardia spp., 531 target parasites and dosage of, 1335-1337

Nitenpyram, 426t target parasites of, 1335-1337 toxicity of, 140-141 Nitrofurantoin causing toxic polyneuropathy, 1116-1117 for urinary tract infections, 924, 1220-1221, 1220t Nitrogen dioxide toxicity, 1027b, e45 Nitrogen mustard compounds, ototoxicity from, 468b Nitroglycerine ointment, for heart failure, in dogs, 764t-765t, 767-768 Nitroprusside for cardiogenic shock, 783 for heart failure, in dogs, 764t-765t, 767-768 for hypertension, 870-871 from acute renal failure, 870 with chordae tendineae rupture, 793 Nitrous oxide anesthesia in critical care, 66 use of with cesarean section, 955 Nitrovasodilators, for heart failure, in dogs, 767-768 Nizatidine for esophagitis, e240 for motility disorders, 516-518 potency and use of, 505, 506b toxicity of, 119 Noise, ototoxicity from, 468b, 469 Non-immunologic transfusion reactions, 313 Nonbenzodiazepine hypnotic agents, toxicity of, 112-114 Noncardiogenic pulmonary edema as cause of respiratory distress, 46-47, 46t from herbicide toxicity, 131 from seizures, 1058, 1061 vs. acute respiratory distress syndrome, 49-50 with fluid therapy in critical care, 6 Nonepidermolytic ichthyosis, 475-476 Noni juice toxicity, 124-125 Nonsteroidal antiinflammatory drug(s) (NSAIDs) adverse effects of, 34t-35t, 60 cutaneous, 489 gastric ulcerations, e252-e253, e253f dosages for, 62t for canine uveitis, 1165, 1165t for feline caudal stomatitis, 494 for feline uveitis, 1168-1169, 1169t for hemangiosarcoma, 396 for kidney disease, 863-867 for treatment of cancer, 359 influence on thyroid function, 181t interaction of, with glucocorticoids, 34t-35t metabolism of, e33 renal effects of, 864-866, 865t role of cyclooxygenase isoenzymes of, 863-864 topical use of, 419-421 toxicity of, 116-117, 864, e32-e33 animals at risk for, 864-865, 865t use of

Nonsteroidal antiinflammatory drug(s) (NSAIDs) (Continued) with chronic kidney disease, 866-867, 866b with misoprostol, 506-507 Nonthermal irreversible electroporation, for intracranial tumors, 1046 Nontuberculous cutaneous granulomas, 445-448, 446f-447f, 448t Nonulcerative corneal disease in dogs, 1152-1156 Nonvolatile buffer ion acid-base abnormalities, causes of, e5b acidosis, e5 alkalosis, e5 Norepinephrine for seizure patients, 1061t receptor activities of, 15t use and dosage of, 15t, 16 Norepinephrine reuptake inhibitors toxicity, 112-114 Norfolk terrier(s) epidermolytic ichthyosis in, 475 glaucoma in, 1171b ichthyosis in, 475 portal vein hypoplasia in, 599 Nosodes, for feline retrovirus infections, 1280t-1281t, 1283 Notoedric mange diagnosis and treatment of, in cats, 429-430 treatment options for, 429t Nova Scotia duck tolling retriever(s) direct mutation tests for, 1018t-1020t hypoadrenocorticism in, 233 NPH insulin. See Neutral protamine Hagedorn (NPH) insulin NT-proBNP. See N-terminal pro-B-type natriuretic peptide (NT-proBNP) Nuclear scintigraphy for localizing parathyroid tissue, e71 for portosystemic shunt, 595 Nutraceuticals causing pregnancy loss, 1007-1008 for asymptomatic heart disease, 766 for heart disease, 777, 778b for liver disease, 587, 596, 598f, 617-618, 617b probiotic, 527 toxic exposures to, 94-96, 95t, 569 Nutrition after stabilization of shock, 24 and feeding with hepatic lipidosis, 610-612 and risk reduction of urinary bladder cancer, 370 assessment of, 38-39 association to cancer, 319 causing polyneuropathy, 1116-1117 during pregnancy and lactation, 961-966 enteral support of, 42-43, 42b feeding tubes (See Feeding tube(s)) food elimination diets for adverse reactions, 422-424 for the cancer patient, 349-354 for the heart patient, 720-725 in critical care, 38-43

Index Nutrition (Continued) management of obesity, 254-260 pharmacologic agents in support of, 43 problems causing pregnancy loss, 1007 with diabetes mellitus, 199-204, 201t in cats, 210 Nutritional requirements, calculation of, 39 Nutritional supplements, for neuromuscular disease, 1118 Nystagmus, from vestibular disease, 1067, 1067t Nystatin, otic therapy, 465t O Obesity and risk of hospital-acquired urinary infections, 877 and risk of urinary bladder cancer, 370 as risk for heat-induced illness, 71 causing hyperlipidemia, 262t diagnosis and treatment of, 254-260 diseases associated with, 255b impact of, on canine bronchial diseases, 672 in cats, management of, with diabetes mellitus, 203 insulin resistance with, 206-207, 206b role of, in development of feline hepatic lipidosis, 609 Obsessive-compulsive disorder, with acral lick dermatitis, e177 Obstetrical monitoring equipment, 949-951, 950f Obstructive uropathy, causing renal failure, e30b Occult hyperadrenocorticism, 221-224 Octreotide for feline hypersomatotropism, 219 for insulinomas, e134 for superficial necrolytic dermatitis, 487 Ocular. See also under Ophthalmic disease(s) changes secondary to hypertension, 726 changes with diabetes mellitus, e78 complications of hypothyroidism, e85 emergencies, e377-e384 Ocular neoplasia canine, 1201-1206 feline, 1207-1210 Odontogenic fibroma, 363 Off-Gassing emissions, e46 Oils in ear cleaners, 472t, 473 toxicity from botanical oil extract, 139-140 citrus, 126 essential, 125-127, 126t melaleuca, 126-127, 140 pennyroyal, 127, 139-140 salicylate-containing, 125t Ointment(s) as topical therapy for skin infections, 441t for keratoconjunctivitis sicca, 1146t, 1147

Ointment(s) (Continued) for Malassezia spp. infections, e215 potency of topical steroid, 460f Old English mastiff(s), direct mutation tests for, 1018t-1020t Old English sheepdog(s), avermectin toxicity in, 145 Oleander toxicity, 121b Oligospermia, e350-e353 Oliguria associated with hospital acquired kidney injury, 845 from acute renal failure, 869-870 Ollulanus tricuspis, common symptoms and syndromes caused by, 1214t-1215t Oltipraz, for aflatoxicosis, 161 Omega-3 fatty acids for asymptomatic heart disease, 766 for heart disease, 722-723 for hyperlipidemia, 265 requirements during pregnancy and lactation, 963 supplementation of, with diabetes mellitus, 201 Omega-6 fatty acids, for heart disease, 722-723 Omentalization for chylothorax, 699 for local peritonitis, e14-e15 Omeprazole (Prilosec) action and use of, 505-506, 506b drug interactions with, 34t-35t, 37 for craniocervical junction abnormalities, 1102 for esophagitis, e240 for gastric ulceration, e254 for gastroesophageal reflux, 503 for hydrocephalus, 1036 for vomiting with acute renal failure, 870 toxicity from, 118 Oncept vaccine, 335, 336t Onchocerca spp., causing conjunctivitis, 1142 Oncology. See also under Neoplasia interventional, 345-349 reproductive, 1022-1026 surgical principles for, e168-e172 Oncotic support for canine parvovirus, 534 for protein-losing enteropathy, 543-544 Ondansetron for adverse effects from cancer therapy, 331 for canine pancreatitis, 562-563 for canine parvovirus, 535 for feline cholangitis, 617, 617b for feline pancreatitis, 567t for hepatic lipidosis, 612 for vomiting with acute renal failure, 870 Onion toxicity, 98-99, 147-148 Onychodystrophy, systemic lupoid, pentoxifylline for, e204 Open fractures, 83-86 Open peritoneal drainage, e10-e12, e15-e17

1389

Ophthalmic disease(s) canine conjunctivitis, 1138-1143 glaucoma, 1170-1176, 1171b, 1171t, 1173b nonulcerative corneal disease, 1152-1156 ocular neoplasia, 1201-1206 retinal detachment, e370-e374 retinopathy, 1188-1192 tear film disorders, 1143-1147 uveitis, 1162-1166 corneal ulcers, 1148-1152 emergencies, e377-e384 epiphora, e374-e377 evaluation of blindness, 1134-1138 feline corneal, 1156-1161 glaucoma, 1177-1180 herpesvirus 1, 1157t ocular neoplasia, 1207-1210 retinopathy, 1189f, 1193-1196, 1194f uveitis, 1166-1170, 1169t from Bartonella spp. infections, 1263b hyperlipidemia and, 263t involving the eyelid, e363-e369 involving the periocular skin, e363-e369 keratoconjunctivitis sicca, 1143-1147 lens disorders, 1181-1187 orbital, 1197-1200 pearls of the examination for, 1128-1133 Ophthalmic examination direct vs. indirect ophthalmoscopy, 1131 evaluating anisocoria, e388-e395 fluorescein dye, 1132 fundic, 1131 pearls of the, 1128-1133 retroillumination, 1128-1129, 1129f Schirmer tear test, 1132 slit lamp, 1130-1131 tonometry, 1130 transillumination, 1128-1129, 1129f Ophthalmoscope, use of direct and indirect, 1131 Opiates, causing syncope, e328f Opioid(s) adverse effects of, 34t-35t, 60 causing bradyarrhythmias, 731-732 for nephroliths and ureteroliths pain, 894-895 for the critical patient, 59-60, 62t reversal agent for, 30 toxicity of, 111 use of prior to cesarean section, 955 with cardiovascular dysfunction, 64-65, 65t with benzodiazepine, for anesthetic induction in critical patients, 66 Optic chiasm lesions, 1137, 1137f-1138f causing anisocoria or mydriasis, e390f, e393t, e394

1390

Index

Optic nerve disorders causing anisocoria or mydriasis, e390f, e393t, e394 causing blindness, 1136-1137, 1136t coloboma, 1136 hypoplasia, 1136 neuritis, 1136-1137, e383 tumors, 1205-1206 with glaucoma in dogs, 1171t Optic tract lesions, 1137, 1138f causing anisocoria or mydriasis, e394 OptiChamber spacers, 623-624 Oral evaluation with caudal stomatitis, in cats, 492-493 with oropharyngeal dysphagia, 495-500 irritation from plants, 121b phases of swallowing, 495-496 Oral neoplasia, 362-366 Orbifloxacin for lower respiratory tract infection(s), 1220t for superficial bacterial folliculitis, 438t topical, for otitis, 464t Orbital abscess, 1198-1199 cellulitis, 1198-1199 disease, 1197-1200 evaluation of, 1128-1133 neoplasia, 1199 tumors of, 1205-1206 Orchidectomy, early age, in dogs and cats, 982-984 Orchids, 121b Orchitis, causing oligospermia, e350 Organic acidopathies, 1052-1053 Organic acidosis, e7-e8, e7b Organic phosphorus/phosphonomethyl herbicide toxicity, 130 Organophosphate toxicity, 135-137, 136b Ormetoprim/sulfadimethoxine, for superficial bacterial folliculitis, 438t Oropharyngeal dysphagia, 495-500, e259-e262 Oropharynx, deformities with brachycephalic airway obstruction syndrome, 650t Orthopedic trauma in dogs, 80-83 Oseltamivir, for canine parvovirus, 535 Oslerus osleri as bronchopulmonary parasite, e271-e272, e271f-e272f common symptoms and syndromes caused by, 1214t-1215t Oslerus rostratus, e272 Osmol gap, from ethylene glycol toxicity, 151-152 Osmolarity composition in fluid therapy, 3t of parenteral nutrition products, 40-41 Osteo-allograft mix, for open fracture repair, 86 Osteomyelitis common pathogens causing, 1222-1223

Osteomyelitis (Continued) empiric antimicrobial therapy for, 1220t, 1222-1223 from bartonellosis, 1261 from borreliosis, 1273 infectious causes of, 1214t, 1216-1217 with open fractures, 84 Osteosarcoma diagnosis and treatment of, 388-392, 391t immunotherapy for, 334, 336t nasal, radiation therapy for, 338-340 Otitis causing deafness, 468-469, 468b treatment and prevention, 470 contact, from adverse drug reactions, 488t ear-flushing techniques for, 471-474 from demodicosis, 432 from Pseudomonas, 459, 463 glucocorticoids for, 459 systemic antimicrobials for, 466-467, 466t topical antimicrobials for, 458 from staphylococci causing pyoderma, 435-436 glucocorticoids for, 416t, 417 systemic, 460-462, 461t topical, 460, 460t principles of therapy for, 458-459 topical antimicrobials for, 462-465, 464t treating severe fibrosis and stenosis, 460-461 Otitis interna, causing vestibular disease, 1068 Otitis media, 466 causing vestibular disease, 1068 causing xeromycteria, in dogs, 643 primary secretory with Chiari-like malformation, 1101 with nasopharyngeal disorders, 654 Otoacoustic emissions, 469-470 Otodectes cynotis causing otitis, and treatment of, 458 diagnosis and treatment of, 430-431, 431t use of avermectins for, e182 Ototoxicity, 468-471 causing vestibular disease, 1068 from ear cleaners, 474 from topical therapy, 464 treatment and prevention of, 468-471 Ovarian remnant syndrome, 1000-1003 Ovarian tumors, 1024-1025 Ovaries, reproductive toxins targeting the, 1027-1028 Ovariohysterectomy early age, in dogs and cats, 982-984 for ovarian tumors, 1024-1025 for uterine tumors, 1025-1026 ovarian remnant syndrome from, 1000-1003, 1001f urethral sphincter mechanism incompetence from, 919 with cesarean section, 955-956 with mammary tumor removal, 377 Over-the-counter drug toxicosis, 115-120

Overfeeding, 39 Overgrooming, drug therapy for behavior-related dermatoses e.g., 482-485 Ovotestes, 997 Ovulation, 930, 931f and luteinizing hormone surge, 931f, 931t relationship to proestrus, 932f relationship to progesterone concentration, 933f, 935f relationship to vaginal cytology, 933f Oxacillin, for pyoderma, 1220t, 1221-1222 Oxazepam for behavior-related dermatoses, 483t, 484 toxicity of, 113-114 Oxibendazole, associated hepatotoxicity, 581b Oxibendazole-DEC associated hepatotoxicity, 570b Oxybutynin, for urinary incontinence disorders, 916t Oxycodone toxicity, 111 Oxygen consumption in the brain, 1047-1048 delivery and oxygen consumption, 19f needs with seizure patients, 1061 saturation, 20 Oxygen therapy, 52-54 cage for, 53-54 for heat-induced illness, 73 for pneumonia, 687 for pneumothorax, 701 for respiratory acidosis, e5 for shock, 18-20, 19f hyperbaric, 54 techniques for administration of, 52-54 toxicity from, 54, 58 weaning from, 54 with anesthesia in critical care patients, 68-69 Oxyglobin, 11, 13 characteristics of, 10t Oxymorphone dosage for, 62t for the critical patient, 59, 64, 66 for thromboembolism pain, 814 Oxytetracycline/polymyxin B ointment (Terramycin), for keratomalacia, 1151-1152 Oxytocin for dystocia, 952f, 954-955 for postpartum hemorrhage, 957, 958t levels with normal gestation, 949 Ozagrel hydrochloride, for feline infectious peritonitis, 1305t, 1306 Ozone, causing reproductive toxicity, 1027b P P-glycoprotein, 33-36 Pacemaker advances in artificial, e283-e285 biventricular, e284 conventional, e282-e283

Index Pacemaker (Continued) dual-lead dual-chamber, e284, e284f for arrhythmias, in cats, 750f-751f for atrioventricular block, 735 in cats, 754-755 for bradyarrhythmias, e281-e286 for persistent atrial standstill, 734 programmable parameters for, e282t rate responsive ventricular, e283-e284, e284f single-lead atrial synchronous, e284-e285, e284f-e285f temporary, e285 transvenous pacing prior to, e21-e28 Pacing in the ICU setting, e21-e28, e23f, e285 Paclitaxel, e140-e141, e140t for hemangiosarcoma, 396 hypersensitivity reactions to, 333 premedication and protocol for, e141b Pad inverted papillomas, e185 Pain, causing feline arrhythmias, 750f-751f Pain management after cesarean section, 956 for feline cholangitis, 617, 617b for feline pancreatitis, 567, 567t for nephroliths and ureteroliths, 894-895 for open fractures, 85 for thromboembolism, 810, 814 in the critical patient, 59-63, 62t Paint thinner toxicity, 154-155 Pak far oil toxicity, 125t Palatability enhancers, 723-724 Palatoplasty, for brachycephalic airway obstruction syndrome, 651 Palliative care, client questions about, 321 Palmar-plantar erythrodysesthesia syndrome, from doxorubicin, e139-e140 Palpation of canine orthopedic trauma, 80-82 of pregnancy, 944 Pamidronate for cholecalciferol toxicity, e33-e34 for feline idiopathic hypercalcemia, 246-247 for multiple myeloma, 385 for osteosarcoma, 391-392 Pancreas. See also Exocrine pancreatic insufficiency (EPI) evaluation of, for insulinoma tumor, e131-e132 imaging of, for diagnosis of endocrine disorder(s), 172-174, 173t islet amyloidosis of, insulin resistance and, 205 laboratory testing of the exocrine, 554-557 measuring fecal elastase-1, 556, 559 serum pancreatic lipase immunoreactivity (PLI) of, 555-557 serum trypsin-like immunoreactivity (TLI) of, 555, 559 Pancreatectomy, for insulinoma, e131-e132

Pancreatic abscess, treatment of local peritonitis with, e14-e15 Pancreatic endocrine neoplasia, imaging of, 174 Pancreatic enzyme(s) for flatulence, e250 replacement therapy, 559 Pancreatic insufficiency laboratory testing for, 556-557 with diabetes mellitus, e77-e78 Pancreatic lipase immunoreactivity (Spec cPL) for the diagnosis of pancreatitis, 554, 561 with chronic pancreatitis, 564 Pancreatic lipase immunoreactivity (Spec fPL), for the diagnosis of pancreatitis, 566 Pancreatitis after pancreatic surgery, e132 canine acute vs. chronic, 561-565 nutritional support with, 563-564 treatment of, 561-565 causing exocrine pancreatic insufficiency (EPI), 558 causing hyperlipidemia, 262t effect of, on gastric emptying, 514, 516 feline, 565-568 medical therapies for, 567t with cholangitis, 615-616 with diabetes mellitus, 209 from hypothyroidism, e86 imaging for, 172-174 insulin resistance with, 206, 206b laboratory testing for, 554-557 pulmonary thromboembolism associated with, 705, 708 risk of with diabetes mellitus, 200-201 with hypertriglyceridemia, 261 with diabetes mellitus, e77-e78, e77, e83 Panleukopenia, feline, as cause of thrombocytopenia, 281t-282t Pannus. See also under Keratitis atypical, 1141, 1141f Panting, to dissipate heat, 70-71 Pantoprazole action and use of, 505-506, 506b for vomiting with acute renal failure, 870 toxicity from, 118 Panuveitis, canine, 1162 Papillary adenomas, ovarian, 1024-1025 Papilloma, of the eyelid, e368 Papillomavirus canine diagnosis and treatment of, e184-e187 exophytic, e185 oral, e184 cutaneous inverted, e185 feline, causing skin lesions, e195-e196 from cyclosporine, 405 immunotherapy for, 1231-1232, 1231f, e220-e221

1391

Papillon(s) direct mutation tests for, 1018t-1020t von Willebrand disease in, 288t Papule(s) from adverse drug reactions, 488t from superficial bacterial folliculitis, 437 Para-aminopropiophenone, for population control, 142-144 Parachlorometaxylenol, in ear cleaners, 472t, 473 Paragonimus kellicotti as bronchopulmonary parasite, e275-e276 common symptoms and syndromes caused by, 1214t-1215t Paranasal sinus disorders, causing rhinitis in dogs, 636b Paraneoplastic causes of hepatobiliary enzyme elevations, 570b syndrome, causing cachexia, 350 Paraparesis, from degenerative myelopathy, 1076-1077, 1076t Paraphimosis, 1029-1030, 1030b concerns regarding risk, with early age neutering, 983t vs. priapism, e354 Paraquat herbicide toxicity, 130-131, e266 Parasite(s) causing blepharitis, e364 causing conjunctivitis, 1142 causing myocarditis, e304t causing pregnancy loss, 1010 causing uveitis in dogs, 1164b common symptoms and syndromes caused by, 1214t-1215t flea and tick control products for, 426t in raw meat diets, 1240b nasal, 636b, 655-656, e269-e271 respiratory, e269-e276 skin, treatment of, 428-432 target parasites of common drugs, 1335-1337 treatment of common, 1335-1337 Parasiticide toxicoses, avermectins, 145-146 Parathyroid gland, imaging of, for diagnosis of endocrine disorder(s), 170 Parathyroid hormone (PTH) injections for hypoparathyroidism, e124 testing for diagnosis of hyperparathyroidism, e70-e71 for diagnosis of hypoparathyroidism, e122-e123, e124, e125f values of, with hypercalcemia in cats, 242-243 Parathyroid hormone-related protein (PTHrP), for diagnosis of hyperparathyroidism, e71 Parathyroidectomy, hypocalcemia from, e124-e125 Parenteral nutrition, 39-40, 42b administration of, 40-42 complications of, 43

1392

Index

Parenteral nutrition (Continued) compounding, 40 for acute pancreatitis in cats, 567-568 in dogs, 563-564 for patients with cancer, 353 with gastric dilation-volvulus, e19-e20 worksheet for calculating, 41b-42b Paroxetine HCl (Paxil) for behavior-related dermatoses, 483-484, 483t toxicity of, 113 Pars planitis, 1167 Partial thromboplastin time (PTT) for monitoring antithrombotic agents, 706-707, 707t in disseminated intravascular coagulation, 294t with bleeding abnormalities, 287f Parturition, use of ultrasound and radiology for predicting, 945t-946t Parvovirus infection and risk of hospital-acquired urinary infections, 877 canine causing thrombocytopenia, 281t-282t diagnosis and treatment of, 533-536 causing myocarditis, e307 causing nonregenerative anemia, e161, e161b effect on gastric emptying, 514 feline, causing thrombocytopenia, 281t-282t Pasturella spp. causing pneumonia, 682t human infection from pets, 1244-1246 role of with feline caudal stomatitis, 492 Patent ductus arteriosus (PDA), e309-e313 classification scheme for, e311, e311f complications of ductal closure, e313 device occlusion for, e310-e311, e310-e312, e310f, e311-e312 diagnosis of, e309-e310 prevalence of in cats, 757t in dogs, 756, 757t surgery ligation for, e312-e313 treatment of, e310-e313 Pathologist, tips for tissue sample submission, 322-326, 325b Paw pad, lesions with superficial necrolytic dermatitis, 485-486 PCR testing. See Polymerase chain reaction (PCR) testing Pediculosis diagnosis and treatment of, 428 drugs targeting, 1335-1337 lice species affecting dogs and cats, 429t use of avermectins for, e182-e183 Pelvic, abnormalities causing dystocia, 951 Pelvic bladder, ultrasound findings with, 842 Pelvic trauma in dogs, 81-82

Pembroke Welsh corgi(s) degenerative myelopathy in, 1076-1077 direct mutation tests for, 1018t-1020t glaucoma in, 1171b von Willebrand disease in, 288t Pemoline toxicity, 109-110 Pemphigus erythematosus, causing blepharitis, e366-e367 Pemphigus foliaceus causing blepharitis, e366 from metaflumizone/amitraz (ProMeris), 489 glucocorticoids for, 417 use of cyclosporine for, 409-410 Penciclovir, for feline ocular herpesvirus 1, 1158 Penicillamine for copper-associated liver disease, 589 for lead toxicity, 158 Penicillin G for leptospirosis, 1289 legend of spinal cord damage with, 99 Penicillin(s) adverse effects of, 34t-35t drug incompatibility with, 33t for septicemia, 1220t, 1223 skin reactions from, 488t Penicillium mold toxicity, 149 Penicillium spp., causing epistaxis, 1216 Penis nonneoplastic disorders of the, 1029-1031 paraphimosis and the, 1029-1030 physiology of the erection and, e354, e355f priapism and the, e354-e357 tumors of, 1023 Penny toxicity, 99-100 Pennyroyal oil, 127, 139 associated hepatotoxicity, 570b Pennyroyal senna associated hepatotoxicity, 581b Pentastarch, 11-12 characteristics of, 10t Pentobarbital drug incompatibilities with, 33t for central nervous system stimulant toxicity, 110 for emergent seizures, 1045, 1059-1060 for strychnine toxicity, 134 Pentosan polysulfate, for persistent urinary tract infections, 882-883 Pentoxifylline adverse effects of, e203 for cutaneous drug reactions, 488-489 for feline infectious peritonitis, 1305t, 1306 for vasculitis, from vaccines, 1251 use of, e202-e205 Pepsinogen, e251 Peptic ulcers, 509 Pepto-Bismol, toxicity from, 117 Percorten-V. See Desoxycorticosterone pivalate (DOCP) Percutaneous cystolithotomy, 890 Percutaneous nephrolithotomy, 885, 885f

Percutaneous ultrasound-guided ablation, for treatment of hyperparathyroidism, e72 Perfusion fluid therapy and using colloids, 8 using crystalloids, 4 monitoring of, with shock, 18-20 problems from prolonged seizures, 1060 Perianal adenocarcinoma, 366-369 Perianal adenoma, 366-369 Perianal fistulas, e190, e219 cyclosporine for, 269-271, 409 topical immunomodulators for, e219 Perianal gland tumor, 366 Pericardectomy, 821-823, 822f for chylothorax, 699 for hemangiosarcoma, 395 Pericardial disease causing chylothorax, 698 causing effusion, 816-823, 822b Pericardial effusion causes of, 817 collection of cytology specimens from, e155 diagnosis and treatment of, 816-823, 821f, 822b fluid analysis from, 817 malignant, 341-344 Pericardiocentesis, 820-821, 821f, 822b Perineal tumors, 366-369 Perineal urethrostomy, indications for, 925 Perinephric pseudocysts, ultrasound findings with, 843 Perinuclear antineutrophilic cytoplasmic antibodies, with inflammatory bowel disease, 538 Periocular skin diseases, e363-e369 Periodontitis, with feline caudal stomatitis, 492 Peripheral nerve dysfunction from hypothyroidism, 179, e84 rehabilitation considerations with, e360-e362 treatment of, 1116-1117 Peritoneal drainage comparison of techniques, e16t methods of, e10t lavage, for septic abdomen, e14 Peritoneal chemotherapy, 343-344 Peritoneal effusion. See also Ascites causing hyperkalemia and hyponatremia, e93, e93b collection of cytology specimens from, e155 malignant, 341-344 Peritoneocentesis, with nephrotic syndrome, 856 Peritonitis determining the severity of, e11b effect of, on gastric emptying, 516 from biliary mucoceles, e223 septic, drainage techniques for, e13-e20

Index Perivulvar dermatitis, 971, 977f concerns regarding risk, with early age neutering, 983t Periwinkle toxicity, 124t Permethrin for flea control, 426t for pediculosis, 429t for tick prevention, 1274-1275, 1294 toxic exposures to, 95-96, 115-116, 136b, 427, 489 toxicity of muscle relaxants for, 102t-104t use of IV lipid emulsion therapy for, 115-116 Persian cat cholangitis in, 618 corneal sequestrums in, 1159-1160 glaucoma in, 1177 portosystemic vascular anomalies in, 571b retinal degeneration in, 1195 risk of urolithiasis in, 897 Persistent atrial standstill, 733-734 Persistent Müllerian duct syndrome, 997-998, 998f Persistent right aortic arch, prevalence of in cats, 757t in dogs, 757t Personal protective equipment, for hazardous drugs, 327 Pertechnetate, of thyroid gland, 167-168 Pesticide(s) causing nephrotoxicity, e30b for vertebrate pest species, 142-144 reporting adverse events of, to FDA, e37-e38 Pet food aflatoxins in, 159 nephrotoxins in, e29-e34 reporting adverse effect of, e38 Pet Partners program, stand on raw meat diets, 1242 Pet Poison Helpline toxin exposures, 93-96, 95t Pet-associated illness, 1244-1249 Petechiae from adverse drug reactions, 488t with thrombocytopenia, 283 Petroleum compound toxicity, 154-155 pH changes, with acid-base disorders, e1-e8 composition in fluid therapy, 3t Phacoemulsification, 1184-1185 Phaeohyphomycosis, antifungal therapy for, 1234-1238 Phallopexy, 1029 Pharyngeal phase of swallowing, 495-496 weakness, 499 Pharyngoscopy, for evaluation of dysphagia, 498 Phenazopyridine associated hepatotoxicity, 581b Phenobarbital adverse effects of, 34t-35t associated hepatotoxicity, 570b, 576, 581b

Phenobarbital (Continued) causing hyperlipidemia, 262t dosing of, with liver disease, 32-33 drug interactions with, 35t, 677 effect on hepatobiliary enzymes, 570-571 enterohepatic recirculation of, 105 for emergent seizures, 1059-1060 for intracranial tumors, 1041t, 1045 influence on thyroid function, 181t, 184 Phenolic chemicals associated hepatotoxicity, 581b Phenols associated hepatotoxicity, 581b Phenothiazine(s) causing syncope, e328f toxicity of, 118-119, 581b Phenotypic sex, 993, 995t Phenoxy acid herbicide toxicity, 130-131 Phenoxybenzamine for urinary retention disorders, 917t, 918 to promote ureterolith passage, 894 Phentermine, toxicity of, 109-110 Phenylbutazone associated hepatotoxicity, 581b causing nephrotoxicity, e32-e33 Phenylephrine causing anisocoria or mydriasis, e392 for feline uveitis, 1169, 1169t for localization of anisocoria, e395 for priapism, e356 use of, with shock, 23 Phenylpropanolamine as decongestant, 627 for urinary incontinence disorders, 915, 916t, 925 hypertension from, 727, 727t, 780b Phenytoin (Dilantin) associated hepatotoxicity, 581b causing adverse skin reactions, 488t drug interactions with, 119, 507, 677 Pheochromocytoma hypertension from, 727t, 729 imaging for diagnosis of, 171 insulin resistance with, 206b Pheromone, for behavior-related dermatoses, 485 Phimosis, 1029-1030, 1030b concerns regarding risk, with early age neutering, 983t Phosphate binders, with chronic kidney disease, 862 Phosphate intake restriction, with chronic kidney disease, 862 Phosphofructokinase deficiency, direct mutation test for, 1018t-1020t Phosphorus, and calcium, causing mineralization, 244 Physaloptera canis, common symptoms and syndromes caused by, 1214t-1215t Physical examination findings relative to dehydration, 5t of the eye, 1128-1133 with respiratory distress, 45-46

1393

Physical therapy and rehabilitation for neurologic disorders, e357-e362 for degenerative myelopathy, 1078-1080 for neuromuscular disease, 1118 Phytosphingosine, 420t in ear cleaners, 474 topical, 420t, 421, 441t Pilocarpine causing anisocoria or mydriasis, e392 for canine glaucoma, 1173b, 1174 for feline glaucoma, 1179-1180 for keratoconjunctivitis sicca, 1145, 1155 Pimecrolimus as topical immunomodulators, e216-e220, e219 safety concerns of, e219-e220 topical, 420t, 421 Pimobendan (Vetmedin) for asymptomatic heart disease, 766 for cardiogenic shock, 783 for congenital heart disease, 760 for dilated cardiomyopathy, in dogs occult, 797-798 with heart failure, 799 for feline cardiomyopathy, 806t, 808-809 for heart failure in cats, 808 in dogs, 764t-765t, 768-770, 777-779, 787t, 791 for myocarditis, e306 for pulmonary hypertension, 714, 716 with valvular heart disease, 793-794 Pind-avi/Pind-orf, for feline retrovirus infections, 1280t-1281t, 1282 Pine oil associated hepatotoxicity, 570b Pineal gland tumors, 1039-1047 Pinnal-pedal reflex, with sarcoptic mange, 428 Pioglitazone, for diabetes mellitus, in cats, e137-e138 Piperazine toxicity, 118-119 Piperidine toxicity, 118-119 Piroxicam as cancer therapy, 336t, 359 for hemangiosarcoma, 396 for inflammatory mammary carcinoma, 378 for ocular neoplasia, 1207 for oral tumors, 364 for rhinosinusitis in cats, 646 for urinary bladder cancer, 372-373 metronomic chemotherapy of, 343-344 toxicity of, 116-117, 359, e32-e33 use of, with toceranib, 359 Pituitary gland imaging of, for diagnosis of endocrine disorders, 172 reproductive toxins targeting the, 1027 tumors adenoma, 172 causing acromegaly, in cats, 216-217 causing blindness, 1137

1394

Index

Pituitary gland (Continued) diagnosis and treatment of, 10391047, 1042t large, with pituitary-dependent hyperadrenocorticism, e88-e91 Placental site subinvolution, 957 Plant(s) and herbs of toxic concern, 124t causing nephrotoxicity, e34 salicylate containing, 125t toxic and nontoxic, 121, 121b toxic exposures to, 92t, 94, 95t Plaque as cause of thrombocytopenia, 281t-282t bacteria, role in feline caudal stomatitis, 494 Plasma characteristics of, 10t for treatment of von Willebrand disease, 290, 290t Plasma cell neoplasms, 384-387 Plasma protein C with acute liver failure, 600 with portal vein hypoplasia, 599-600 with portosystemic shunt, 595-596 Plasma transfusions for canine pancreatitis, 562 for disseminated intravascular coagulation, 295 for feline pancreatitis, 567t for hypoalbuminemia, 543-544 for therapy of shock, 21-22 Plasma von Willebrand factor, 287-288 Plasmacytic stomatitis, use of cyclosporine for, 410b Plasmacytomas, diagnosis and treatment of, 386-387 Plasmapheresis, for multiple myeloma, 385 Plasminogen, with disseminated intravascular coagulation, 294f Platelet function analyzer, use of, with bleeding abnormalities, 287 Platelet inhibition, for autoimmune hemolytic anemia, 277-278 Platelet transfusion(s), for thrombocytopenia, 284-285 Platelet(s). See also Thrombocytopenia activation, with autoimmune hemolytic anemia, 275-276 activity, in hypercoagulable states, 298, 298f, 811-815 assessment with thrombocytopenia, 283-284 counts with hereditary factor deficiencies, 287f function, with disseminated intravascular coagulation, 292, 293f, 294t Platelet-rich plasma, 311 Platinum toxicity, 1027b Plerixafor, for feline retrovirus infections, 1279-1280, 1279t Pleural chemotherapy, 343-344

Pleural effusion causes of, 692b causing hyperkalemia and hyponatremia, e93, e93b characterization of, 692-695, 692t chylous, 695 clinical signs of, 692 collection of cytology specimens from, e155 diagnosis and treatment of, 691-700 hemorrhagic, 694 infectious causes of, 1216 malignant, 341-344 neoplastic, 694-695, e165-e166 septic, 695-697 transudates, 694 types of, 694-695 with cardiogenic shock, 783 with feline pancreatitis, 567 with refractory heart failure, 781 Pleural port placement, for chylothorax, 699-700 Pleural space disease anesthesia for patients with, 68 causes of, 46t Pleural space neoplasia, e165-e166 Pleurectomy, for malignant effusions, 343 Pleurodesis for malignant effusions, 342 for treatment of pneumothorax, 704 Pleuroperitoneal shunt for chylothorax, 699 for malignant effusions, 343 Pneumocystosis, e409-e411 clinical findings with, e410 diagnosis of, e410 treatment of, e410-e411 Pneumonia anesthesia for patients with, 68 aspiration, 681, 683-685, 683b post-op with laryngeal paralysis surgery, 661 prevention of, 685 with megaesophagus, e229 with myasthenia gravis, 1109-1110 common infectious agents causing, 1218 community-acquired, 681-682, 682t diagnosis and treatment of, 681-688, 684f eosinophilic, e267b from canine infectious respiratory complex, 633-634 hospital-acquired, 682-683, 682t-683t, 683b, 684f reasons for treatment failure with, 687-688 risk factors for, 683b, 684-685 with feline pancreatitis, 567 with ventilator therapy, 58 Pneumonyssoides caninum common symptoms and syndromes caused by, 1214t-1215t nasal mite, 655-656, e270 Pneumonyssus caninum, causing nasal discharge, 636b, 637

Pneumothorax anesthesia for patients with, 68 blood patching for, 704 diagnosis and treatment of, 700-704 iatrogenic, 693-694, 703, 703f spontaneous, 703 traumatic, 702 Pododermatitis from cornification disorders in dogs, 475 from Malassezia spp., e213 use of cyclosporine for, 410b Poinsettia toxicity, 99 Poison. See Toxicity(ies) Poison hemlock toxicity, 124t Poison tobacco toxicity, 124t Pollakiuria, infectious causes of, 1217 Polyarthritis diagnosis of, 1225 differential diagnosis for, 1224-1225 from feline upper respiratory infection, 630t infectious causes of, 1216-1217, 1224-1228 treatment of, 1225 Polybrominated biphenyls toxicity, 1027b Polychlorinated biphenyls toxicity, 1027b Polydimethylsiloxane, for urinary incontinence, e349, e349f Polyglandular endocrinopathy, with hypothyroidism, e87-e88 Polyinosinic:poly-cytidylic acid, for feline retrovirus infections, 1280t-1281t, 1282 Polymerase chain reaction (PCR) testing for American leishmaniasis, e396-e397 for bacteremia with endocarditis, e293-e294, e294-e295 for canine hepatozoonosis, 1285 for canine leproid granuloma, 446 for canine parvovirus, 533-534 for canine respiratory infection, 633 for cytauxzoonosis, e407-e408 for feline Bartonella spp., 1269 for feline upper respiratory infection, 630 for hemotropic mycoplasmosis, e400-e401 for leptospirosis, 1287-1289 Polymyopathy causing laryngeal paralysis, 659 from hypernatremia, 1116 hypokalemic, with feline hyperaldosteronism, 239 Polymyositis, 1114 causing dysphagia, 496b extraocular, 1199 from ehrlichiosis, 1292 Polymyxin ototoxicity from, 468b topical, for otitis, 464t Polyneuropathy, 1116-1117 Polyprenyl, for feline infectious peritonitis, 1306 Polyps nasal, 656-657

Index Polyps (Continued) nasopharyngeal, 656-657 vestibular signs from, 1068 Polysaccharopeptide, for hemangiosarcoma, 396 Polysulfated glycosaminoglycans, for persistent urinary tract infections, 882-883 Polytetrafluoroethylene paste, for urinary incontinence, e348 Polyuria, from acute renal failure, 870 Polyuria and polydipsia (PU/PD) fluid therapy considerations with, 6 from glucocorticoids, 461 potassium supplementation and, 6-7 Pomeranian, risk of urolithiasis in, 897 Ponazuril for canine hepatozoonosis, 1285 for toxoplasmosis, 1297 target parasites and dosage of, 1335-1337 Poodle(s) alopecia X in, 166 atlantoaxial subluxation in, 1083 congenital hydrocephalus in, 1034 dilated cardiomyopathy in, 795-796 direct mutation tests for, 1018t-1020t glaucoma in, 1171b hypoadrenocorticism in, 233 mammary cancer in, 375 paraphimosis in, 1029 pericardial effusion in, 817 progressive retinal atrophy in, 1188-1190, 1189t retinal atrophy in, 1189t risk of bladder cancer in, 371t sebaceous adenitis ion, e209, e209-e210 testicular dysgenesis in, 997 thrombocytopenia in, 283 von Willebrand disease in, 288t Population control, pesticides for vertebrate pest species, 142-144 Porcine Lente insulin (Vetsulin), 190-191, 210 Portal circulation, 599 Portal hypertension causing ascites, therapy of, 591-592 compared to portal vein hypoplasia, 601 from hepatobiliary disease, 572-574, 581-582, 584-585 postoperative PSS surgery, 597-598 Portal vein hypoplasia as differential diagnosis for portosystemic shunt, 595-596 compared to portal hypertension, 601 compared to portosystemic shunt, 599-600 diagnosis and treatment of, 599-602, 600b with portosystemic shunt, 599 Portosystemic shunts (PSS), 594-598 breeds predisposed to, 594 compared to portal vein hypoplasia, 599-600 diagnosis of, 594-595 liver function tests for, 595

Portosystemic shunts (PSS) (Continued) medical management of, 596 postoperative care with, 597-598, 598f prognosis with, 596 surgery for, 596-597 treatment of hepatoencephalopathy with, 592-594 with portal vein hypoplasia, 599 Portosystemic vascular anomalies breeds predisposed to, 571b ultrasound changes with, 573-574 Portuguese water dog(s) direct mutation tests for, 1018t-1020t genetic marker test for dilated cardiomyopathy in, 1021t Posaconazole for fungal rhinitis in cats, 647t topical, for otitis, 463-464 use and protocols for, 1235t, 1237 Positive end-expiratory pressure (PEEP), with ventilator therapy, 56 Positive inotropic drugs for heart failure, in dogs, 763b, 768-770 for therapy of shock, 22-23 Postobstructive hypokalemia, 251-252 Postpartum disorders, diagnosis and treatment of, 957-960, 958t Postprandial hyperlipidemia, 262t Potassium. See also Hyperkalemia; Hypokalemia approach to low levels of, 248-253 composition in fluid therapy, 3t diagnostics for, 252 dietary recommendations for, with heart disease, 723, 763 role and function of, 251 supplementation IV, 253t with fluid therapy, 6-7, 7t, e80t-e81t, e82 with gastric dilation-volvulus, e17, e18-e19 Potassium blocker(s), causing syncope, e328, e328f Potassium bromide influence on thyroid function, 181t interaction of, with furosemide, 34t-35t, 37 with intracranial tumors, 1045 Potassium channel blockers for dogs, 763b for supraventricular tachyarrhythmias, 742t, 743-744 for ventricular arrhythmias, 746-748 Potassium chloride for glaucoma in dogs, 1173b supplementation, 253, 253t Potassium citrate, for calcium oxalate urolithiasis, 899-900 Potassium gluconate, supplementation, 252-253 Potassium penicillin G, before musculoskeletal surgery, 1220t, 1222 Pradofloxacin for Bartonella spp., 1265 for feline upper respiratory infection, 631t

1395

Pradofloxacin (Continued) for nontuberculous cutaneous granulomas, 448t Pralidoxime hydrochloride, as antidote, e56t Pramoxine, topical, 420t Praziquantel for Giardia spp., 530t for lung worms, e276 target parasites of, 1335-1337 Praziquantel/pyrantel, target parasites of, 1335-1337 Prazosin for urinary retention disorders, 917t, 918 to promote ureterolith passage, 894 Prebiotic therapy, 525 Precorneal tear film, e384, e385f Prednisolone. See also Glucocorticoid(s) for otitis, systemic, 461t use of, for immunosuppression, 269 Prednisone. See also Glucocorticoid(s) as rescue therapy for canine lymphoma, 382t for feline gastrointestinal lymphoma, 547-548, 548t for multiple myeloma, 385-386 for otitis systemic, 461t topical, 460t for rescue chemotherapy for canine lymphoma, 381-383 Prednisone sodium succinate, use of, with hypoadrenocorticism testing, 235-236 Pregabalin, for craniocervical junction abnormalities, 1102 Pregnancy. See also Dystocia and risk of pyometra, 967 antibiotic therapy during pregnancy, 947-948 breeding management of the bitch for optimal, 930-935 complications of, 947-948 diagnosis, 944-948 with radiography, 938 with ultrasound, 939 differential diagnosis of, 947 false, 947 loss in the bitch and queen, 10031011, 1005t infectious agents causing, 1218 medical termination of, 989-992 nutrition during, 961-966 postpartum disorders after, 957-960 use of endoscopy transcervical insemination, 940-944, 941t Premature atrial complexes, in cats, 749-753, 750f-751f Premedication, with cardiovascular dysfunction, 64-65 Prepuce, nonneoplastic disorders of the, 1029-1031 Preputial hypoplasia, concerns regarding risk, with early age neutering, 983t Preputial tumors, 1023 Presbycusis, causing deafness, 468b

1396

Index

Prescription diet(s), for diabetes mellitus, 201t, 204t Priapism, e354-e357, e355f pathophysiology of, e354-e356 Primidone associated hepatotoxicity, 581b Proanthocyanidin, for persistent E. coli urinary tract infections, 881b, 882 Probiotic therapy, 525-528 for flatulence, e250 for persistent E. coli urinary tract infections, 882 mechanism of action of, 526 Procainamide causing adverse skin reactions, 488t for heart failure, in dogs, 764t-765t with arrhythmias, 771 for supraventricular tachyarrhythmias, 743 for ventricular arrhythmias, 746-747, 747f, 747t ProcalAmine, 40 Procarbazine, as rescue therapy for canine lymphoma, 382t Proestrus, 931 relationship to ovulation, 932f Progesterone changes with pyometra, 967 concentrations and pregnancy complications, 947-948 relationship to ovulation, 933f, 935, 935f to detect ovarian remnant syndrome, 1001-1002 with normal gestation in the bitch, 949 excess, insulin resistance with, 206b supplementation during pregnancy complications, 947-948 to maintain pregnancy, 1006 Progesterone receptor blocker(s), for pregnancy termination, 991 Progestins, for estrus suppression in the bitch, 984-985 Progressive retinal atrophy direct mutation test for, 1018t-1020t in cats, 1195 in dogs, 1188-1190, 1189f classifications of, 1189t Progressive rod cone degeneration, direct mutation test for, 1018t-1020t Prokinetic drug(s) for hepatic lipidosis, 612 for motility disorders, 516-518 action and use of, 517t for urinary retention disorders, 918 Prolactin, concentrations with false pregnancy, 947 Prolactin inhibitor(s), for pregnancy termination, 990-991 used with prostaglandin F2α, 990-991 Proligestone, for estrus suppression in the bitch, 987 Propane toxicity, 154-155 Propantheline for bradycardias, 736 for urinary incontinence disorders, 916t

Propentofylline, for feline infectious peritonitis, 1305t, 1306 Propionibacterium acnes for cancer immunotherapy, 335 for feline retrovirus infections, 1280t-1281t, 1282 Propofol drug interactions with, 35t for cesarean section, 955 for emergent seizures, 1060 long term use of, in cats, 55 to calm respiratory distress pets, 47t to evaluate laryngeal function, 660 with intracranial pathology, 69 with ventilator therapy, 55 Propranolol adverse effects of, 34t-35t causing adverse skin reactions, 488t drug interactions with, 35t for hyperthyroid cats, e103t influence on thyroid function, 181t toxicity of, use of IV lipid emulsion therapy for, 106 Proprioceptive deficits exercises to build strength with, e358, e358-e359 from vestibular disease, 1067t Proptosis, e377-e378, e378f Propylene glycol causing adverse skin reactions, 488t in ear cleaners, 472-473, 472t toxicity, 153-154 Propylthiouracil causing adverse skin reactions, 488t for hyperthyroid cats, e103t, e105 Prostaglandin analog(s) for canine glaucoma, 1173, 1173b, e381 for feline glaucoma, 1180, e381 Prostaglandin F2α for postpartum metritis, 958t for pregnancy termination, 990 used with prolactin inhibitors, 990-991 for pyometra, 963 side effects of, 990 Prostaglandin(s), role of, with kidney disease, 863 Prostate cancer, 1023-1024 immunotherapy for, 336t urethral stenting for, 346f disease, causing oligospermia, e350 fluid collection from, 1013-1014 Prostatic abscess, treatment of, 1014-1015 local peritonitis with, e14-e15 Prostatic hypertrophy, benign, 1012-1015 Prostatitis, diagnosis and treatment of, 1012-1015 Prosthesis, eye, with glaucoma, 11751176, 1176f Prosthesis, for feline glaucoma, 1180 Protamine zinc insulin, 211, 212b Protectant(s), as antipruritic agents, 419

Protein catabolism, with diabetes mellitus, 201 dietary needs in patients with cancer, 352 recommendations with diabetes mellitus, 200-201, 201t, 203, 204t recommendations with heart disease, 722 requirements in parenteral nutrition products, 40, 41b with weight loss diets, 255-259 Protein C, role of, in hypercoagulable states, 297 Protein electrophoresis, for multiple myeloma, 384-385 Protein-losing enteropathy causes of, 540-541 comparisons of diets for, 542-543, 543t diagnosis of, 540-544 pulmonary thromboembolism associated with, 705 treatment of, 539-544 Protein-losing nephropathy causing hyperlipidemia, 262t from Borrelia burgdorferi, 1272, 1274 pulmonary thromboembolism associated with, 705, 812 Proteinuria asymptomatic, when to worry, 926-927 causes of, 850-851 detection and management of, 849-852 for staging of kidney disease, 858-859, 860t from amyloidosis, 855 from Borrelia burgdorferi, 1273 from glomerular disease, 853-855 from idiopathic vacuolar hepatopathy, 607 localization of the source of, 850-851 treating hypertension with, 729 treatment of, with chronic kidney disease, 861 Prothrombin deficiency, coagulation factor abnormalities with, 288t Prothrombin time (PT) in disseminated intravascular coagulation, 294t with anticoagulant rodenticide toxicity, 133 with bleeding abnormalities, 287f Proton pump inhibitor(s) action and use of, 505-506 for esophagitis, e240 for gastric ulceration, e254 for gastroesophageal reflux, 503 for vomiting with acute renal failure, 870 intravenous formulations of, 506 protocol for helicobacter spp., 511-513, 511t toxicity from, 118 Protozoa causes of thrombocytopenia, 281t-282t causing gastrointestinal disease, 528-532

Index Protozoa (Continued) causing myocarditis, e304t causing uveitis in dogs, 1164b drugs used to treat common, 1335-1337 Provera, for estrus suppression in the bitch, 987 Prucalopride, action and use of, for motility disorders, 516-518 Pruritic alopecia, in dogs, 164 Pruritus from adverse drug reactions, 488t from atopic dermatitis, 406 from methimazole, e103-e104 glucocorticoids for, 415-417, 416t topical therapy for, 419-421 Pseudocyesis, 947 from hypothyroidism, e85 Pseudoephedrine for priapism, e356-e357 for urinary incontinence disorders, 915, 916t Pseudomonas infection causing aspermia, e350 causing endocarditis, e293-e294, e294t causing prostatitis, 1013 in feline airways, 676 otitis, treatment of, 458-459, 463, 466-467, 466t ear-flushing techniques for, 472 with glucocorticoids, 459 Pseudopelade, use of cyclosporine for, 410b Pseudothrombocytopenia, 280 Psoriasiform-lichenoid dermatosis, cyclosporine-induced, 489 Psoriasis cream toxicity, e33-e34 Psychogenic alopecia, drug therapy for behavior-related dermatoses e.g., 482-485 Psychotropic drugs, behavior-related dermatoses, 482-484 Psyllium, for canine colitis, 551b, 552 Ptyalism, from feline hepatic lipidosis, 613 Puerperal tetany, 958t, 959-960 Pug(s) brachycephalic airway obstruction syndrome in, 650t encephalitis, 1064 pigmentary keratitis in, 1154 risk of vaccine hypersensitivity in, 1250-1251 Pulmonary artery catheter, for monitoring shock, 19 Pulmonary artery pressure, 711, 713-714 Pulmonary artery velocity profile, 714 Pulmonary capillary leak, from acute respiratory distress syndrome, 49-50, 50f Pulmonary compliance, 45f Pulmonary contusions, fluid therapy considerations with, 6 Pulmonary diseases. See also under Respiratory disease(s) eosinophilic, 688-691

Pulmonary edema as cause of respiratory distress, 45, 46t causing feline arrhythmias, 750f-751f from chronic valvular disease, 786-788, 787t from heart failure, 767-769, 767f in dogs, 773, 778b, 782 from hemoglobin-based oxygen solutions, 11, 13 morphine use with, 47t oxygen therapy for, 52 post-arrest, 31 reexpansion, after thoracocentesis, 693-694 toxins causing, 125, 131, 152-153 with acute respiratory distress syndrome, 48, 49b with brachycephalic airway obstruction, 649 with cardiogenic shock, 783 with dilated cardiomyopathy, 796-798 with feline myocardial disease, 805, 807-809 with feline pancreatitis, 567 with pericardial effusion, 816 with pneumonia, 687 with pulmonary hypertension, 716 with ruptured chordae tendineae, 793 with status epilepticus, 1061 Pulmonary fibrosis, e267, e267b acetylcysteine for, 627 causing pulmonary hypertension, 711, 712t Pulmonary function tests, 690 Pulmonary hypertension arterial, 714-715, 715f associated with lung disease, 716 associated with thrombosis, 716 causes of, 712t classification and histologic lesion of, 712t clinical signs of, 711 diagnosis and treatment of, 711-717, 715f, 768 neurocardiogenic syncope with, e327, e329 prognosis for, 716 venous, with left-sided heart failure, 716 with congenital heart disease, 760 with interstitial lung disease, e268 with refractory heart failure, 781 with valvular heart disease, 793-794 with ventricular septal defect, e336-e337 Pulmonary mineralization, e267b Pulmonary neoplasia, e165-e168 Pulmonary parenchymal disease, causes of, 46t Pulmonary thromboembolism diagnosis and treatment of, 705-710 prevention of, 708-710 with cardiogenic shock, 783 with hemolytic anemia, 812 Pulmonary valve stenosis, e314-e319 classification of disease severity, e317 diagnosis of, e314-e317

1397

Pulmonary valve stenosis (Continued) interventional therapy for, e317-e318, e318-e319 prevalence of in cats, 757t in dogs, 756, 757t therapy of, 759-760 treatment of, e317-e319 Pulse oximetry, use of, 52 Pulseless electrical activity, 29f Pulsus paradoxus, 816 Punctum imperforate, e375 obstructed, e376 Pupillary escape, e391 Pupillary light reflex abnormalities, e388-e395, e393t assessment of, e391 defects of the, e390f direct vs. consensual, e391 evaluation of, 1134, 1135f functional anatomy of the, e389 grid to record, e389f Puppy strangles, rational use of glucocorticoids for, 1301 Purina Glucotest, 197-198 Purine content of foods, 905b Pustule, from superficial bacterial folliculitis, 437 Pyelocentesis, use of ultrasound for, 844 Pyelography for diagnosis of nephroliths and ureteroliths, 893 use of ultrasound for, 844 Pyelonephritis infectious agents that cause, 1212 ultrasound findings with, 842-843 with urolithiasis, 893-894 Pyloric atony, with brachycephalic airway obstruction syndrome, 650t Pyloric mucosal hyperplasia, with brachycephalic airway obstruction syndrome, 650t Pyloric stenosis, with brachycephalic airway obstruction syndrome, 650t Pyoderma common pathogens causing, 1221-1222 empiric antimicrobial therapy for, 1220t from Staphylococcus spp. infection, 435-436 immunotherapeutics for, 1230t topical therapy for, 440-442, 441t with methicillin-resistant Staphylococcal, 442, 444 with superficial necrolytic dermatitis, 486 Pyogranulomatous dermatitis, from nontuberculous cutaneous granulomas, 446-447 Pyometra, 947 causing pregnancy loss, 1005-1006, 1005f, 1005t diagnosis and treatment of, 967-969 pathogenesis of, 967

1398

Index

Pyometra (Continued) risk with progestin drugs, 985 with tamoxifen, 377 use of renourethroscope for treating, 943-944 Pyothorax, 695-697 blood patching for, 704 causes of, 695-697, 1216 medical treatment of, 696-697 surgery treatment of, 697 Pyotraumatic dermatitis, e206-e208 causes of, e207b treatment of, e207-e208 Pyrantel for Giardia spp., 530t target parasites of, 1335-1337 Pyrethrin for Otodectes infestation, 431t for pediculosis, 429t toxicity, 95-96, 136b, 137-138 Pyrethroid toxicity, 136b, 137-138 Pyridostigmine for myasthenia gravis, 1110-1111, e228-e229 for urinary retention disorders, 917t Pyrimethamine, for canine hepatozoonosis, 1285 Pyriproxyfen for dust mite control, e199 toxicity, 140-141 Pyruvate dehydrogenase 4 gene mutation, testing for canine dilated cardiomyopathy, 797 Pyruvate kinase deficiency, direct mutation test for, 1018t-1020t Pythiosis, e412-e415 antifungal therapy for, 1234-1238 diagnosis of, e413 treatment of, e413-e414 Pyuria, effect of, on urine protein and albumin, 850 PZI. See Protamine zinc insulin Q Quadrigeminal cyst, 1038-1039 Quality control, for the in-clinic laboratory, 306-309 Quaternary ammonium compounds, for methicillin-resistant Staphylococcal sp., 455-456 Queen-of-the-meadow toxicity, 124t Questions, to consultants, urinary, 923-927 Quetiapine, toxicity of, use of IV lipid emulsion therapy for, 106 R Rabeprazole action and use of, 505-506 toxicity from, 118 Rabies vaccine, injection site reactions from, 489 Rabies virus causing nervous system signs, 1212 common symptoms and syndromes caused by, 1215t

Rabies virus (Continued) human infection from, 1244 vaccine-associated sarcomas from, 1253 Radiation therapy client questions about, 320-321 for acral lick dermatitis, e176 for hemangiosarcoma, 396 for intracranial tumors, 1043-1044 for mammary cancer, 378 for multiple myeloma, 385 for nasal tumors, 338-340, e157-e159 in cats, 648 in dogs, 641-643 for oral tumors, 364 for osteosarcoma, 391 for perianal adenocarcinoma, 367-369 for pituitary macroadenoma, e90-e91 for soft tissue sarcomas, e151 for thyroid tumors, 399-400 for treatment of feline hypersomatotropism, 219-220, 220f for urinary bladder cancer, 372 for vaccine-associated sarcoma, 1254 with interventional oncology, 348 Radioactive iodine therapy. See Radioiodine therapy Radiography for diagnosis of nephroliths and ureteroliths, 893 for diagnosis of osteosarcoma, 388 for diagnosis of prostatic enlargement, 1012 for evaluation of causes of pulmonary hypertension, 713 for evaluation of dysphagia, 497 for evaluation of hepatobiliary disease, 573 for evaluation of hypercalcemia and hyperparathyroidism, in dogs, e69-e70 for evaluation of kidney size, 841 for evaluation of the eye, 1133 of the ear, with otitis, 458 of the female reproductive tract, 938 for predicting parturition, 946t for pregnancy diagnosis, 945-947, 946f-947f to determine pregnancy loss, 1004 with contrast, 939 of the heart with congenital heart disease, 758 with dilated cardiomyopathy in dogs, 797 with mitral valve dysplasia, e300 with myocarditis, e304-e305 with pericardial effusion, 817-818 with pulmonic stenosis, e315 with tricuspid valve dysplasia, e333, e334f with valvular heart disease, 788, 789f, 792-793 with ventricular septal defect, e337 of the lungs for evaluation of respiratory distress, 46-47

Radiography (Continued) with acute respiratory distress syndrome, 50f with bronchopulmonary parasites, e269-e276 with eosinophilic pulmonary diseases, 689 with feline asthma, 675 with feline heartworm disease, 827-829, 828f with interstitial lung diseases, e266-e267 with pleural effusion, 691-700 with pneumonia, 685-686 with pneumothorax, 701f with atlantoaxial subluxation, 1083-1084, 1085f with barium, for evaluation of gastric emptying, 515 with biliary tract disease, 603 with cervical spondylomyelopathy, 1093 with hemangiosarcoma, 393-394, 394f with intervertebral disk disease, 1072-1073 with lumbosacral stenosis, 1106 with nasal discharge in cats, 645-646 in dogs, 636-637, 640-641 with nasopharyngeal disorders, 654 with pancreatitis in dogs, 561 with portosystemic shunt, 595 with thyroid gland neoplasia, 168-169 with urinary bladder cancer, 371 with urolithiasis, 906f calcium oxalate, 898 urate double-contrast cystography, 902f monitoring of, 903 Radioiodine therapy, 399-400 adverse effects of, e118, e119-e121, e119 estimation of dose for, e117-e118 failure to respond to, e119 follow-up testing after, e118-e121 for thyroid carcinoma, e118 mechanism of action of, e107, e112-e122 medical therapy before, e105 prognosis after, e121 pros and cons of, e103t Radiology, interventional, 345-349 strategies for urinary disease(s), 884-892 Radionuclide iodine imaging, of thyroid gland, 167-168 Radiosurgery, stereotactic, for osteosarcoma, 392 Radius trauma in dogs, 81 Radon, as respiratory toxicants, e47 Raison. See Grape and raison toxicity Ranitidine (Zantac) action and use of, for motility disorders, 516-518, 517t for esophagitis, e240 for feline pancreatitis, 567t for gastric ulceration, e254 potency and use of, 505, 506b toxicity of, 119

Index Rapamycin, use of, for immunosuppression, 271-272 Rapid urease test, 510, 510f Rauwolscine, for retrograde ejaculation, e351-e352 Raw meat diets causing disease transmission from pets to humans, 1245t, 1248 causing pregnancy loss, 1007-1008 during pregnancy and lactation, 965 infectious diseases from, 1239-1243 Neospora caninum from, 1290-1291 toxoplasmosis from, 1297-1298 Receptors for cancer immunotherapy, 334-335 Recombinant cytokine therapy, 335 Recombinant human granulocyte colony-stimulating factor, for canine parvovirus, 535 Recombinant human NPH insulin, 190-191 Rectal neoplasms, immunotherapy for, 336t Rectovaginal fistula, 977-978 Rectovestibular fistula, 977-978 Red blood cell transfusions, 309-313 Red cell aplasia, 316, e162 Red flower oil toxicity, 125t Red puccoon toxicity, 124t Red root toxicity, 124t Reflux, gastroesophageal, 501-504 Rehabilitation and physical therapy for neurologic disorders, e357-e362 recommendations postop disk herniation, e361b Rehydration, fluid therapy for, 4-5 Relative adrenal insufficiency, 78-79, 174-178 rational use of glucocorticoids for, 1301 Relaxin for pregnancy diagnosis, 947 with pregnancy loss, 1004 Remifentanil, with maintenance anesthetic, 66, 67t Renal regulation of magnesium, 249-250 regulation of potassium, 251-252 Renal aplasia, ultrasound findings with, 841 Renal cell carcinoma, immunotherapy for, 335 Renal cysts, ultrasound findings with, 842 Renal disease and risk of urinary tract infections, 877 anemia from, e160 causing hyperkalemia and hyponatremia, e92, e93b drug incompatibilities and interactions with, 36 from complications of hypoparathyroidism, e129 from diabetes mellitus, e76 from heat-induced illness, 72 from hypothyroidism, e85

Renal disease (Continued) from plants, 121b glomerular disease and nephrotic syndrome, 853-857 hypertension and, 726-727, 727t, 729-730 hypokalemia from, 251b hypokalemia-induced, 252 hypomagnesemia from, 249b insulin resistance with, 206, 206b use of H2 receptor antagonists with, 505 use of nonsteroidal anti-inflammatory drugs for, 863-867 Renal dysplasia, ultrasound findings with, 841, 842f Renal failure acute from leptospirosis, 1286-1287 hospital acquired, 845-848 management of, 868-871 oliguria or anuria with, 869-870 pathophysiologic stages of, 868 polyuria with, 870 prognosis with, 870-871 treatment of toxin induced, e32b use of continuous renal replacement therapy with, 871-875, 875b and hypercalcemia, in cats, 242-243, 243b anemia from, e160 causes of, e29, e30b chronic and risk of hospital acquired infections, 877 diagnosis of, 857-863, 858b management of, 857-863 staging of, 857-863 substaging of, 858-860, 859t-860t treatment of, effect on staging, 860t use of NSAID’s with, 866-867, 866b continuous renal replacement therapy for, 871-875 drug effects on, 34t-35t formula for adjustment of antibiotic intervals, 34t-35t, 36 formula for adjustment of drug dosage and intervals, 36 from amphotericin, 1234-1235 from ethylene glycol toxicity, 151 from NSAID toxicity, 116 hyperthyroidism and, 185-189, 188f, e104, e118 nephrotoxins causing, e29-e34 treatment of, e32b pancreatic lipase immunoreactivity (PLI) testing with, 556 potassium supplementation with, 6-7 subcutaneous fluid administration for, 7 trypsin-like immunoreactivity (TLI) testing with, 557 with proteinuria and albuminuria, 851-852 Renal function with drugs used to treat heart failure, 779 with hyperthyroidism, 186-187

1399

Renal infarct(s) from feline thromboembolism, 812 ultrasound findings with, 842 Renal replacement therapy, 871-875 Renal threshold, for diabetes mellitus, in cats, 208 Renal transplantation immunosuppressive drugs for, 268-274 with nephroliths and ureteroliths, 895 Renin-angiotensin-aldosterone system function of, 238, 766 nutritional effects on, with heart disease, 720-722 sites of action of inhibitors on, 854-855, 854f stock and, 18 Renourethroscope, 943-944. See also Vaginoscopy for pyometra treatment, 943-944 Repetitive licking behavior, drug therapy for, 482-485 Reporting adverse drug and product events to (FDA), e35-e43 animal cruelty, e52 human drugs of abuse, e52 Reproductive disorder(s) aspermia/oligospermia caused by retrograde ejaculation, e350-e353 benign prostatic hypertrophy, 1012-1015 controversy with early age neutering, 982-984 effects of hypothyroidism, e85 estrus suppression in the bitch and, 984-989 inherited, 993-999 medical termination of pregnancy, 989-992 neoplasia, 1022-1026 of the female reproductive tract, 936-939 ovarian remnant syndrome, 1000-1003 postpartum, 957-960 pregnancy loss, 1003-1011, 1005t priapism as, e354-e357 problems of the male external genitalia, 1029-1032 prostatitis, 1012-1015 pyometra, 967-969 surgical repair of vaginal anomalies in the bitch, 974-981 toxins and teratogens, 1026-1028 vaginitis, 969-973 vulvar discharge from, 969-973 Reproductive physiology breeding management in bitch and, 930-935 exfoliative vaginal cytology, 932-933 female, 930 normal sexual development, 993, 994f onset of vulvar softening, 932 optimal time for breeding, 930-935 relationship of ovulation to luteinizing hormone surge, 931f, 931t proestrus, 932f

1400

Index

Reproductive physiology (Continued) progesterone concentration, 933f, 935f vaginal cytology, 933f reproductive toxins causing changes to, 1027-1028 Reproductive toxins and teratogens, 1026-1028, 1027b Reproductive tract diagnosis of diseases of the female, 936-939 examination of caudal, 932-934 female, figure of, 970f inherited disorders of the, 993-999, 995t Rescue chemotherapy, for canine lymphoma, 381-383, 382t Resistance from methicillin, with Staphylococcal infections, 443-445 multidrug, associated with pneumonia, 683b, 683t, 686 Resolve cleaner, toxic exposure to, 98 Respiratory acidosis causes of, e4b compensatory response to, e2t management of acid-base disorders and, e4-e5 Respiratory alkalosis causes of, e4b compensatory response to, e2t management of acid-base disorders and, e3-e4 Respiratory depression, intermittent positive pressure ventilation for, 66-67 Respiratory disease(s) anesthesia for patients with, 68 as risk for heat-induced illness, 71 brachycephalic airway obstruction syndrome, 649-653 canine infectious, 632-635 chronic bronchial, in dogs, 669-672 chronic bronchitis and asthma in cats, 673-680 drug therapy for, 622-628 eosinophilic pulmonary, 688-691 feline upper, 629-632 heartworm-associated, in cats, 826t interstitial lung, e266-e269, e267b laryngeal, 659-662 nasopharyngeal disorders causing, 653-658 parasites causing, e269-e276 pleural effusion with, 691-700 pneumonia, 681-688 pneumothorax, 700-704 pulmonary hypertension and, 711-717 pulmonary thromboembolism, 705-710 rhinitis in cats, 644-648, 1232 in dogs, 635-643 tracheal collapse, 663-668 with concurrent heart disease, 792-793 Respiratory distress acute syndrome of, 48-51, 49b causes of, 46t

Respiratory distress (Continued) from feline cardiomyopathy, 807-809 from heart failure, 782-783 from pleural effusion, 693-694 from tracheal collapse, 664-665 pathophysiology of, 44 physical examination with, 45-46 stabilization of patient with, 44-48 syndrome, causing interstitial lung disease, e267b treatment plan for, 46t, 47-48 Respiratory failure, 44-45 Respiratory particle spread, from pets to humans causing disease, 1245t, 1246 Respiratory protection, for handling hazardous drugs, 327 Respiratory toxicant(s), e43-e48 Respiratory tract infection(s) canine infectious, 632-635 common pathogens causing, 1222 empiric antimicrobial therapy for, 1220t feline upper, 629-632, 1232 use of glucocorticoids for, 1300 Resting energy requirements (RER), 39, 41b-42b, 259 Resuscitation. See also Cardiopulmonary resuscitation (CPR) end points for shock, 24 fluid therapy for using colloids, 8, 12t using crystalloids, 2-4 monitoring of, 19-20 Retina artificial, 1192 changes in, with glaucoma in dogs, 1171t tumors of, 1205-1206 Retinal degeneration in cats, 1194-1195 in dogs, 1192 Retinal detachment causing anisocoria, e392 from chorioretinitis, 1162 from hypertension, 726, 729, 1122, 1192 gemcitabine causing, e141 in cats, 1193-1194, 1194f in dogs causes of, e370-e372 diagnosis of, e372-e373, e372f from hypothyroidism, e85 pathogenesis of, e370 prognosis for, e373-e374 treatment of, e373 in dogs and cats, e383 Retinal disease, causing anisocoria or mydriasis, e394 Retinal dysplasia, in dogs, 1188, 1189f Retinal dystrophy, 1190-1192 Retinal pigment epithelial dystrophy, 1190 Retinochoroiditis, causing retinal detachment, in dogs, e371 Retinoids causing adverse skin reactions, 488t for actinic dermatoses, 481 for sebaceous adenitis, e211

Retinopathies causing blindness, 1135-1136, 1136t direct mutation test for, 1018t-1020t in cats, 1193-1196, 1194f hypertensive, 1193-1194 taurine, 1194-1195 in dogs, 1188-1192 Retrobulbar pain, from orbital diseases, 1198 Retrograde ejaculation, aspermia/ oligospermia caused by, e350-e353 Retroillumination, 1128-1129, 1129f with the neuro-ophthalmic exam, e391-e392 Retropulsion of the globe, 1132, 1197 Reverse sneezing, with nasopharyngeal disorders, 653 Rheumatoid arthritis, immunosuppressive drugs for, 268, 272 Rhinitis antibiotics for, 1220t, 1222 in cats diagnosis of, 644-646 from upper respiratory infection, 630t treatment of, 646-648 in dogs, 635-643 causes of, 636b treatment of, 637-643 Rhinoplasty, for brachycephalic airway obstruction syndrome, 651 Rhinoscopy for diagnosis of nasal disorders in dogs, 637 of cats with nasal discharge, 645-646 Rhinosinusitis, chronic, in cats, 644-648 Rhinosporidium seeberi, causing rhinitis in dogs, 637-640 Rhipicephalus sanguineus tick, transmitting Ehrlichia canis, 12271228, 1292-1294 Rhodesian ridgeback(s) degenerative myelopathy in, 1075-1076 epidermolytic ichthyosis in, 475 papillomatosis in, 1231f Rhododendron toxicity, 121b Rhodotorula spp., causing perivulvar dermatitis, 971 Ribavirin, for feline retrovirus infections, 1279 Riboflavin, for mitochondrial encephalopathy, 1051, 1051t Rickettsial infection(s) canine and feline monocytotropic ehrlichiosis, 1292-1294 causing myocarditis, e304t causing nervous system signs, 1212 causing polyarthritis, 1224-1228 causing renal infections, 1212 causing thrombocytopenia, 281t-282t common symptoms and syndromes caused by, 1214t immunosuppressive therapy for, 1232-1233

Index Rickettsial infection(s) (Continued) immunotherapy for, 1231-1233 rational use of glucocorticoids for, 1300-1301 Rifampicin for methicillin-resistant Staphylococcal skin infections, 444 for nontuberculous cutaneous granulomas, 448t Rifampin for Bartonella spp., 1266t for brucella canis, 972 for superficial bacterial folliculitis, 438t Right-to-left vascular shunt, with hypoxemia, 52 Riluzole, for degenerative myelopathy, 1078 Rinse(s), for pyoderma, 441t Rituximab, as cancer immunotherapy, 334 Robenacoxib adverse effects of, 60 dosage for, 62t Rocky Mountain spotted fever causing thrombocytopenia, 281t-282t causing uveitis in dogs, 1164b Rod cone dysplasia, direct mutation test for, 1018t-1020t Rodenticide toxicity, 133-135 exposures to, 92t, 96 Ronidazole for Tritrichomonas foetus, 528-530, 529f target parasites and dosage of, 1335-1337 Ropivacaine, toxicity of, use of IV lipid emulsion therapy for, 106 Rose bengal stain, 1132 with keratoconjunctivitis sicca, 1144 Roses, 121b Rosiglitazone, for diabetes mellitus, in cats, e137-e138 Rottweiler(s) cervical spondylomyelopathy in, 1092 colitis in, 553 hyperlipidemia in, 261, 262t hypoadrenocorticism in, 233 laryngeal paralysis in, 659 osteosarcoma in, 388 protein losing enteropathies in, 540-541 risk of pyometra in, 967 subaortic stenosis in, e319, e320f Royal Canin Veterinary diet Urinary SO, for calcium oxalate urolithiasis, 899t Rubeosis iridis, with canine uveitis, 1163t Rush immunotherapy, 412 Rutin, for chylothorax, 699 S S-adenosylmethionine (SAMe) as hepatic support therapy, e256-e257 for toxicities, 139-140, 143, 150, 161, 332-333, 577 for acetaminophen toxicity, 577 for chronic hepatitis, 585f, 587 for extrahepatic biliary tract disease, 604

S-adenosylmethionine (SAMe) (Continued) for feline hepatic lipidosis, 613 for idiopathic vacuolar hepatopathy, 608 for liver failure, 582 for portal vein hypoplasia, 600 for portosystemic shunts, 596 Sachet fresh-packet exposure, 97-98 Safety, associated with hazardous drug handling, 329 Sago palms toxicity, 121b Salicylate(s) containing oils, 125t containing plants, 125t containing preparations, 125 ototoxicity from, 468b toxicity of, 117 Salicylic acid as topical therapy for skin issues, 441t ear cleaner, 472-473 in ear cleaners, 472t Salmon poisoning disease, as cause of thrombocytopenia, 281t-282t Salmonella spp., 520 causing diarrhea, 519 causing pregnancy loss, 1005t, 1006, 1008 causing thrombocytopenia, 281t-282t common symptoms and syndromes caused by, 1213t in raw meat diets, 1240b, 1241 Salmonella typhimurium (Tapet), as cancer immunotherapy, 335, 336t Saluki(s) glaucoma in, 1171b thyroid hormone differences in, 180t Samoyed(s) alopecia X in, 477-479 direct mutation tests for, 1018t-1020t glaucoma in, 1171b sebaceous adenitis in, e209-e210 uveitis in, 1164 Sandimmune, 270 Sandostatin, for insulinomas, e134 Sarcoma(s) feline mammary, 378 soft tissue, e148-e152 vaccine-associated, in cats, 1252-1255 Sarcoptic mange, 403 diagnosis and treatment of, 428-430 treatment options for, 429t use of avermectins for, e181-e182 Sargramostin, for feline retrovirus infections, 1280t-1281t Scaling, from adverse drug reactions, 488t Scapula trauma in dogs, 81 Schiff-Sherrington syndrome, from intervertebral disk disease, 1072 Schirmer tear test technique and use of, 1132 with keratoconjunctivitis sicca, 1144, 1155 Schnauzer(s) direct mutation tests for, 1018t-1020t fibrocartilaginous embolism in, 1123 hyperlipidemia in, 261 risk of pancreatitis in, 261

1401

Schnauzer(s) (Continued) risk of urolithiasis in, 892, 897 sick sinus syndrome in, 732-733, 733f Scintigraphy for evaluation of esophagus, e227-e228 for evaluation of hepatobiliary disease, 573-574 for portosystemic shunt, 595 with portal vein hypoplasia, 600 Sclera tumors, 1204 Sclerosing agents, for malignant effusions, 342 Sclerotherapy, for essential renal hematuria, 886f Scotch broom, toxicity of, 124t Scott sliding potassium scale, 7t Scottish terrier(s) breed related alkaline phosphatase elevations, e245b, e246 direct mutation tests for, 1018t-1020t idiopathic vacuolar hepatopathy in, 607 prostatic hypertrophy in, 1012 risk of bladder cancer in, 371t Scraping, for cytology, e154 Scratch, from pets to humans causing disease, 1245t, 1246 Scratching behavior in cats, 913 Scrotum nonneoplastic disorders of the, 1031 tumors of, 1023 Sebaceous adenitis diagnosis of, e210 therapy of, e209-e212 use of cyclosporine for, 409 Sebaceous gland hyperplasia, 476-477 Seborrhea, use of cyclosporine for, 410b Seborrhea oleosa, with Malassezia spp. infections, e213 Seborrhea sicca, with Malassezia spp. infections, e213 Secnidazole, for Giardia spp., 530-531 Second-hand smoke, e44 Sedation for thoracocentesis, 693 with cardiovascular dysfunction, 64-65 Sedums, 121b Seidel’s test, 1132 Seizure(s) causes of, 1058-1059, 1059t fluid resuscitation in, 1061t from hypoparathyroidism, e123-e124 from insulinoma, e130 infectious agents that cause, 1212 new anticonvulsants for, 1054-1057 pathophysiology of, 1058 therapy for increased intracranial pressure from, 1061-1062, 1062t treatment of cluster, 1058-1063 treatment of status epilepticus, 1058-1063 vs. syncope, e325 with portosystemic shunt, 596 Selamectin (Revolution), 426t for cheyletiellosis, 430t, e182 for dermatologic disorders, e178, e180 for flea infestation, e183 for lung worms, e274

1402

Index

Selamectin (Revolution) (Continued) for nasal mites, 637, 655-656, e270 for Otodectes infestation, 431t, e182 for pediculosis, 429t for sarcoptic and notoedric mange, 429t target parasites of, 1335-1337 toxicity of, 145-146 Selective serotonin reuptake inhibitors (SSRIs) for behavior-related dermatoses, 483-484, 483t toxicity of, 112-114 Selenium associated hepatotoxicity, 570b Self-mutilating behavior(s) drug therapy for, 482-485 with hot spots, e206 Semen and endoscopy transcervical insemination, 943 frozen, fresh or chilled, 943 Seminomas, 1022-1023 Senile retinal degeneration, 1192 Sensorineural hearing loss, 468-469, 468b treatment and prevention of, 470-471 Sepsis causing gastric ulcerations, e253 causing uveitis in dogs, 1164b drainage techniques for the abdomen, e13-e20 drug incompatibilities and interactions with, 37 from heat-induced illness, 71 pulmonary thromboembolism associated with, 705 rational use of glucocorticoids for, 1301 Septic abdomen, drainage techniques for, e13-e20 Septic arthritis, common pathogens causing, 1220t, 1222-1223 Septic shock, 18 catecholamine use for, 15t Septicemia as cause of thrombocytopenia, 281t-282t common pathogens causing, 1223 empiric antimicrobial therapy for, 1220t Serology for Borrelia burgdorferi, 1272-1273 for feline Bartonella spp., 1269 Serotonin, and acral lick dermatitis, e177 Serotonin antagonist reuptake inhibitors (SARIs) for behavior-related dermatoses, 483t, 484, e177 toxicity of, 112-114 Serotonin syndrome, signs of, 34t-35t Serotoninergic effects, of prokinetic drugs, 516-518, 517t Serratia marcescens, for feline retrovirus infections, 1280t-1281t, 1282 Sertoli cell tumor, 1022-1023 causing alopecia, in dogs, 165

Sertraline for behavior-related dermatoses, 483-484, 483t toxicity of, 113 Serum pancreatic lipase immunoreactivity (PLI), with pancreatitis, 555-556 Serum proteomics, with myocarditis, e305 Serum therapy, for keratomalacia, 1151 Serum trypsin-like immunoreactivity (TLI) with exocrine pancreatic insufficiency, 556-557, 559 with feline pancreatitis, 566 with pancreatitis, 555 Sevoflurane, anesthesia in critical care, 66 Sex chromosome disorders of sexual development, 994, 995t Sex hormone panel testing, 223 role in alopecia X, 477 Sexual development disorders of, 993-999, 995t normal, 993, 994f Shampoo therapy for atopic dermatitis, 405 for dermatophytosis, 450t for ichthyosis, 476 for Malassezia spp. infections, e215 for methicillin-resistant Staphylococcal skin infections, 444 for pyoderma, 439-443, 441t for sebaceous adenitis, e210-e211 Shar-pei dog, amyloidosis in, 855 Shelter(s) canine respiratory infection in, 632, 634-635 feline upper respiratory infection in, 629, 631-632 multicat outbreaks with dermatophytosis in, 452-454 Shetland sheepdog(s) avermectin toxicity in, 145 dermatomyositis in, 1115 direct mutation tests for, 1018t-1020t hyperlipidemia in, 261 mitochondrial encephalopathy in, 1048-1051, 1049t, 1051t risk of bladder cancer in, 371t Shih tzu dog(s) Chiari-like malformation in, 1101 cilia abnormalities in, 1155 glaucoma in, 1171b hepatobiliary disease in, 571b intracranial arachnoid cysts in, 1038 mammary cancer in, 377-378 mitochondrial encephalopathy in, 1048-1051, 1049t, 1051t risk of urolithiasis in, 892, 897 Shock, 18-25 cardiogenic, 783 dobutamine for treatment of, 16-17 dopamine for treatment of, 16 use of catecholamines for, 15t causing gastric ulcerations, e253 classifications and examples of, 19b

Shock (Continued) dose of fluids, 2-4, 20-22 hypovolemic fluid therapy for, 2, 12t physical findings with, 5t resuscitation end points for, 24 septic (See Septic shock) therapy for, 20-25 with illness-related corticosteroid insufficiency, 78, 174-178 Shoulder trauma in dogs, 81 Shunt reversal, 760 Siamese cat chylothorax in, 698 glaucoma in, 1177 hepatic amyloidosis in, 571b progressive retinal atrophy in, 1195 resting nystagmus in, 1067 retinal degeneration in, 1195 risk of asthma in, 674 risk of diabetes in, 208 vestibular disease in, 1068 Siberian husky alopecia X in, 477-479 breed related alkaline phosphatase elevations, e245b direct mutation tests for, 1018t-1020t laryngeal paralysis in, 659-661 zinc-responsive dermatosis, causing blepharitis in, e365 Sick sinus syndrome, 732-733 causing syncope, e328f, e330 temporary pacing for, e21 Sildenafil (Viagra) for heart failure, in dogs, 764t-765t, 768 for pulmonary hypertension, 715-716 with valvular heart disease, 793-794 Silibin/phosphatidylcholine (PPC) for feline hepatic lipidosis, 613 for liver failure, 582 Silver sulfadiazine, topical, for otitis, 464t Silymarin (milk thistle) as hepatic support therapy, e256 for cholangitis, 617-618, 617b for hepatic lipidosis, 613 for portosystemic shunts, 596-598 for toxicities, 102t-104t, 161 Simethicone, for flatulence, e250 Sinoatrial node abnormalities, 732-733 Sinus arrest, temporary pacing in, e28f Sinus tachycardia, with gastric dilationvolvulus, e17 Sinusitis, causing rhinitis in dogs, 637-640 Sirolimus, use of, for immunosuppression, 271-272 Skin. See also under Dermatologic disorder(s) disease from Bartonella spp. infections, 1263b lesions from adverse drug reactions, 488t Skin biopsy, for diagnosis of alopecia, 166 Skin scale, 475-477

Index Skin scraping for demodex as cause of alopecia, 165 for demodicosis, 432-433 for sarcoptic mange, 428 Slide preparation for cytology, e154e156, e155f Slings, e359 Sloughi(s) direct mutation tests for, 1018t-1020t thyroid hormone differences in, 180t Small intestinal bacterial overgrowth, 520-521 antibiotic-responsive, 519 treatment for, 520t Smears, for cytology, e155, e155f Smog toxicity, e45-e46 Smoke, second-hand, e44 and risk of asthma, 675 Sneezing and rhinitis in dogs, 635-648 infectious causes of, 1217-1218 Snoring, with nasopharyngeal disorders, 653 Sodium composition in fluid therapy, 3t requirements during pregnancy and lactation, 963 restriction with heart disease, 721b, 723, 777, 790, 792 treats, 721t Sodium bicarbonate drug incompatibilities with, 33t during CPR, 30 for acid-base disturbances, e5-e8 for acute renal failure acidosis, 870 for diabetic ketoacidosis, 236, e80te81t, e82 for gastric dilation-volvulus acidosis, e16 formula for calculation of deficit, 870 Sodium channel blockers for dogs, 763b, 771 for supraventricular tachyarrhythmias, 742t, 743 for ventricular arrhythmias, 746-748, 799 Sodium chloride, supplementation with calcium oxalate urolithiasis, 898-899 Sodium hypochlorite as topical therapy for skin infections, 441t for disinfection of methicillin-resistant Staphylococcal sp., 456 Sodium lauryl sulfate, in ear cleaners, 472t Sodium polyborate, for dust mite control, e199 Sodium stibogluconate, for American leishmaniasis, e397 Sodium tetraborate pentahydrate (Borax), in ear cleaners, 472t Sodium-chloride difference, calculation of, with acid-base disorders, e2, e3b Sodium/potassium ratio (Na/K ratio), with hypoadrenocorticism, 233, 234t

Soft palate deformities with brachycephalic airway obstruction syndrome, 650t, 651, 652f surgical access to, 655 Soft tissue sarcoma, e148-e152 cancer immunotherapy for, 336t, 337 Solitary osseous plasmacytoma, 387 Somatostatin, for insulinomas, e134 Somogyi phenomenon, 195, 213 Sorbitol cathartic(s), for toxin ingestions, 105 Sotalol causing bradyarrhythmias, 732 causing syncope, e328 for arrhythmia with congestive heart failure, 783-784 for arrhythmia with dilated cardiomyopathy, in dogs, 799 for feline arrhythmias, 750f-751f, 752 for feline cardiomyopathy, 806t for heart failure, in dogs, 764t-765t with arrhythmias, 771 for supraventricular tachyarrhythmias in dogs, 742t, 743-744 for ventricular arrhythmias in cats, 753-754 in dogs, 746-747, 747f, 747t with arrhythmogenic right ventricular cardiomyopathy, 803 Space, and environmental enrichment for domestic cats, 910-911 Spastic pupil syndrome, e395 Specialist referral, with legal claim regarding poisonings, e50-e51 Specimen(s), tissue handling and fixation of, 322-326, 323b Spill management, associated with hazardous drugs, 328 Spinal cord injury from intervertebral disk disease, 1071 injury scores, 1072, 1072t reflexes occurring during ejaculation, e351t Spindle cell tumor, ocular, 1205 Spindle tree, European toxicity, 124t Spinosad, 426t potentiation of ivermectin toxicity with, e179 target parasites of, 1335-1337 Spinosad/milbemycin, 426t target parasites of, 1335-1337 Spirochetes, causing myocarditis, e304t Spironolactone causing adverse skin reactions, 488t for ascites, from liver disease, 591, e257-e258 for asymptomatic heart disease, 766 for dilated cardiomyopathy, in dogs, 798-799 for feline cardiomyopathy, 805-807, 806t, 809 for glomerular disease, 854 for heart failure, in dogs, 763-765, 764t-765t, 777-779, 791 for hepatic fibrosis, 587 for pulmonary hypertension, 714

1403

Spitz(s), alopecia X in, 477-479 Splenectomy, for thrombocytopenia, 285-286 Splenic disease from Bartonella spp. infections, 1263b injury with gastric dilation-volvulus, e14, e18-e19 masses with arrhythmogenic right ventricular cardiomyopathy, 802 Splenic hemangiosarcoma, 394 Splint(s), with open fractures, 84 Sponge(s), pot scrubbing, ingestion of, 98 Sporothrix schenckii causing epistaxis, 1216 common symptoms and syndromes caused by, 1214t Sporotrichosis, antifungal therapy for, 1234-1238 Sporozoites, from toxoplasmosis, 1295 Spray(s) for pyoderma, 441t potency of topical steroid, 460f Springer spaniel(s atrial standstill in, 734 direct mutation tests for, 1018t-1020t hepatobiliary disease in, 571b mammary cancer in, 375 oropharyngeal dysphagia in, 497 Squalene, in ear cleaners, 472t Squamous cell carcinoma anal sac, e189-e190 eyelid, e368 immunotherapy for, 336t mammary canine, 376 feline, 378 nasal, radiation therapy for, 338-340 ocular in cats, 1207-1210 in dogs, 1204 oral, 365 papillomaviruses causing, e185 penis and preputial, 1023 scrotal, 1023 topical immunomodulators for, e220 Squamous papillomas, 1202 Staging of canine heartworm disease, 826-827 of heart disease, 773-775, 787t of mammary cancer, 376t of nasal tumors, e157 of renal failure, 857-863 of thyroid tumors, 399t tumor, e170 Stanozolol, associated hepatotoxicity, 570b Staphage lysate (SPL) for infectious disease immune therapeutics, 1230t for superficial bacterial folliculitis, 439 Staphylococcus aureus causing endocarditis, e292-e293, e294t causing pyoderma, 435 in raw meat diets, 1240-1241, 1240b Staphylococcus intermedius, causing endocarditis, e293-e294, e294t

1404

Index

Staphylococcus protein A, for feline retrovirus infections, 1280t-1281t, 1282 Staphylococcus pseudintermedius causing pyoderma, 435 common symptoms and syndromes caused by, 1213t Staphylococcus schleiferi, causing pyoderma, 435-436 Staphylococcus spp. infection causing blepharitis, e363 causing conjunctivitis, 1141-1142 causing keratoconjunctivitis sicca, 1144 causing otitis, 466 causing pneumonia, 682t causing pregnancy loss, 1005t, 1006 causing prostatitis, 1013 causing pyoderma, 435-436 causing septic mastitis, 959 disinfection of environments with, 455-457 methicillin-resistant infections, 443-445 role of, in hot spots, e206 topical therapy for, 440-442, 441t with open fractures, 84, 86 Starch, dietary requirements for, with diabetes mellitus, 200-201 Starling-Landis equation, 8, 9f Statins, for hyperlipidemia, 265-266 Status epilepticus, 1058-1063 Stavudine, for feline retrovirus infections, 1278, 1279t Stenosis, lumbosacral, 1105-1108 Stenotic nares, and brachycephalic airway obstruction syndrome, 649-653, 650t Stenting bronchial, 668 choledochal, in cats, 568 of malignant obstructions, 345-347 tracheal, 664-668, 666f-667f ureteral, 887-888 urethral, 889-890, 889f-890f Stereotactic radiation therapy, for nasal tumors, 338-339 Stereotactic radiosurgery, for osteosarcoma, 392 Sterile neutrophilic dermatosis, 489 Steroid contraceptives, 984-985, 987 Steroid myopathy, 1116 Steroid tachyphylaxis, 461 Steroid(s). See Glucocorticoid(s) Stertor, with nasopharyngeal disorders, 653-654 Stevens-Johnson syndrome, from drug reactions, 488 Stevia rebaudiana, as diabetes supplement, toxicity of, 125 Stifle joint trauma in dogs, 81-82 Stillbirth. See Pregnancy Stomach, deformities with brachycephalic airway obstruction syndrome, 650t Stomatitis feline caudal, 492-495 from feline upper respiratory infection, 630t infectious causes of, 1216

Stone basketing, 890 Strabismus from orbital diseases, 1197, 1198b from vestibular disease, 1067, 1067t Straelensia cynotis, 431-432 Streptococcus canis causing endocarditis, e293-e294, e294t causing feline upper respiratory infections, 629 Streptococcus equi var. zooepidemicus causing respiratory infections, 1217-1218 common symptoms and syndromes caused by, 1213t Streptococcus spp. infection causing conjunctivitis, 1141-1142 causing pneumonia, 681, 682t causing pregnancy loss, 1005t, 1006 causing prostatitis, 1013 causing septic mastitis, 959 Streptokinase, for pulmonary thromboembolism, 707-708 Streptozocin, toxicity from chemotherapeutic drugs, 332 Streptozotocin, for insulinomas, e132-e133 Stress causing pregnancy loss, 1010-1011 effect of, with feline upper respiratory infection, 629, 631 Stress related mucosal disease (SRMD), from shock, 24 Stroke. See Cerebrovascular accident Strong ion difference acidosis, causes of, e6-e8, e7b alkalosis, causes of, e6, e6b calculation of, with acid-base disorders, e2 disorders of, e5-e8 mechanisms for, e6t Strong ion gap, calculation of, with acid-base disorders, e2, e3b Strongyloides stercoralis, common symptoms and syndromes caused by, 1214t-1215t Struve urolithiasis, and nephroliths, 926 Struvite crystalluria, 926 Strychnine toxicity, 134 Styrene toxicity, 1027b Subaortic stenosis, e319-e324 causes of, e319 diagnosis of, e320-e323, e320f-e321f, e323f pathophysiology of, e320 predisposing to endocarditis, e291-e292 prevalence of, in dogs, 756, 757t prophylaxis with, e297-e298 therapy of, 759-760, e323-e324 Subcutaneous fluid therapy, 7 Subinvolution of placental sites, 957 Sublingual immunotherapy, 413, 413b Succimer, for lead toxicity, 158 Sucralfate (Carafate) action and use of, 507 drug incompatibilities with, 33t for esophagitis, e240 for gastric ulcerations, e254 for gastroesophageal reflux, 503

Suction, with thoracostomy tubes, 702 Sudden acquired retinal degeneration, e383 Sudden death with arrhythmogenic right ventricular cardiomyopathy, 803 with dilated cardiomyopathy, 798 Sulfadiazine/trimethoprim, target parasites and dosage of, 1335-1337 Sulfadimethoxine, target parasites and dosage of, 1335-1337 Sulfasalazine for canine colitis, 551b for inflammatory bowel disease, 539 Sulfonamide(s) adverse effects of, 34t-35t associated hepatotoxicity, 570b, 577-578 causing adverse skin reactions, 488t causing keratoconjunctivitis sicca, 1144 Sulfosalicylic acid (SSA) precipitation test, 849 Sulfur, as topical therapy for skin issues, 441t Sulfur dioxide toxicity, e45 Sulindac toxicity, 116-117, e32-e33 Sun exposure, as risk factor for ocular neoplasia, 1207 Sun protection for actinic dermatoses, 480-482 with clothing, 481 with sunscreens, 481 Superficial bacterial folliculitis, 437-439 Superficial necrolytic dermatitis, 485-487 causing blepharitis, e365-e366 Superficial punctate keratitis, 1153 Superior vena cava syndrome, stenting for, 347 Superoxide dismutase 1 gene, in degenerative myelopathy, 1075-1076 Supraventricular tachyarrhythmias, in dogs, 737-744 classification of, 738 clinical signs of, 738-739 treatment of, 741-744, 742t Supraventricular tachycardia, in dogs, 739 Suprofen, for canine uveitis, 1165t Suramin, for feline retrovirus infections, 1278-1279, 1279t Surgery cesarean section, 951-956 empiric antimicrobial therapy for musculoskeletal, 1220t for acral lick dermatitis, e176 for atlantoaxial subluxation, 10861088, 1087f-1089f for canine glaucoma, 1174-1176 for cataracts, 1184-1185 for congenital heart disease, 760-761 for correction of vaginal anomalies in the bitch, 974-981, 975f-976f for craniocervical junction abnormalities, 1103-1104, 1103f for feline cholangitis, 617 for feline corneal disease, 1160, 1161t

Index Surgery (Continued) for feline gastrointestinal lymphoma, 547 for feline glaucoma, 1180 for gastric dilation-volvulus, e18 for hemangiosarcoma, 395 for hyperadrenocorticism in ferrets, e95 for insulinoma, e131-e132 for intervertebral disk disease, 1073-1074 for intracranial tumors, 1039-1047 for keratoconjunctivitis sicca, 1147 for laryngeal paralysis, 660-661 for ligation of patent ductus arteriosus, e312-e313 for malignant effusions, 342-343 for mammary cancer, 377 for mechanical occluder devices, 921 for nontuberculous cutaneous granulomas, 448 for oral neoplasia, 363-364 for osteosarcoma, 389-390 for pituitary macroadenoma, e90 for portosystemic shunt(s), 596-597, 598f for pyothorax, 697 for soft tissue sarcomas, e150-e151, e151 for thyroid tumors, 399, 399f for treatment of hyperparathyroidism, e72 for urinary bladder cancer, 372 for vaccine-associated sarcoma, 1254 for valvular heart disease, 794 for ventriculoperitoneal shunt, 1036-1037, 1037f indications for post-op peritoneal drainage with, e14 margins, demarcating specimens for evaluation, 324, 324b minilaparotomy-assisted cystoscopy for urocystoliths, 905-909, 906f-907f of the gall bladder, 602-605 of the nasopharynx, 655 palliative vs. curative, e171 pericardectomy, 821-823, 822f principles for oncology, e168-e172 pulmonary thromboembolism associated with, 705 technique for early age neutering, 983 to detect ovarian remnant syndrome, 1002, 1003f Susceptibility testing, for methicillinresistant Staphylococcal skin infections, 444 Suture pattern for eyelid laceration, e379f temporary tarsorrhaphy, e378f Swallowing phases of, 495-496, e224-e225, e259 signs of dysfunction, e260t studies, 497-498 Sweet cane toxicity, 124t Sweet cinnamon toxicity, 124t Sweet flag toxicity, 124t Sweet root toxicity, 124t Swiffer WetJet ingestion, 97

Swinging flashlight test, e391 Swiss Mountain dog(s), cervical spondylomyelopathy in, 1092 Symblepharon, from feline herpesvirus 1, 1157t Sympathomimetic agent(s) for glaucoma in dogs, 1173b, 1174 for retrograde ejaculation, e352-e353 for urinary incontinence disorders, 915, 916t Symptoms, causing by common infectious agents, 1212-1218 Synbiotic(s), for flatulence, e250 Syncope, e324-e331 and arrhythmia in cats, 748, 750f-751f causes of, e326-e329 diagnosis of, e329 pathophysiology of, e325 reflex-mediated, 736 temporary pacing for, e22 treatment of, e329-e330 vs. seizure, e325 with congenital heart disease, 759-760 Syringomyelia, 1100-1101 Systemic illness, from adverse reactions to vaccines, 1251 Systemic inflammation and cancer cachexia, 350 drug incompatibilities and interactions with, 37 with disseminated intravascular coagulation, 292, 293f Systemic inflammatory response syndrome (SIRS), 18 fluid movement with, 9t from heat-induced illness, 71 rational use of glucocorticoids for, 1301 with feline pancreatitis, 567 Systemic lupoid onychodystrophy, pentoxifylline for, e204 Systemic lupus erythematosus, causing blepharitis, e367 T T-cell leukemia, 303-304 T-cell lymphoma, 303-304 masitinib for, 361t Table of common drugs: approximate dosages, 1307-1334 Tachyarrhythmias feline, 750f-751f supraventricular, in dogs, 737-744 Tachycardia causing syncope, e326 sinus, in cats, 749 supraventricular tachyarrhythmias causing syncope, e326 in dogs, 737-744 Tachycardiomyopathy, 738 Tachyzoites, from toxoplasmosis, 1295 Tacrolimus and risk of ocular squamous cell carcinoma, 1204 as topical immunomodulators, e216-e220, e217 for anal furunculosis, e190 for atopic dermatitis, 406, e217-e218

1405

Tacrolimus (Continued) for chronic superficial keratitis (Pannus), 1154 for discoid lupus erythematosus, e218 for episcleritis, 1141 for immune-mediated diseases, e218 for keratoconjunctivitis sicca, 1145, 1155 monitoring blood levels of, 271 safety concerns of, e219-e220 topical, 420t, 421 use of, for immunosuppression, 271 Tadalafil (Cialis), for pulmonary hypertension with valvular heart disease, 793-794 Taenia spp. infection common symptoms and syndromes caused by, 1214t-1215t drugs targeting, 1335-1337 Tamoxifen, for mammary cancer, 377 Tamsulosin for urinary retention disorders, 917t, 918 to promote ureterolith passage, 894 Tannic acid associated hepatotoxicity, 570b for dust mite control, e199 Tape preparation, of skin, for diagnosis of alopecia, 165 Tapetal reflex, 1128-1129 Taurine deficiency cardiomyopathy, 795, 797, 800, 809 for asymptomatic heart disease, 766 for feline hepatic lipidosis, 613 requirements with heart disease, 724 retinopathy, 1194-1195 Tea as poisoning antidote, 98 toxicity, 98, 148t Tear film disorders in cats, e384-e388 diagnosis of, e385-e386 lipid layer abnormalities, e385 mucin layer abnormalities, e385 physiology and pathophysiology of, e384, e384-e385, e385f treatment of, e386-e387 in dogs, 1143-1147 causes of, 1144 mucin deficiency causing, 1155 Tear substitutes, e386-e387 for keratoconjunctivitis sicca, 11451147, 1146t Tearing. See Epiphora Tellurium, causing reproductive toxicity, 1027b Temazepam toxicity, 113-114 Temozolomide, e140t, e142 Temporary tarsorrhaphy, e378f Tenosynovitis common pathogens causing, 1222-1223 empiric antimicrobial therapy for, 1220t Tepoxalin, for canine uveitis, 1165t Teratogens, 1026-1028

1406

Index

Terbinafine for dermatophytosis, 451, 451t for fungal rhinitis in cats, 647-648, 647t for Malassezia spp. infections, e215, e215t for nasal aspergillosis, 639-640 use and protocols for, 1235t, 1238 Terbutaline for atrioventricular block, in cats, 754 for bradycardias, 736 for bronchial diseases, 671 for feline asthma, 675, 677 for premature labor, 947-948 for priapism, e356-e357 for respiratory diseases, 623 for tracheal collapse, 664 Terminator rodenticide toxicity, 134 Terrier(s), sebaceous gland hyperplasia in, 476-477 Testicle dysgenesis, partial, 997 nonneoplastic disorders of the, 1031-1032 reproductive toxins targeting the, 1027-1028 tumors of the, 1022-1023 Testosterone, for estrus suppression in the bitch, 987 Tetrachloroethylene toxicity, 1027b Tetracycline(s) adverse effects of, 34t-35t associated hepatotoxicity, 570b, 581b causing adverse skin reactions, 488t causing pregnancy loss and fetal disorders, 1010 drug incompatibilities with, 33t for brucellosis, e404 for canine babesiosis, 1259 for epiphora, e375 for feline tear film disorders, e387 for hemotropic mycoplasmosis, e401 for keratomalacia, 1151 for lower respiratory tract infection(s), 1220t, 1222 for pleurodesis, 342 for sebaceous adenitis, e211 for urinary tract infections, 1220t, 1221 interaction with GI drugs, 37 topical, for feline ocular herpesvirus 1, 1158 Tetralogy of Fallot, e339-e340 prevalence of in cats, 757t in dogs, 757t Tetramine, for copper-associated liver disease, 589, e236 Tetraplegia, from degenerative myelopathy, 1076-1077, 1076t Tetrastarch, 11-12 characteristics of, 10t Thallium, causing reproductive toxicity, 1027b Thelazia spp., causing conjunctivitis, 1142 Theobromine toxicity, 148-149

Theophylline adverse effects of, 625 drug interactions with, 35t, 677 enterohepatic recirculation of, 105 for canine bronchial diseases, 671 for feline bronchitis and asthma, 677 for tracheal collapse, 664 formulations of, 624 pharmacokinetics and dosing of, 624-625 Thermal injury, 71 Thermal tumor ablation, for malignant obstructions, 348 Thermoregulatory center, 70-71, 73 Thiabendazole causing adverse skin reactions, 488t topical, for otitis, 465t Thiabendazole/neomycin/ dexamethasone, for Otodectes infestation, 431t Thiacetarsemide aplastic anemia from, e162 associated hepatotoxicity, 570b, 581b Thiamine deficiency causing vestibular signs, 1068-1069 with liver failure, 582 Thiazide diuretic(s) for calcium oxalate urolithiasis, 900 for congestive heart failure, 798 for feline myocardial disease, 809 for hypercalciuria, e128 for hypoparathyroidism, e128 for insulinomas, e133 impact on potassium levels, 122-123, 251-252, 251b, 723, e93 Thiazolidinedione, for diabetes mellitus, in cats, e135, e136f, e137-e138 Third eyelid. See Nictitating membrane Thoracic pump theory, 27 Thoracocentesis complications of, 693-694 for malignant effusions, 342 for pleural effusion, 692-693 with refractory heart failure, 781 for pneumothorax, 701 procedure for, 693 Thoracoscopic subtotal pericardectomy, 822f, 823 Thoracostomy tube(s) “three strikes” rule for placement of, 702-703 for pneumothorax, 701-702 for pyothorax, 696-697 Thoracotomy for pleural effusion, 697, 699-700 for pneumothorax, 702 Thorn apple toxicity, 124t Thoroughwort toxicity, 124t Three-dimensional conformal radiation therapy, for nasal tumors, 339, 339f-340f Thrombi formation in hypercoagulable states, 297-301, 298f reduction of, 813 risk of, 708 Thrombin, abnormalities with disseminated intravascular disorders, 293f

Thrombocytopenia determining the cause of, 283-284 diagnosis and treatment of, 280-286 diagnostic workup for, 315f from canine parvoviral enteritis, 533 from chemotherapeutic drugs, 331 from heat-induced illness, 72 from methimazole, e103 immune-mediated, immunosuppressive drugs for, 268 infectious causes of, 281-283, 281t-282t prognosis for, 286 Thromboelastography, 74-77, 75t, 706, 710 Thromboembolic disease, 812-813 causing pulmonary hypertension, 712t, 716 from hypercoagulable states, 297-301 risk of, with protein-losing enteropathy, 544 Thromboembolism causing Ischemic strokes, 1119-1120 feline arterial, 809-815 thromboprophylaxis for, 710 from autoimmune hemolytic anemia, 276 from cytauxzoonosis, e408 from endocarditis, e293 from feline heartworm disease, 830 from glomerular disease, 854-855 Thrombolysis, 813-814 for pulmonary thromboembolism, 707-708 Thrombophilia, causing pulmonary thromboembolism, 705 Thrombophlebitis, from parenteral nutrition products, 40-41 Thymectomy, for myasthenia gravis, 1111 Thymidine kinase, with hemangiosarcoma, 395 Thymol, as topical antipruritic agents, 419 Thymoma, lymphocytosis associated with, 304 Thyroid diseases, interpretation of tests results for, e97-e102 Thyroid gland CT images of, 168f imaging of, for diagnosis of endocrine disorder(s), 167-170, 168t influence of drugs on function of, 181t physiology, in cats, e107, e108f Thyroid scintigraphy, 167, e113-e117, e114f-e115f, e116f Thyroid tumors diagnosis and treatment of in cats, 400 in dogs, 397-400 staging of, 399t Thyroid-stimulating hormone levels in hypothyroidism, 181-182, 182t suppression with radioiodine therapy, e119-e120 test, 182, e100

Index Thyroidectomy, e109 hypocalcemia post, e124-e125 pros and cons, e103t Thyroiditis diagnosis and treatment of, 182-184 hypothyroidism with, 178-179 Thyroxine (T4) levels with hyperthyroidism, 169-170, e101, e107 levels with hypothyroidism, 178-185, 180t, e99-e101, e100 age related differences, 180t autoantibodies with, e100 effect of drugs on, 181t free, 180, e100 total, 180 levels, while on glucocorticoids, 461 test sensitivity of, 181t Tibetan terrier(s), direct mutation tests for, 1018t-1020t Ticarcillin-clavulanate (Timentin) for feline pancreatitis, 567t for infective endocarditis, e294t, e297 for otitis, 466t, 467 for pneumonia, 683, 683t Tick collar toxicity, 138-139 Tick prevention product(s) avermectins as, e182-e183 drug reactions from, 489 for cats, 426t for dogs, 426t, 1294 formulations of, dosage for and target parasites of, 1335-1337 Tick(s) causing cytauxzoonosis, e405 causing Hepatozoon americanum, 1283-1284 drugs targeting, 1335-1337 transmission of disease by, from pets to humans, 1248 transmitting polyarthritis, 1224-1228 vectors for ehrlichiosis, 1292 Tiger balm liniment toxicity, 125t Timolol for canine glaucoma, 1173b, 1174, e381 for feline glaucoma, 1179, e381 Tinidazole for Giardia spp., 530-531, 530t target parasites and dosage of, 1335-1337 Tissue factor with disseminated intravascular coagulation, 292, 293f-294f with hypercoagulable states, 297 Tissue factor pathway inhibitor(s), for disseminated intravascular coagulation, 296 Tissue handling and fixation, for biopsy and specimen submission, 322-323, 323b Tissue plasminogen activator (t-PA), 813 for feline thromboembolism, 810 for pulmonary thromboembolism, 707-708 Tissue sloughing, from extravasation of chemotherapeutic drugs, 333

Tobramycin, causing renal failure, e31-e32 Toceranib (Palladia) for malignant effusions, 344 for oral tumors, 364 for osteosarcoma, 392 for thyroid cancer, 400 toxicity of, 359-360 Tocodynamometer, 950, 950f Tolazoline hydrochloride, as antidote, e56t Tolbutamide, associated hepatotoxicity, 581b Toll-like receptor agonists, for local immunotherapy, 335 Tolmetin toxicity, e32-e33 Toluene toxicity, 1027b Toluidine toxicity, 1027b Tongue tumors, 364-365 Tonka and tonka bean toxicity, 124t Tono-pen, 1171-1172 Tonometry, 1130 for canine glaucoma, 1171-1172, 1174 in cats artificial elevations of, 1178-1179 with glaucoma, 1178 Tonsillar tumor, 365 Tooth resorption, for feline caudal stomatitis, 493 Topical therapy for acral lick lesions, e176-e177 for atopic dermatitis, 406 for dermatophytosis, 450, 450t for hot spots, e207-e208 for infectious skin diseases, 439-443, 441t for Malassezia spp. infections, e215 for otitis antimicrobials, 462-465 with glucocorticoids, 460t for pruritus, 419-421 ototoxicity from, 468b Torsemide for heart failure, in dogs, 762-763, 764t-765t for refractory heart failure, 781 Total parenteral nutrition, 39-40, 41b Toxic epidermal necrolysis, from drug reactions, 489 Toxicity(ies) and risk of urinary bladder cancer, 370 ASPCA Animal Poison Control Center exposures, 92-93 causing blindness, e383 causing hepatobiliary disease, 569, 570b, 581b causing myocarditis, e304t causing polyneuropathy, 1116-1117 causing pregnancy loss, 1010 causing retinal detachment, in dogs, e371 deaths from, 94, 94t drug-associated liver, 575-579 drugs used to treat, 101-105, 102t-104t exposures to, 92-93 from aflatoxins, 159-161 from antidepressants and anxiolytics, 112-114

1407

Toxicity(ies) (Continued) from automotive and garage items, 151-155 from chemotherapeutic drugs, 330-333 from cyclosporine, 270-271 from essential oils, 125-127, 126t from herbal supplements, 122-129 from human drugs of abuse, 109-112 from human foods, 147-150 from lawn and garden products, 130-132 from mycophenolate mofetil, 272 from plants, 121, 121b insecticide, 135-141 IV lipid emulsion therapy for, 106-109 lead, 156-159 legal claim considerations with, e49-e52 nephrotoxins causing, e29-e34 pesticides for vertebrate pest species, 142-144 Pet Poison Helpline exposures to, 93-96 regulatory points to consider with treatment of, e54-e68 reporting adverse events from, e35-e43 reproductive, 1026-1028, 1027b respiratory, e43-e48 rodenticide, 133-135 source of help for, e53 urban legends of, 97-100 Toxocara canis, common symptoms and syndromes caused by, 1214t-1215t Toxocara cati, common symptoms and syndromes caused by, 1214t-1215t Toxocara leonina, common symptoms and syndromes caused by, 1214t-1215t Toxocara spp. infection causing infection in humans, 1247 drugs targeting, 1335-1337 in raw meat diets, 1240b, 1242 Toxoplasma gondii, 1295 causing infection in humans, 1216, 1246-1247 causing myocarditis, e307 causing myositis, 1115 common symptoms and syndromes caused by, 1214t-1215t in raw meat diets, 1240b, 1242 Toxoplasmosis, 1295-1298 associated hepatotoxicity, 581b causing blindness, 1136 causing corneal sequestrums, 1159-1160 causing feline uveitis, 1167 causing nervous system signs, 1212 causing pregnancy loss, 1010, 1218 causing thrombocytopenia, 281t-282t causing uveitis, 1218 clinical features of in cats, 1295-1296 in dogs, 1296 cyclosporine use with, 403 diagnosis of, 1296-1297 dosage for and drugs targeting, 1335-1337 feline, 1295-1296

1408

Index

Toxoplasmosis (Continued) immunotherapy for, 1231-1232, 1232f lymphocytosis associated with, 305 treatment of, 1297 zoonosis from, 1297-1298, 1298b Trachea deformities of, with brachycephalic airway obstruction syndrome, 650t, 652 normal bacterial isolates in, 682b Tracheal carcinoma, stenting for, 346f Tracheal catheter, for oxygen administration, 53 Tracheal collapse as risk for heat-induced illness, 71 causing pulmonary hypertension, 711 diagnosis and treatment of, 663-668 stenting for, 664-668, 666f with concurrent bronchial disease, 672 Tracheal stenting, of malignant obstructions, 346-347, 346f Tracheobronchial culture, for feline asthma, 676 Tracheobronchial disease, with concurrent heart disease, 792-793 Tracheobronchitis canine infectious, 632-635 from feline upper respiratory infection, 630t Tracheostomy tube care, 57b Traction alopecia, in dogs, 165b Tramadol after cesarean section, 956 dosage for, 62t drug interactions with, 34t-35t for cervical junction abnormalities, 1102-1103 for cervical spondylomyelopathy, 1095f for corneal ulcerations, 1149 for degenerative lumbosacral stenosis, 1106-1107 for orbital cellulitis or abscess, 1198-1199 for the critical patient, 59 Tranexamic acid, for treatment of von Willebrand disease, 290-291 Transcervical hysteroscopy, 937-938 for insemination, 940-944 Transcolonic pertechnetate scintigraphy (TCPS),for evaluation of hepatobiliary disease, 574 Transcutaneous external pacing, e21-e28 technique for, e26-e28, e27f Transdermal medication(s) amlodipine, 729 analgesia, 61-63, 62t carbimazole, e103t methimazole, e104-e105, e104 toxicity with, 579, e103t, e108 nitroglycerine, 764t-765t toxicity of nicotine, 119-120 Transfusions. See Blood transfusions Transillumination, 1128-1129, 1129f Transitional cell carcinoma, bladder diagnosis and treatment of, 370-374 immunotherapy for, 336t

Transitional cell carcinoma, bladder (Continued) intraarterial chemotherapy for, 890, 891f ultrasound findings with, 843, 844f Transmissible venereal tumors, penis and preputial, 1023 Transsplenic portal scintigraphy, for evaluation of hepatobiliary disease, 574 Transtracheal wash collection of cytology specimens from, e155 for diagnosis of pneumonia, 686 Transurethral resection of bladder, for urinary bladder cancer, 372 Transvenous pacing, e21-e28 technique for, e22-e26, e24f troubleshooting problems with, e24-e26 Tratruzumab, as cancer immunotherapy, 334 Trauma associated sarcoma of the eye, in cats, 1209 causing pregnancy loss, 1010-1011 causing retinal detachment, in dogs, e370 causing uveitis in dogs, 1164, 1164b cellular, causing hyperkalemia and hyponatremia, e93, e93b colloid use for, 12t induced pneumothorax, 702 open fractures from, 83-86 orbital, 1200 orthopedic, in dogs, 80-83 pulmonary thromboembolism associated with, 705 to the penis and prepuce, 1030-1031 to the testes, 1031-1032 wound care with, 87-90 Travoprost, for glaucoma in dogs, 1173, 1173b Trazodone, for behavior-related dermatoses, 483t, 484 Treats, sodium-restricted, 721t Tree(s), toxicity of, 124t Tremorgenic mycotoxins, 149 Trephination, for treatment of nasal aspergillosis, 638-639 Triaditis syndrome, in cats, 615-616 Triamcinolone causing adverse skin reactions, 488t for feline caudal stomatitis, 493-494 for otitis systemic, 461t topical, 460t inhaled, for respiratory diseases, 626t subconjunctival, for eosinophilic keratitis, 1159 submucosal esophageal injections of, 503-504 topical, for hot spots, e207 Triazapentadiene compounds, amitraz, 136b Triazole herbicide toxicity, 131 Trichiasis, e369, e377 causing frictional irritant conjunctivitis, 1140

Trichloroethylene toxicity, 1027b Trichodectes canis, 429t Trichogram, 164 Trichophyton mentagrophytes, causing blepharitis, e363-e364 Trichophyton spp., causing dermatophytosis, 449-451 Trichuris vulpis common symptoms and syndromes caused by, 1214t-1215t drugs targeting, 1335-1337 Tricuspid valve disease. See also Valvular heart disease diagnosis and treatment of, 784-794 staging of, 787t Tricuspid valve dysplasia, e332-e335 diagnosis of, e332-e334 prevalence of in cats, 757, 757t in dogs, 756, 757t treatment of, e334-e335 Tricuspid valve stenosis, e332 Tricyclic antidepressant drugs for behavior-related dermatoses, 482-483, e177 for urinary incontinence disorders, 917 influence on thyroid function, 181t toxicity of, 112-114 Trientine, for copper-associated liver disease, 589 Triethanolamine polypeptide oleate, ear cleaner, 472-473, 472t Trifluridine, for feline ocular herpesvirus 1, 1158 Triiodothyronine (T3), levels in hypothyroidism, 178-185 Trilostane for adrenal-dependent hyperadrenocorticism, 229 for alopecia X, 479 for idiopathic vacuolar hepatopathy, 607-608 for pituitary-dependent hyperadrenocorticism, 225-229, 227f monitoring therapy, e98 Trimethoprim sulfonamide/ sulfamethoxazole, induced thrombocytopenia, 280-281 Trimethoprim/sulfadiazine, for canine babesiosis, 1259 Trimethoprim/sulfonamide associated hepatotoxicity, 581b for superficial bacterial folliculitis, 438t for toxoplasmosis, 1297 influence on thyroid function, 181t Tritrichomonas foetus, 528-530 causes and prevention of treatment failure of, 529-530 common symptoms and syndromes caused by, 1214t-1215t treatment of, 529f Tritrichomonas spp. infection, dosage for and drugs targeting, 1335-1337 Troglitazone, for diabetes mellitus, in cats, e137-e138 Trombiculiasis, diagnosis and treatment of, 431-432

Index Tromethamine/ ethylenediaminetetraacetic acid (Tris-EDTA) in ear cleaners, 472t, 473-474 topical, for otitis, 464t Tropicamide causing anisocoria or mydriasis, e392 for feline uveitis, 1169t Troponin. See Cardiac troponin I Tru-Cut biopsy, of liver, 574-575 Trypanosoma cruzi causing myocarditis, e303-e304 causing myositis, 1115 common symptoms and syndromes caused by, 1212-1213, 1214t-1215t Trypsin-like immunoreactivity (TLI), 555-557 Trypsinogen-activation peptide (TAP), for the diagnosis of pancreatitis, 554 Tubulopapillary carcinoma, mammary, 379t Tularemia, as cause of thrombocytopenia, 281t-282t Tumor ablation, for malignant obstructions, 348 Tumor biology, e169 Tumor biopsy, and specimen submission, 322-326 Tumor excision, surgical oncology principles for, e168-e169 Tumor immunotherapy. See Immunotherapy Tumor-node-metastasis staging system, for mammary cancer, 376, 376t, 380t Tutin, for population control, 142-144 Tylenol. See Acetaminophen Tylosin for canine colitis, 551b, 552 for protein-losing enteropathy, 544 target parasites and dosage of, 1335-1337 Tylosin-responsive diarrhea, 519b, 520t, 521, e262-e265 Tympanic membrane, assessment of, 471-472, 474 Tyrosine kinase inhibitor(s) induced cardiomyopathy, 795 masitinib, 360-362 toceranib, 358-360 U Ulna trauma in dogs, 81 Ultrafiltration, slow continuous renal, 872, 872f Ultrasonography fetal monitoring with, 949-951 for endocrine disorders, 167-174 for evaluation of hypercalcemia and hyperparathyroidism, in dogs, e69-e70 for evaluation of respiratory distress, 47 for feline gastrointestinal lymphoma, 546-547 for hemangiosarcoma, 393-394, 394f for localizing parathyroid tissue, e71

Ultrasonography (Continued) for pancreatitis in cats, 566 in dogs, 561 of adrenal gland(s), 170-172 for hyperaldosteronism in cats, 240 of the eye, 1133, 1197 of the female reproductive tract, 939 of ovaries for follicular dynamics, 934 to detect ovarian remnant syndrome, 1002 with septic mastitis, 959, 959f of the liver and gall bladder, 603, 604f, e222-e223 for biliary tract disease, 603 for biopsy acquisition, 574-575, 610 for feline hepatic lipidosis, 610 for hepatobiliary disease, 573-574 for idiopathic vacuolar hepatopathy, 607 for portal vein hypoplasia, 600 for portosystemic shunt, 595 with alkaline phosphatase elevations, e245 with superficial necrolytic dermatitis, 485-486 of the prostate for prostatic hypertrophy, 1012 for prostatitis, 1014 of the thyroid gland, 167, 169-170 of the urinary tract, 840-845 for nephroliths and ureteroliths, 893, 903 for urinary bladder cancer, 371-372 interventional strategies for urinary disease, 884-892 ureter, 840-845 with urachal diverticulum, 842 of the uterus for pregnancy diagnosis, 944-945, 945f, 945t-946t for pyometra or mucometra, 947 to determine pregnancy loss, 1004, 1006 with priapism, e355-e356, e356f Uncinaria spp. infection, drugs targeting, 1335-1337 Upper airway obstruction, as risk for heat-induced illness, 71 Upper motor neuron, signs with degenerative myelopathy, 1076-1077 Upper respiratory tract infection(s) common pathogens causing, 1222 empiric antimicrobial therapy for, 1220t feline, 629-632 Urachal diverticulum, ultrasound findings with, 842 Urate crystalluria, 904, 926 Urban legends of toxicology, 97-100 Ureaplasma spp. infection, causing pregnancy loss, 1010 Urease test, for Helicobacter spp., 510 Uremia, treatment of signs with acute renal failure, 870

1409

Ureter(s) bypass device placement, 888-889, 889f interventional approach to nephrolithiasis, 884-889 stenting, 887-888, 889f ultrasound of, 840-845 Ureteral, stenting of malignant obstructions, 346 Ureterocele, ultrasound findings with, 841-842 Ureterolithiasis concurrent infections with, 893-894 medical management of, 892-896 Ureteroscopy for essential renal hematuria, 886 for laser lithotripsy, e341 Urethra antegrade catheterization of, 889-891 indications for perineal urethrostomy of, 925 interventional approach to stones in, 890 lithotripsy for stones in the, e340e344, e342t-e343t stent placement, 890f ultrasound of, 840-845 Urethral hypertonicity causing urinary retention, 917 pressure profile, e346 stenting of malignant obstructions, 345-346, 346f Urethral sphincter artificial, 919-922, 920f, 921t, 922f mechanism incompetence, 919 Urethrospasms, treatment of, 918 Uric acid, metabolism causing urolithiasis, 901 Urinalysis changes with hepatobiliary disease, 572 crystals in asymptomatic, 926 urate, 904, 926 for monitoring urate urolithiasis, 903 for surveillance of hospital-acquired urinary infections, 878 leukocyte indicators on dipsticks, 923 pH and risk of oxalate urolithiasis, 898 monitoring, 900 target, and risk of oxalate urolithiasis, 899t protein in (See Proteinuria) Urinary bladder antegrade urethral catheterization of, 889-891 atony, treatment of, 918 interventional approach to stones, 890 minilaparotomy-cystoscopy assisted, surgery of, for urocystoliths, 907f-908f ultrasound of, 840-845 Urinary bladder cancer, 370-374, 371t staging of, 371b

1410

Index

Urinary diseases. See also Renal disease; Renal failure albuminuria and, 849-852 as risk factors for urinary tract infections, 881b hospital-acquired, 877 calcium oxalate urolithiasis, 897-901 causing hyperkalemia and hyponatremia, e92, e93b glomerular disease, 853-857 hospital-acquired urinary tract infections, 876-879 incontinence disorders, 915-919 mechanical occluder devices for, 919-923 interventional strategies for, 884-892 laser lithotripsy for uroliths, e340-e344 medical management of nephroliths and ureteroliths, 892-896 minilaparotomy-assisted cystoscopy for urocystoliths, 905-909 nephrotic syndrome, 853-857 persistent Escherichia coli infection, 880-883, 881b proteinuria and, 849-852 retention disorders, 915-919 risk of hospital acquired infections, 876-879 top questions to consultants, 923-927 urate urolithiasis, 901-905 use of biomarkers for diagnosis of, 846-847 use of ultrasound for diagnosis of, 840-845 Urinary incontinence disorders causes of, e341 causing vestibulitis, 970-971 concerns regarding risk, with early age neutering, 983 diagnosis of, 915-919, e341-e342 mechanical occluder devices for, 919-923 not responsive to standard therapy, 925 treatment of, 915-919, 916t, e346-e349 with injectable bulking agents, e345-e350, e347f Urinary retention disorders, 915-919 therapeutic options for, 917t Urinary retinol-binding protein, 846-847 Urinary tract diagnosis of disease with ultrasound of, 840-845 toxicity from chemotherapeutic drugs, 332 Urinary tract infections asymptomatic, treatment of, 924-925 common pathogens causing, 1217, 1219-1221 concerns regarding risk, with early age neutering, 983 concurrent urolithiasis with, 881-882, 893-894 conditions that predispose to, 881b empiric antimicrobial therapy for, 1219-1221, 1220t from cyclosporine, 405 from diabetes mellitus, e77, e81

Urinary tract infections (Continued) highly resistant, treatment of, 924 hospital-acquired asymptomatic, 876-879 multidrug resistance in, 881 nonantimicrobial therapies for, 882-883 persistent Escherichia coli causing, 880-883, 881b, 924 prophylactic antimicrobial therapy for, 881-883 reinfection, 880, 924 relapse, 880-881, 924 superinfection, 881 ultrasound findings with, 843, 844f Urinary tract obstruction from urinary bladder cancer, 370, 373 in ferrets with hyperadrenocorticism, e96 potassium levels from, 253 with portosystemic shunt, 594 Urination-induced syncope, e327 Urine bile acids, 573 ketone monitoring with diabetic ketoacidosis, e81, e83 production with acute renal failure, 869-870 protein and albumin, 849-852 protein and enzyme markers, 846-847 tests for human drugs of abuse, e51 Urine antigen tests, for urinary bladder cancer, 371 Urine biomarkers, 846-847 Urine cortisol : creatinine ratio use of test with hyperadrenocorticism, e99 with alopecia X, 478 Urine culture for surveillance of hospital-acquired urinary infections, 877-878 why results are negative FAQ, 923-924 with highly resistant infections, 924 with long-term use of glucocorticoids, 418 with recurrent infections, 924 Urine glucose monitoring of with diabetes mellitus, 197-198 with diabetic ketoacidosis, e81, e83 threshold for, in cats, 208 Urine protein-creatinine (UPC) ratio elevations from diabetes mellitus, e76 for staging of chronic kidney disease, 859t-860t with glomerular disease, 849-851 with proteinuria and albuminuria, 849, 851, 926-927 with pyometra, 967-968 Urine specific gravity, as indicator of predicting renal failure with hyperthyroidism, 187 Urogenital concerns regarding, with early age neutering, 983 disease transmission from pets to humans, 1245t, 1247-1248

Urohydropropulsion, of urate urolithiasis, 902f, 903 Urokinase, 813 Urolithiasis calcium oxalate, 897-901 monitoring for recurrence, 900 target pH of diets for, 898-899, 899t concurrent infections with, 893-894 interventional approach to, 890 laser lithotripsy for, e340-e344 medical management of nephroliths and ureteroliths, 892-896 minilaparotomy-assisted cystoscopy for, 905-909, 906f-907f percutaneous cystolithotomy for, 890 stone basketing for, 890 ultrasound findings with, 843, 844f urate, canine, 901-905, 902f medical dissolution of, 902-903, 902f reoccurrence of, 904 Ursodeoxycholic acid for cholelithiasis, 603-604 for chronic hepatitis, 582, 585f, 587 for feline cholangitis, 617-618, 617b for portal vein hypoplasia, 600 Ursodiol, for biliary mucoceles, e223 Urticaria, from adverse drug reactions, 488t Urticaria pigmentosa, use of cyclosporine for, 410b Usnic acid, associated hepatotoxicity, 581b Uterine causes of vaginal discharge, 970t culture, 938 cytology, 938 hypercontractility, 954-955, 954f inertia causing dystocia, 951, 954f prolapse, 957-958 stump granuloma, 938 tumors, 1025-1026 Uteroverdin, 949 Uterus. See Pyometra Uvea anatomy and physiology of, 1162 tumors of, 1204-1205, 1204f Uveitis aqueous flare causing, 1130-1131, 1131f canine causes of, e382b diagnosis and treatment of, 11621166, 1163t, 1164b, e382 differential diagnoses of, 1163t from leptospirosis, 1287 with glaucoma, 1166, 1173t feline causes of, 1167b, 1177, e382b diagnosis and treatment of, 11661170, 1169t, e382 with glaucoma, 1178 infectious causes of, 1218 lens induced, 1183-1184, 1184t with complicated/melting corneal ulcers, 1151 with ocular neoplasia, 1206

Index V Vaccination accidental injection of intranasal, 635 for canine respiratory infection complex, 634-635 for feline immunodeficiency virus, 1276 for feline leukemia virus, 1276 for feline upper respiratory infections, 631-632 for lyme disease, 1274-1275 of retrovirus-infected cats, 1276 with leptospirosis, effect on titers, 1288 Vaccine(s) adverse effects of in cats, 1252-1256 associated sarcoma, 1252-1255 in dogs, 1249-1252 causing uveitis, 1164b allergic reactions to, 1250-1251 autoimmune reactions to, 1250-1251 failure, 1251 induced thrombocytopenia, 280-281 influence on testing for feline herpesvirus 1, 1157-1158 reporting adverse events of, to FDA, 1251, e38 tumor, 335 Vacuolar hepatopathy, 606-608 Vacuum-assisted closure for peritoneal drainage, e17-e18 of wound, 87-90, 88b, 89f Vagal maneuver in cats, 753 triggers causing syncope, e326-e327, e327f-e328f Vaginal anomalies in the bitch, surgical repair of, 974-981, 975f, 978f band, septum and stenosis, 979-980 culture, 937 cytology for breeding management, 932-933 for diagnosis of disease, 937 technique for, 937 to detect ovarian remnant syndrome, 1001 with pyometra, 967 with pyometra or mucometra, 947 with septic metritis, 958 discharge, diagnosis and treatment of, 969-973 postpartum, 957 with normal gestation, 949 with pyometra, 967-968 edema, 980 endoscopy, 934 fluid changes, 933-934 hyperplasia, 980, 981f prolapse, 980-981 Vaginitis adult-onset, 970 concerns regarding risk, with early age neutering, 983t diagnosis and treatment of, 969-970 puppy, 970, 978f

Vaginoscopy for breeding management, 934, 943 use and technique of, 936-937 with ovarian remnant syndrome, 1001, 1003f Vaginourethrogram, 979f Vaginourethrography, retrograde, 939 Valerian associated hepatotoxicity, 581b Valsalva leak point pressure, e346 Valvular heart disease asymptomatic, 775-777, 790 with murmur, 786 atrial tear with, 793 classification and staging of, 775-781, 786t-787t congestive failure with, 790-792 refractory, 780-781, 791 diagnosis and treatment of, 775-781, 784-794, 785f, 787t, 789f pulmonary hypertension with, 793-794 ruptured chordae tendineae with, 793 surgery for, 794 with concurrent respiratory disease, 792-793 Vanadium, for diabetes mellitus, in cats, e136f, e136t, e137-e138 Vapor(s), as respiratory toxicants, e46 Vaporizer(s), for pneumonia, 687 Vascular, causes of hepatobiliary enzyme elevations, 570b Vascular access, for shock fluid therapy, 20 Vascular disease, of the central nervous system, 1119-1126 Vascular endothelial growth factor, causing malignant effusions, 341, 344 Vascular injury, in hypercoagulable states, 298f Vascular permeability factor, causing malignant effusions, 341 Vascular ring anomaly, prevalence of in cats, 757t in dogs, 757t Vascular stenting, of malignant obstructions, 347 Vasculitis cutaneous,topical immunomodulators for, e218-e219 from adverse reactions to vaccines, 1251 from feline upper respiratory infection, 630t from leptospirosis, 1287 infections causing, with nervous system signs, 1212 pentoxifylline for, e204 Vasodilation, from prolonged seizures, 1060 Vasodilator drugs adverse effects of, 768 for heart failure, in dogs, 763b, 766-768 Vasopressin during CPR, 28-29 for seizure patients, 1061t

1411

Vasopressin (Continued) for the diagnosis and treatment of diabetes insipidus, e73-e75 receptor activities of, 15t use and dosage of, 15t, 17 use of with shock, 23 Vasopressor(s) during CPR, 28-29 for therapy of shock, 22-23 therapy for seizure patients, 1061t use of, with feline pancreatitis, 567-568, 567t Vasovagal syncope, e324-e325 Vector, disease transmission from pets to humans, 1248 Vehicle effect on potency of topical steroids, 460f for topical antimicrobials, for otitis, 462-463 Venovenous hemofiltration, slow continuous renal, 872-873, 873f Ventilation during CPR, 27-28 for acute respiratory distress syndrome, 50-51 issues associated with prolonged seizures, 1060-1061 mechanical during CPR, 31 Ventilation/perfusion (V/Q) fluid therapy considerations with, 6 with hypoxemia, 52 Ventilator therapy, 55-59 available studies of, 56t causing respiratory acidosis, e4b causing respiratory alkalosis, e4b choosing settings for, 55-56 complications of, 58 patient care with, 56-58 sedation for, 55 tracheostomy tube care and, 57b weaning from, 58-59 Ventral bulla osteotomy, in cats with polyps, 656-657 Ventricular arrhythmias in cats, 753-754 in dogs diagnosis and treatment of, 745-748, 747f, 747t treatment of with heart failure, 771 with dilated cardiomyopathy, 797 with congestive heart failure, 783-784 Ventricular fibrillation, 29f drug therapy for, 30 electrical defibrillation for, 30 Ventricular premature complexes from arrhythmogenic right ventricular cardiomyopathy, 801-804 in cats, 753-754 in dogs, with dilated cardiomyopathy, 797 treatment of, with heart failure, 771, 783-784 Ventricular septal defect (VSD), e335-e340 diagnosis of, e337-e338 left-to-right shunting with, e338-e339

1412

Index

Ventricular septal defect (VSD) (Continued) pathophysiologic features of, e336-e337 prevalence of in cats, 757, 757t in dogs, 756, 757t right-to-left shunting with, e339-e340 surgery for, e339 Ventricular tachycardia, 746-748, 747f, 747t cardioversion for, e290 causing syncope, e326 in cats, 750f-751f, 753-754 in dogs, with dilated cardiomyopathy, 797 treatment of with heart failure, 771, 783-784 Ventriculoperitoneal shunt, for hydrocephalus, 1036-1037, 1037f Verapamil, toxicity of, use of IV lipid emulsion therapy for, 106 Vertebrate pest species pesticides, 142-144 Vesicles, from adverse drug reactions, 488t Vestibular anatomy, 1066-1067 central system, 1067 peripheral system, 1066 Vestibular disease causes of, 1068-1069 congenital, 1068 from hypothyroidism, 1068, e84, e84-e85, e86 from neoplasia, 1068-1069 idiopathic, 1068 paradoxic, 1068-1069 peripheral and central, 1066-1070, 1067t with nasopharyngeal disorders, 654 Vestibulitis, 970-971 Vestibulovaginal malformations, 971-972 Veterinary Perinatal Service, 950 Vetsulin. See Porcine Lente insulin Vidarabine, for feline ocular herpesvirus 1, 1158 Vinblastine, extravasation and tissue sloughing from, 333 Vincristine adverse effects of, 331 extravasation and tissue sloughing from, 333 for feline gastrointestinal lymphoma, 547-548, 548t for hemangiosarcoma, 395-396 for multiple myeloma, 386 for thrombocytopenia, 285 rescue chemotherapy for canine lymphoma, 381-383 Vinorelbine, e140t, e141 extravasation and tissue sloughing from, 333 Vinyl chloride toxicity, 1027b Vinylidene chloride toxicity, 1027b Viral infection(s) causing conjunctivitis, 1141-1142 causing myocarditis, e304t

Viral infection(s) (Continued) causing pregnancy loss, 1005t, 1009-1010 causing skin disease, in cats, e194-e197 causing skin lesions in cats, e194-e197 causing thrombocytopenia, 281t-282t causing uveitis in dogs, 1164b causing vulvar discharge, 972 common symptoms and syndromes caused by, 1215t immunotherapy for, 1229-1233, 1230t Viral papilloma, ocular, 1204 Virchow’s triad factors causing thrombosis, 298f, 705 from heat-induced illness, 71 Virus isolation, for canine infectious respiratory diseases, 633 Vision assessment of, e390-e391 evaluation of, 1134-1138 grid to record visual status and reflexes, e389f loss of (See also Blindness) from canine uveitis, 1163t with canine glaucoma, and surgical options, 1174-1175, 1176b Visual pathway defects of the, e390f lesions of the, e393f signs of lesions in, e393f, e393t Vitamin A for actinic dermatoses, 481 for sebaceous adenitis, e210-e211 requirements during pregnancy and lactation, 963 responsive dermatosis, 476 toxicity of, 99 Vitamin B complex, drug incompatibilities with, 33t Vitamin B1, drug incompatibilities with, 33t Vitamin B12. See Cobalamin; Cobalamin deficiency Vitamin B3, for hyperlipidemia, 265 Vitamin C, drug incompatibilities with, 33t Vitamin D for evaluation of hypocalcemia, e125f for postpartum puerperal tetany, 960 requirements during pregnancy and lactation, 963 role of, in idiopathic hypercalcemia in cats, 245-246 supplements for hypocalcemia, e127-e128, e128t, e129 toxicity of, 99 Vitamin E as hepatic support therapy, e255-e256 for chronic hepatitis, 587 for liver failure, 582 for protein-losing enteropathy, 543 for retinal dystrophy, 1190-1191 Vitamin K1 deficiency from feline hepatic lipidosis, 610, 612 from hepatobiliary disease, 572 from liver failure, 582

Vitamin K1 (Continued) for hepatic-disease associated coagulopathy, e257 for protein-losing enteropathy, 543 for rodenticide toxicity, 133-134 supplementation with liver failure, 582 Vitiligo, of the eyelid, e367 Vitis fruit toxicity, 149 Vivonex, 542 Vizsla(s) polymyositis in, 1114 sebaceous adenitis ion, e209-e210 VLA Quality Assurance System, 308-309 Vogt-Koyanagi-Harada-like syndrome causing canine uveitis, 1164 of eyelid, e367-e368 Volvulus, gastric dilation and, e13-e20 Vomiting chronic, from Helicobacter spp., 508-513 control of with acute pancreatitis in dogs, 562-563 with canine parvovirus, 535 from intestinal motility disorders, 513-518 from uremia with acute renal failure, 870 induced syncope, e327 induction of, 105 von Willebrand disease, 286-291 blood products for, 290t direct mutation test for, 1018t-1020t subtype classification, 288t Voriconazole adverse effects of, 1237 for fungal rhinitis in cats, 647t for nasal aspergillosis, 639-640 use and protocols for, 1235t, 1237 Vulva hooded, 971, 971f, 978f Vulvar discharge diagnosis and treatment of, 969-973, 971f from pyometra or mucometra, 947 Vulvar hypoplasia, 977 Vulvar softening, 932 W Wahoo, toxicity of, 124t Walchia americana, 431-432 Warfarin (Coumadin) for arterial thromboembolism, 815 for feline thromboembolism, 810 for hypercoagulable states, 299 for thromboprophylaxis, 708-709 Warfarin rodenticide toxicity, 133-134 Water, as antipruritic agent, 419 Wedge biopsy, of liver, 574-575 Weight gain diagnosis and treatment of obesity, 254-260 during pregnancy, 961-963, 962f Weight loss diets, 255-259 from protein losing enteropathy, 541 with cancer cachexia, 349-354

Index Weimaraner(s) cervical spondylomyelopathy in, 1092 hypertrophic osteodystrophy in, 1251 masticatory muscle myositis in, 1199 pruritic alopecia in, 164 risk of vaccine hypersensitivity in, 1250-1251 vaccine reactions in, 1250 West Highland white terrier(s) atopic dermatitis in, 403 copper-associated hepatopathy in, 571b direct mutation tests for, 1018t-1020t glaucoma in, 1171b hyperplastic dermatosis in, e201 hypoadrenocorticism in, 233 intracranial arachnoid cysts in, 1038 metabolic brain disorder in, 1052 plasmacytomas in, 386 pulmonary fibrosis in, 501, e267 risk of urinary bladder cancer in, 371t sick sinus syndrome in, 732-733 Wheals, from adverse drug reactions, 488t Wheelchairs, for rehabilitation, e359 WhelpWise veterinary orders, 952f Whippet(s) actinic dermatoses in, 480 avermectin toxicity in, 145 direct mutation tests for, 1018t-1020t glaucoma in, 1171b thyroid hormone differences in, 180t White flower oil toxicity, 125t Willow, white toxicity, 125t Windhound(s), avermectin toxicity in, 145 Windshield washer fluid toxicity, 151 Wintergreen oil toxicity, 125t Wipes, for pyoderma, 441t Wirehaired terrier(s) risk of bladder cancer in, 371t sebaceous gland hyperplasia in, 476-477 von Willebrand disease in, 288-289, 288t Wireless motility capsule, for evaluation of gastric emptying, 514-515, 515f Wobbler syndrome. See Cervical spondylomyelopathy Wolbachia, role in heartworm disease, 820, 826 Wolf’s bane, toxicity of, 124t Wood’s lamp examination, for dermatophytosis, in multicat environments, 449, 453 Woody, toxicity of, 124t

Wound care and vacuum-assisted wound closure, 87-90 closure and, 88 with open fractures, 84-86 Wound healing, 87 X X-lined factor deficiencies, 289 Xanthine oxidase inhibitor(s), for dissolution of urate stones, 902 Xanthine urolithiasis, dose of allopurinol to dissolve urates and prevent, 903-904 Xenobiotic(s), causing nephrotoxicity, e29 Xeromycteria, in dogs, 643 XX disorders of sexual development, 994-996, 995t XY disorders of sexual development, 997-999 Xylazine for emesis induction, 105 for retrograde ejaculation, e351-e352 use of, with cardiovascular dysfunction, 64-65 Xylene toxicity, 1027b Xylitol toxicity, 98, 149-150, 570b, 581b Y Yeast bread dough toxicity, 147 Yersinia pestis causing infection in humans, 1246 causing thrombocytopenia, 281t-282t common symptoms and syndromes caused by, 1213t Yew toxicity, 121b Yohimbine, 30 action and use of, for motility disorders, 517-518 as antidote, e56t for retrograde ejaculation, e351-e352 Yorkshire terrier(s) acinar hypoplasia in, 1144 alopecia in, 164 atlantoaxial subluxation in, 1083 Chiari-like malformation in, 1101 encephalitis in, 1063 hydrocephalus in, 1034 intracranial arachnoid cysts in, 1038 mammary tumors in, 375 mitochondrial encephalopathy in, 1048-1051, 1049t, 1051t ovarian tumors in, 1024 portosystemic shunts in, 594 protein-losing enteropathies in, 540-541 risk of urolithiasis in, 892, 897 Yucca schidigera, for flatulence, e250

1413

Z Zafirlukast, for feline asthma, 678 Zalcitabine, for feline retrovirus infections, 1278, 1279t Zaleplon, toxicity of, 113-114 Zidovudine (AZT), for feline retrovirus infections, 1277-1278, 1279t Zileuton, for feline asthma, 678 Zinc role of, with diabetes mellitus, 202 to restrict copper update, e236 toxicity, from coin ingestion, 99-100 Zinc acetate, for flatulence, e250 Zinc chloride, in Febreze, 98 Zinc phosphide toxicity, 134-135 Zinc therapy for copper-associated liver disease, 590 for hepatoencephalopathy, 593 Zinc-responsive dermatosis, causing blepharitis, e365 Zolazepam, toxicity of, 113-114 Zoledronate, for osteosarcoma, 391-392 Zollinger-Ellison syndrome imaging for diagnosis of, 174 proton pump inhibitors for, 118 Zolpidem toxicity, 113-114 Zonisamide associated hepatotoxicity, 570b, 578, 581b for intracranial tumors, 1041t for seizures, 1056-1057 Zoonosis, 1244-1249, 1245t and disinfection of environments with staphylococcal spp., 455 associated with raw meat diets, 1248, 1291 from dermatophytosis, 449, 450b from intranasal vaccination, 635 from methicillin-resistant Staphylococcal infections, 444 from toxoplasmosis, 1297-1298, 1298b individuals at risk for, 1246b prevention of, 1248-1249 route of transmission of, 1244-1248 spread from animals to humans, 1245t with American leishmaniasis, e396 with Bartonella spp., 1266, 1270-1271 with Brucella canis, 972 with brucellosis, e402 with Giardia spp., 531 with Helicobacter spp., 509 with Malassezia spp. infections, e213 Zygomycosis, antifungal therapy for, 1234-1238

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Conversion Table of Weight to Body Surface Area (in Square Meters) For Dogs kg

m2

kg

m2

kg

m2

kg

m2

0.5 1.0 2.0 3.0 4.0 5.0 6.0 7.0 8.0 9.0 10.0 11.0 12.0

0.06 0.10 0.16 0.21 0.25 0.29 0.33 0.37 0.40 0.44 0.47 0.50 0.53

13.0 14.0 15.0 16.0 17.0 18.0 19.0 20.0 21.0 22.0 23.0 24.0 25.0

0.56 0.59 0.61 0.64 0.67 0.69 0.72 0.74 0.77 0.79 0.82 0.84 0.85

26.0 27.0 28.0 29.0 30.0 31.0 32.0 33.0 34.0 35.0 36.0 37.0 38.0

0.89 0.90 0.93 0.95 0.97 1.00 1.02 1.04 1.06 1.08 1.10 1.12 1.14

39.0 40.0 41.0 42.0 43.0 44.0 45.0 46.0 47.0 48.0 49.0 50.0

1.16 1.18 1.20 1.22 1.24 1.26 1.28 1.30 1.32 1.33 1.35 1.37

Although the above chart was compiled for dogs, it can also be used for cats. These conversions are approximations with fractions > 0.006 rounded up. A more precise value can be calculated as follows: BSA in m = (K × W2/3) × 10-4 where m2 = square meters, BSA = body surface area, W = weight in grams, and K = constant of 10.1 in dogs and 10.0 in cats.

Système International (SI) Units in Clinical Chemistry Analyte

Traditional Unit (with examples)

Alanine aminotransferase Albumin Alkaline phosphatase Ammonia Amylase Aspartate aminotransferase Bile acids (total) Bilirubin Calcium Carbon dioxide Chloride Cholesterol Copper Cortisol Creatine kinase Creatinine Fibrinogen Folic acid Glucose Iron Lactate Lead Lipase Sigma Tietz (37° C) Lipase Cherry Crandall (30° C) Lipids (total) Magnesium Mercury Osmolality Phosphorus Potassium Protein (total) Sodium Testosterone Thyroxine Triglyceride Urea nitrogen Uric acid Urobilinogen Vitamin A Vitamin B12 Vitamin E D-Xylose Zinc

0-40 U/L 2.8-4.0 gm/dl 30-150 U/L 10-80 µg/dl 200-800 U/L 0-40 U/L 0.3-2.3 µg/ml 0.1-0.2 mg/dl 8.8-10.3 mg/dl 22-28 mEq/L 95-100 mEq/L 100-265 mg/dl 70-140 µg/dl 2-10 µg/dl 0-130 U/L 0.6-1.2 mg/dl 200-400 mg/dl 3.5-11.0 µg/L 70-110 mg/dl 80-180 µg/dl 5-20 mg/dl 150 µg/dl ≤1 ST U/dl 0-160 U/L 400-850 mg/dl 1.8-3.0 mg/dl ≤1.0 µg/dl 280-300 mOsm/kg 2.5-5.0 mg/dl 3.5-5.0 mEq/L 5-8 gm/dl 135-147 mEq/L 4.0-8.0 mg/ml 1-4 µg/dl 10-500 mg/dl 10-20 mg/dl 3.6-7.7 mg/dl 0-4.0 mg/dl 90 µg/dl 300-700 ng/L 5.0-20.0 mg/L 30-40 mg/dl 75-120 µg/dl

Conversion Factor 1.00 10.0 1.00 0.5871 1.00 1.00 2.45 17.10 0.2495 1.00 1.00 0.0258 0.1574 27.59 1.00 88.40 0.01 2.265 0.05551 0.1791 0.1110 0.04826 280 1.00 0.01 0.4114 49.85 1.00 0.3229 1.0 10.0 1.00 3.467 12.87 0.0113 0.3570 59.44 16.9 0.03491 0.738 2.32 0.06666 0.1530

SI Unit (with examples) 0-40 U/L 28-40 gm/L 30-150 U/L 5.9-47.0 µmol/L 200-800 U/L 0-40 U/L 0.74-5.64 µmol/L 2-4 µmol/L 2.20-2.58 mmol/L 22-28 mmol/L 95-100 mmol/L 2.58-5.85 mmol/L 11.0-22.0 µmol/L 55-280 nmol/L 0-130 U/L 50-110 µmol/L 2.0-4.0 gm/L 7.93-24.92 nmol/L 3.9-6.1 mmol/L 14-32 µmol/L 0.5-2.0 mmol/L 7.2 µmol/L ≤280 U/L 0-160 U/L 4.0-8.5 gm/L 0.80-1.20 mmol/L ≤50 nmol/L 280-300 mmol/L 0.80-1.6 mmol/L 3.5-5.0 mmol/L 50-80 gm/L 135-147 mmol/L 14.0-28.0 nmol/L 13-51 nmol/L 0.11-5.65 mmol/L 3.6-7.1 nmol/L 214-458 µmol/L 0.0-6.8 µmol/L 3.1 µmol/L 221-516 pmol/L 11.6-46.4 µmol/L 2.0-2.71 mmol/L 11.5-18.5 µmol/L

Conversion Factors

WEIGHT EQUIVALENTS 1 lb = 453.6 g = 4536 kg = 16 oz 1 oz = 28.35 gm 1 kg = 1000 gm = 2.2046 lb 1 gm = 1000 mg 1 mg = 1000 µg = 0.001 gm 1 µg = 0.001 mg = 0.000001 gm 1 µg per gm or 1 mg per kg is the same as 1 ppm VOLUME EQUIVALENTS Household

Metric

1 drop (gt) 15 drops (gtt) 1 teaspoon (tsp) 1 tablespoon (tbs) 2 tablespoons 1 ounce (oz) 1 teacup 1 glass 1 measuring cup 2 measuring cups

= = = = = = = = = =

0.06 milliliter (ml) 1 ml (1 cc) 5 (4) ml 15 ml 30 ml 30 ml 180 ml (6 oz) 240 ml (8 oz) 240 ml (1/2 pint) 500 ml (1 pint)

1 milliliter 1 liter 1 1 1 1 1 1 1 1

grain dram ounce minim fluid dram fluid ounce pint quart

= = = =

= = = =

0.736 mm Hg 1.36 cm H2O 7.5 mm Hg 760 mm Hg

Approximate Equivalents for Degrees Fahrenheit and Celsius* °F

Units Wanted

lb lb oz kg kg kg gm gm mg mg/gm mg/kg µg/kg Mcal kcal/kg kcal/lb ppm ppm ppm mg/kg ppm mg/gm gm/kg

gm kg gm lb mg gm mg µg µg mg/lb mg/lb µg/lb kcal kcal/lb kcal/kg µg/gm mg/kg mg/lb % % % %

0.098 kPa 0.133 kPa 10.2 cm H2O 1033.6 cm H2O

For Conversion Multiply by 453.6 0.4536 28.35 2.2046 1,000,000 1000 1000 1,000,000 1000 453.6 0.4536 0.4536 1000 0.4536 2.2046 1 1 0.4536 0.0001 0.0001 0.1 0.1

°C

0 32 85 86 87 88 89 90 91 92 93 94 95 96 97 98 99 100 101 102 103 104 105 106 107 108 109 110 212

Weight-Unit Conversion Factors Units Given

(1/60) (15) (avoirdupois) (Troy) (15) (1+) (34) (60 mg) (4) (30+) (0.06) (4) (30) (500–) (1000–)

1/65 grain 15.43 grains 2.20 pounds 2.65 pounds 16.23 minims 1.06 quarts 33.80 fluid ounces 0.065 gm 3.9 gm 31.1 gm 0.062 ml 3.7 ml 29.57 ml 473.2 ml 946.4 ml

Figures in parentheses are commonly employed approximate values.

PRESSURE EQUIVALENTS 1 cm H2O 1 mm Hg (torr) 1 kPa 1 atm

= = = = = = = = = = = = = = =

1 milligram 1 gram 1 kilogram

–17.8 0 29.4 30.0 30.6 31.1 31.7 32.2 32.7 33.3 33.9 34.4 35.0 35.5 36.1 36.7 37.2 37.8 38.3 38.9 39.4 40.0 40.6 41.1 41.7 42.2 42.8 43.3 100

*Temperature conversion: °Celsius to °Fahrenheit, (°C) (9/5) + 32°; °Fahrenheit to °Celsius, (°F – 32°) (5/9).

Metric Apothecary Milligrams

Grains

1 mg 15 mg 30 mg 40 mg 50 mg 60 mg

= = = = = =

1/60 gr 1/4 gr 1/2 gr 2/3 gr 3/4 gr 1 gr

Catheter, Wire, and Tubing Size Measurements Gauge 29 22 18 17 16 14

Approximate External Diameter (mm) 0.330 0.711 1.270 1.473 1.651 2.108

*French Gauge = 3 × External diameter in mm.

Approximate External Diameter (in) 0.013 0.028 0.050 0.058 0.065 0.083

French Gauge* 1 2 3 4 5 6